Naturally occurring organoiodines

Abstract

This review, with 290 references, presents the fascinating area of iodinated natural products over the past hundred years for the first time. It covers literature published from 1896 to 2014 and refers to compounds isolated from both biogenic and abiotic sources. In total, 182 naturally-occurring organoiodine compounds are recorded. The emphasis is on the compounds together with the relevant biological activities, sources, collection places, countries of origin, biosynthetic studies, and first total syntheses.

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Lishu Wang

Lishu Wang graduated in chemistry at the University of Nankai, China in 1989. She then joined the Academy of Traditional Chinese Medicine and Chinese Materia Medica of Jilin Province, where she is currently a senior research scientist. She received a PhD degree from Changchun University of Chinese Medicine in 2008. Her research interests are in phytochemistry and the development of new drugs from traditional Chinese medicine; so far, she has succeeded in developing 10 new TCM drugs.

Xuefeng Zhou

Xue-Feng Zhou received his BS and PhD degrees from Tongji Medical College, Huazhong University of Science and Technology in 2003 and 2008 under the guidance of Professor Ji-Zhou Wu. In 2008, he moved to the South China Sea Institute of Oceanology, Chinese Academy of Sciences, where he is currently an associate professor in marine natural products.

Mangaladoss Fredimoses

Mangaladoss Fredimoses obtained his B.Sc and M.Sc degrees from Madurai Kamaraj University, Madurai, India. He completed a PhD degree from Manonmaniam Sundarnar University, Tirunelveli, India, where he carried out research entitled “Isolation of marine actinomycetes from mangrove sediments and evolution of their antibacterial and anticancer property” under the guidance of Professor Dr S. Ravikumar. He then worked as an Assistant Professor in the Department of Biotechnology, K. S. Rangasamy College of Arts and Science, Trichengode, India. At present he is a postdoctoral researcher working on marine natural products at the South China Sea Institute of Oceanology under the guidance of Professor Yonghong Liu. His main research interest is the isolation and structural elucidation of biologically active secondary metabolites of marine organisms.

Shengrong Liao

Shengrong Liao obtained his BS from South China University and his MS from South China Agricultural University, where he focused his study on the design, synthesis and evaluation of metal complexes as superoxide-dismutase mimics. After working for three years in the exploration of small molecules as drug agents for influenza, diabetes and Alzheimer's disease at the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, he continued his study and received a PhD from Sun Yet-Sen University, China, where he studied the design, synthesis and mechanism of benzo[c]acridine derivatives as G-quadruplex DNA binders under the guidance of professor Zhishu Huang. Currently, he works as an assistant professor at the South China Sea Institute of Oceanology, Chinese Academy of Sciences. His research interests are the design, synthesis and evaluation of biologically active secondary metabolites from marine organisms as antifoulants or drugs.

Yonghong Liu

Yonghong Liu obtained his BS and MS degrees from the Changchun College of Traditional Chinese Medicine, China. He then received his PhD degree from Pusan National University, Korea, where he studied the isolation, structural elucidation and structure–activity relationships of biologically active marine natural products under the guidance of Professor Jee H. Jung. He undertook postdoctoral research with Nobutoshi Murakami at Osaka University, Japan and Pedro Abreu at the New University of Lisbon, Portugal, before returning to China to take a position as a senior scientist at the South China Sea Institute of Oceanology, Chinese Academy of Sciences. His research interests are the isolation, structural elucidation, and synthesis of biologically active secondary metabolites from marine organisms.

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1 Introduction

Professor Gordon W. Gribble has written many excellent comprehensive reviews on naturally occurring organohalogens.^1–8 Most of them have focused on naturally occurring organochlorines,⁹ organobromines,^10,11 and organofluorines.¹² To date, no review has focused primarily on natural organoiodines. The first reported, naturally occurring iodinated organic compound, 3,5-diiodotyrosine (DIT, 1), was isolated in 1896 from the coral Gorgonia cavolinii.¹³ Although DIT termed ‘iodogorgoic acid’ has been known for more than 100 years,^13–15 iodine has been much less frequently incorporated into natural compounds than chlorine and/or bromine.² Currently, over 5000 halogenated natural products are known from bacteria, fungi, algae, plants, animals, and humans.⁸ Chlorometabolites and bromometabolites^11,16 are predominant, while fluorinated natural products^17,18 are much less common; organoiodines are rarely found in nature.⁵ In this review, we try to describe all natural organoiodines and relevant halogenases.

2 Biogenic sources

2.1. Marine organisms

Marine natural products tend to incorporate halogens more frequently than secondary metabolites from terrestrial sources.¹⁹ The incorporation of bromine or chlorine is by far the most common, while iodine is rare and fluorine is extremely rare.²⁰ To some extent, this may be considered as a consequence of the relatively low abundance of iodine in seawater (almost one thousand times less than bromine).²¹

2.1.1. Algae. The widely used organic chemical reagent iodomethane (CH₃I, 2) has a large biogenic source in worldwide marine algae and is often detected in emissions from algae.^22–42 It is produced by the marine algae Pavlova gyrans, Papenfusiella kuromo, and Sargassum horneri (Mikuni, Fukui Prefecture; Uozu, Toyama Prefecture; and Tsugaru Channel, Eyama, Hokkaido, Japan, respectively). Methyl halides have been synthesised from S-adenosyl-1-methionine in cell-free extracts of P. gyrans, P. Kuromo, and S. horneri; this mechanism corresponds to the emission of methyl halides from the three algae in vivo.²⁵ In addition, 2 is produced by the marine algae Macrocystis pyrifera,⁴³ Asparagopsis taxiformis,^44,45 A. armata,⁴⁶ and Fucales Sargassum sp.^1,3,8,47 Marine algae produce an array of both simple and complex organohalogens, presumably for chemical defence. Laboratory cultures of marine phytoplankton have also produced 2.²³ Diiodomethane (CH₂I₂, 3) has numerous marine algae sources,^{22,29,31,35–42,48–53} while iodoform (CHI₃, 4) has been found only in Asparagopsis taxiformis, an edible red alga that is highly favoured in Hawaii for its strong aroma and flavour. A. taxiformis is rich in iodine, but free molecular iodine is not present in the live algae plants. The essential oils are composed of mainly bromine- and iodine-containing haloforms⁴⁵ along with small to trace amounts of many other halogenated compounds; CH₂I₂ 3, CHI₃ 4,⁴⁴ dibromoiodomethane (CHBr₂I, 5),² bromodiidomethane (CHBrI₂, 6),⁴⁵ bromochloroidomethane (CHBrClI, 7),⁴⁵ bromoiodomethane (CH₂BrI, 8),² carbonyl iodide (COI₂, 9),⁴⁴ 2-iodoethanol (ICH₂CH₂OH, 10),⁴⁴ 1-bromo-2-iodoethane (BrCH₂CH₂I, 11),^2,54 iodoacetone (CH₃COCH₂I, 12),⁴⁴ 1-bromo-3-iodo-2-propanone (BrCH₂COCH₂I, 13),⁴⁴ 1,1-dibromo-3-iodo-2-propanone (ICH₂COCHBr₂, 14),^44,46 1,3,3-tribromo-1-iodo-1-propene (BrIC=CHCHBr₂, 15),^44,45 and 1-iodo-4,4-dibromo-3-buten-2-one (Br₂C=CHCOCH₂I, 16).^44,46 Related nonvolatile compounds bromoiodoacetamide (BrICHCONH₂, 17),⁵⁵ diiodoacetamide (I₂CHCONH₂, 18),⁵⁵ bromoiodoacetic acid (BrICHCOOH, 19),^56,57 and diiodoacetic acid (I₂CHCOOH, 20)⁵⁵ were present in the methylene chloride⁵⁵ and aqueous extracts of the lyophilised marine algae. Interestingly, none of these iodinated compounds exist in the asexual Falkenbergia rufolanosa. The red alga Bonnemaisonia hamifera (Baja California, USA) possesses high lipid bromine and iodine contents (3,3-dibromo-1-iodo-2-heptanone, CH₃CH₂CH₂CH₂CBr₂COCH₂I, 21),⁵⁸ high antimicrobial activity against Bacillus subtilis, and a remarkably persistent, sweet odor associated with the wet alga.⁵⁸ Marine algae are rich sources of iodoethane (CH₃CH₂I, 22),^{22,31,35,37,42,48,49,59} 1-iodopropane (CH₃CH₂CH₂I, 23),^{22,31,36,39,42,59} 2-iodopropane (CH₃CH₃CHI, 24),^{22,31,39,42,59,60} and iodobutane (CH₃CH₂CH₂CH₂I, 25).⁶¹ Iodoacetic acid (ICH₂COOH, 26),^55,57 3-iodo-2-propenoic acid (ICH=CHCOOH, 27),⁵⁷ 3,3-diiodoacrylic acid (I₂C=CHCOOH, 29),⁵⁷ 2,3-diiodo-2-propenoic acid (ICHCICOOH, 31),⁵⁷ and their ethyl esters (28, 30, and 32) have been isolated from the marine red algae Asparagopsis taxiformis (Hawaii, USA)^46,57 and A. armata (Gulf of California, USA).⁴⁶ The red algae A. taxiformis, A. armata, and Falkenbergia rufolanosa synthesise more than 100 different halogenated compounds including bromoiodoacetacetic acid ethyl ester (BrCHICOOCH₂CH₃, 33),^56,57 chloroiodoacetamide (ClCHICONH₂, 34),⁵⁵ 2,3-dibromo-3-iodo-propenoic acid (BrIC=CBrCOOH, 35),^{45,46,55,57,62–65} chloroiodomethane (CH₂ClI, 36),² 1-bromo-1-chloro-3-iodo-2-propanol (ICH₂CHOHCHBrCl, 37),⁵⁵ 1-bromo-3-iodo-2-propanol (BrCH₂CHOHCH₂I, 38),⁵⁵ chloroiodoacetic acid (ClCHICOOH, 39),⁵⁷ 1-chloro-3-iodo-2-propanol (ICH₂CHOHCH₂Cl, 40),^55,66 1-chloro-3-iodoacetone (ClCH₂COCH₂I, 41),⁴⁶ 1,1-dibromo-3,3-diiodo-2-propanol (I₂CHCHOHCHBr₂, 42),⁵⁵ 1,1-dibromo-3-iodo-2-heptanone (H₃C(CH₂)₃CHICOCHBr₂, 43),⁶⁷ 1,1-dibromo-3-iodo-2-propanol (ICH₂CHOHCHBr₂, 44),⁵⁵ 2,3-dibromo-3-iodo-2-propenoic acid (BrIC=CBrCOOH, 45),⁵⁷ 3,3-dibromo-2-iodo-2-propenoic acid (Br₂C=CICOOH, 46),⁵⁷ 1,3-diiodo-2-propanol (ICH₂CHOHCH₂I, 47),⁵⁵ 2,3-diiodoacrylic acid (ICHCICOOH, 48),⁵⁷ iodoacetamide (ICH₂CONH₂, 49),^55,57 3-iodohexadecanoic acid methyl ester (CH₃(CH₂)₁₂CHICH₂COOCH₃, 50),⁶⁸ 1-iodopentane (CH₃CH₂CH₂CH₂CH₂I, 51),⁶⁹ 1,1,3-tribromo-3-iodo-2-propanol (Br₂CHCHOHCHBrI, 52),⁵⁵ and triioodoacetaldehyde (I₃CCHO, 53).⁷⁰ The red alga Delisea fimbriata produces 1,1-dibromo-2-iodo-1-octen-3-one (H₃C(CH₂)₄COI=CBr₂, 54) and 1,1-dibromo-4-chloro-2-iodo-1-octen-3-one (CH₃(CH₂)₃CHClCOICBr, 55), which shows mild antifungal activity.⁷¹ An unusual nucleoside (4-amino-7-(5′-deoxy-β-D-xylofuranosyl)-5-iodopyrrolo[2,3-d]pyrimidine, 56) was isolated from the alga Hypnea valendiae⁷² and found to cause complete inhibition of cell division in fertilised sea urchin eggs at a concentration of 1 μg mL⁻¹; it also showed weak activity against human colorectal cancer cells (HCT116), with an IC₅₀ > 20 ppm.^73,74 Aromatic sesquiterpene 57 was isolated from the organic extracts of North Aegean Sea Laurencia microcladia (Vroulidia Bay, Chios Island, Greece). The cytotoxicity of 57 was evaluated against five human tumour cell lines (HT29, MCF7, PC3, HeLa, and A431), and the IC₅₀ values were 78.4, 86.3, 88.5, 81.4, and 92.7 μM, respectively.⁷⁵ Polar constituent 2,3,5,6-tetroiodo-tyrosine 58 was isolated from the green alga Cladophora densa Harvey (Mukoujina Reef, Hiroshima Bay, Japan).⁷⁶

A methanol extract of the red alga Hypnea valendiae (Quobba Lagoon, Australia), produced pronounced muscle relaxation and hypothermia in mice and also blocked polysynaptic and monosynaptic reflexes;⁷² 4-amino-7-(5′-deoxyribos-1′β-yl)-5-iodopyrrolo[2,3-d]pyrimidine (5′-deoxy-5-iodotubercidin, 59) and its 1′α isomer 60 have been isolated from this alga. Starting with 5-iodotubercidin 61 (IC₅₀ = 0.026 μM)⁷⁷ as a lead inhibitor of isolated human adenosine kinase (AK), a variety of pyrrolo[2,3-d]pyrimidine nucleoside analogues were designed and prepared by coupling 5-substituted-4-chloropyrrolo[2,3-d]pyrimidine bases with ribose analogues using the sodium salt-mediated glycosylation procedure. 5′-Amino-5′-deoxy analogues of 5-bromo- and 5-iodotubercidins were found to be the most potent AK inhibitors (AKIs) reported to date (IC₅₀ < 0.001 μM). Several potent AKIs were shown to exhibit anticonvulsant activity in the rat maximal electric shock induced seizure assay.⁷⁸ 5-Iodotubercidin (61) increased fatty acid oxidation activity of the liver at the expense of lipogenesis; the effect on fatty acid metabolism was mediated by the inhibition of acetyl-CoA carboxylase, probably due to the greater than two-fold increase in the AMP/ATP ratio and the concomitant stimulation of the AMP-activated protein kinase.⁷⁹ 5-Iodotubercidin (61) blocked β(3) phosphorylation without affecting the efficacy of calyculin A to inhibit platelet aggregation and spreading.⁸⁰ Tumour suppressor p53, which is activated by various stresses and oncogene activation, is a target for anti-cancer drug development. 5-Iodotubercidin is a strong p53 activator. 5-Iodotubercidin (61) is a purine derivative that is used as an inhibitor for various kinases including AK. 5-Iodotubercidin can cause DNA damage, as verified by the induction of DNA breaks and nuclear foci positive for γH2AX and TopBP1, the activation of Atm and Chk2, and the phosphorylation of S15 and up-regulation of p53. 5-Iodotubercidin induces G2 cell cycle arrest in a p53-dependent manner. It also induces cell death in p53-dependent and -independent manners. The DNA breaks were likely generated by the incorporation of 5-iodotubercidin metabolite into DNA. Moreover, 5-iodotubercidin showed anti-tumour activity as it could reduce the tumour size in carcinoma xenograft mouse models in p53-dependent and -independent manners. 5-Iodotubercidin is a novel genotoxic drug that has chemotherapeutic potential.⁸¹ An unusual 3-iodo-δ-lactone (62) was isolated from the ethyl acetate extract of the South China Sea alga Laurencia majuscule (Xisha Islands, Hainan Province, China); the extract contained phytohormone-like compounds and exhibited antifungal activities against Sclerotinia sclerotiorum.⁸² Eiseniaiodides A (63) and B (64) were isolated from the brown alga Eisenia bicyclis (Johgashima Island, Kanagawa Prefecture, Japan); they are ecklonialactone derivatives containing an iodine atom.⁸³ Two iodobromo-aromatic sesquiterpenes, 10-bromo-7-hydroxy-11-iodolaurene (65) and iodoether A (66), were isolated from the red alga Laurencia nana Howe (Isla Mujeres, Mexico).⁸⁴ The peracetylated ethanolic extract of the brown alga Carpophyllum angustifolium (Panetiki Island, Cape Rodney, New Zealand) furnished 2[D′]iododiphlorethol (67),^85,86 which was re-isolated from an ethyl acetate fraction of the brown alga Cystophora retroflexa.⁸⁶ Interestingly, Shibata et al.⁸⁷ found that the Laminariales Eisenia bicyclis and Ecklonia kurome (Itoshima Peninsula, Fukuoka Prefecture, Japan) release dibromo-iodophenol (68) to the surrounding medium and retain oligomers and polymers in their tissues. As UV-absorbing substances, such compounds seem to act as chemical defence agents in brown algae against environmental stresses such as herbivore or pathogen attack. Iodophloroeckol (69) and 4′-iodoeckol (70) were isolated and identified in the Laminariale Eisenia arborea Areschoug (Bamfield, Canada).⁸⁸ These phenols were synthesised by the directed ortho-lithiation and ipso-iododesilylation reactions of O-aryl N-isopropylcarbamates.⁸⁹

The antioxidant iodinated meroterpene 71 was isolated from the Japanese red alga Ascophyllum nodosum.⁹⁰ From an ethyl acetate fraction of the brown alga Cystophora retroflexa, 2-iodophloroglucinol triacetate (72) was isolated.⁸⁶ An investigation of the red alga Delisea pulchra (Cape Banks, New South Wales, Australia) yielded the iodinated furanones 73–75.⁹¹ The absolute configurations of 73–75 were determined by X-ray and CD spectroscopy.⁹² The iodinated furanones 76 and 77 were isolated from the red alga D. fimbriata.^93,94 Non-volatile iodine was mainly concentrated from seawater in the peripheral tissues of brown algae. In Laminariales, several speciation studies concluded that up to 90% of total iodine is stored in a labile inorganic form identified as iodide, while the organic forms in Laminaria are dominated by hormone-like tyrosine derivatives, i.e., monoiodotyrosine (MIT, 78) and diiodotyrosine (DIT, 1). The ubiquity of iodinated tyrosines (e.g., MIT, DIT) across extant eukaryotic phyla indicates their general function as endocrine molecules involved in cell–cell communication (plants) as well as time-coordinated and dose dependent developmental changes.⁹⁵ Trophic transfers of thyroxine and thyroid hormone precursors from primary producers (possibly detected in phytoplankton upon immunological assays) to consumers are essential in the metamorphoses of larvae of marine invertebrates along with gene regulation and signal transcription in vertebrates. Contrary to most organohalogenates of phaeophyte origin, tyrosine halogenation into MIT 78 and DIT 1 is believed to occur spontaneously without mediation by enzymes. MIT 78 and DIT 1 play an important role in the signal mechanism in eukaryotic physiology,⁹⁵ making them possible candidates for hormone-like substances along with known elicitors (alginate hydrolysates) of kelps.⁶¹ MIT 78 and DIT 1 in marine algae have been detected by coupling different chromatographic techniques with UV and ICP-MS.⁹⁶ One theory is that the simple marine haloalkanes such as chloroform, bromoform, etc. arise from in vivo haloform reactions, enabling algae to continuously secrete continuously these ‘anti-predator’ chemicals (Table 1).⁶⁴

Table 1 The names and structures of compounds 2–78

No.	2	3	4	5
Name	Iodomethane	Diiodomethane	Iodoform	Dibromoiodomethane
Structure
No.	6	7	8	9
Name	Bromodiidomethane	Bromochloroidomethane	Bromoiodomethane	Carbonyl iodide
Structure
No.	10	11	12	13
Name	2-Iodoethanol	1-Bromo-2-iodoethane	Iodoacetone	1-Bromo-3-iodo-2-propanone
Structure
No.	14	15	16	17
Name	1,1-Dibromo-3-iodo-2-propanone	1,3,3-Tribromo-1-iodo-1-propene	1-Iodo-4,4-dibromo-3-buten-2-one	Bromoiodoacetamide
Structure
No.	18	19	20	21
Name	Diiodoacetamide	Bromoiodoacetic acid	Diiodoacetic acid	3,3-Dibromo-1-iodo-2-heptanone
Structure
No.	22	23	24	25
Name	Iodoethane	1-Iodopropane	2-Iodopropane	Iodobutane
Structure
No.	26	27	28	29
Name	Iodoacetic acid	3-Iodo-2-propenoic acid	Ethyl ester of 3-iodo-2-propenoic acid	3,3-Diiodoacrylic acid
Structure
No.	30	31	32	33
Name	Ethyl ester of 3,3-diiodoacrylic acid	2,3-Diiodo-2-propenoic acid	Ethyl ester of 2,3-diiodo-2-propenoic acid	Bromoiodoacetacetic acid ethyl ester
Structure
No.	34	35	36	37
Name	Chloroiodoacetamide	2,3-Dibromo-3-iodo-propenoic acid	Chloroiodomethane	1-Bromo-1-chloro-3-iodo-2-propanol
Structure
No.	38	39	40	41
Name	1-Bromo-3-iodo-2-propanol	Chloroiodoacetic acid	1-Chloro-3-iodo-2-propanol	1-Chloro-3-iodoacetone
Structure
No.	42	43	44	45
Name	1,1-Dibromo-3,3-diiodo-2-propanol	1,1-Dibromo-3-iodo-2-heptanone	1,1-Dibromo-3-iodo-2-propanol	2,3-Dibromo-3-iodo-2-propenoic acid
Structure
No.	46	47	48	49
Name	3,3-Dibromo-2-iodo-2-propenoic acid	1,3-Diiodo-2-propanol	2,3-Diiodoacrylic acid	Iodoacetamide
Structure
No.	50	51	52	53
Name	3-Iodohexadecanoic acid methyl ester	1-Iodopentane	1,1,3-Tribromo-3-iodo-2-propanol	Triioodoacetaldehyde
Structure
No.	54	55	56	57
Name	1,1-Dibromo-2-iodo-1-octen-3-one	1,1-Dibromo-4-chloro-2-iodo-1-octen-3-one	4-Amino-7-(5′-deoxy-β-D-xylofuranosyl)-5-iodopyrrolo[2,3-d]pyrimidine	Aromatic sesquiterpene
Structure
No.	58	59	60	61
Name	2,3,5,6-Tetroiodo-tyrosine	5′-Deoxy-5-iodotubercidin	1′α isomer of 5′-deoxy-5-iodotubercidin	5-Iodotubercidin
Structure
No.	62	63	64	65
Name	3-Iodo-δ-lactone	Eiseniaiodide A	Eiseniaiodide B	10-Bromo-7-hydroxy-11-iodolaurene
Structure
No.	66	67	68	69
Name	Iodoether A	2[D′]Iododiphlorethol	Dibromo-iodophenol	Iodophloroeckol
Structure
No.	70	71	72	73
Name	4′-Iodoeckol	Iodinated meroterpene	2-Iodophloroglucinol triacetate	Iodinated furanone
Structure
No.	74	75	76	77
Name	Iodinated furanone	Iodinated furanones	Iodinated furanone	Iodinated furanone
Structure
No.	78
Name	Monoiodotyrosine
Structure

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2.1.2. Sponges. The hydrophilic extract of the sponge Ptilocaulis spiculifer (Dakar, Senegal) has been shown to contain dakaramine 79, a new tyrosine derivative containing iodine, which is an unusual feature for sponge metabolites.⁹⁷ Cyclodepsipeptide geodiamolide A (80)⁹⁸ was found in the Caribbean species of the sponge Geodia (Rusts Bay, Trinidad and Tobago, West Indies) and showed antifungal activity against Candida albicans, with a minimal inhibitory concentration (MIC) of 31.3 μg mL⁻¹.⁹⁸ It has been efficiently synthesised from the polypropionate and tripeptide units using Evans asymmetric alkylation, Mitsunobu esterification, and macrolactamisation with diphenyl phosphorazidate (DPPA) as key steps. Efficient esterification between the complex polyketide and tripeptide units has been realised under high pressure conditions.^99,100 Guided by cytoskeletal bioactivity, a reinvestigation of the sponge Auletta sp. (Milne Bay, East Fields and Port Moresby Regions, Papua New Guinea) yielded geodiamolides A (80), D (81), and G (82), which were shown to cause microfilament disruption.¹⁰¹ Geodiamolide D (81) was also isolated from the Papua New Guinea sponge Pseudaxinyssa sp.;¹⁰² it was shown to be an effective inhibitor of cellular proliferation in MDA-MB-435 cancer cells, with an IC₅₀ value of 0.08 μg mL⁻¹.¹⁰¹ The total synthesis of geodiamolide D (81)¹⁰³ has been achieved. Geodiamolide G (82) was also identified from the sponge Cymbastela sp. (Madang, Papua New Guinea) and showed activity against glioblastoma, astrocytoma U 373, and human ovarian carcinoma HEY.¹⁰⁴ Geodiamolide H (83) was isolated from the marine sponge Geodia sp. (Macqueripe Bay, Trinidad). It dramatically affects the poorly differentiated and aggressive Hs578T cell line and inhibits migration and invasion of Hs578T cells, probably through modifications in the actin cytoskeleton. Normal cell lines were not affected by treatment with 83;¹⁰⁵ it showed in vitro cytotoxicity against a number of human cancer cell lines: non-small cell lung cancer, HOP 92 (118 nM); central nervous system, SF-268 (153 nM); ovarian cancer, OV Car-4 (18.6 nM); renal cancer, A498 (94.8 nM) and UO-31 (185 nM); and breast cancer, MDA-MB-231/ATCC (433 nM) and HS 578T (245 nM).¹⁰⁶ Geodiamolides A (80) and H (83) were also isolated from G. corticostylifera (São Paulo State, Brazil). These peptides inhibited the first cleavage of sea urchin eggs (Lytechinus variegatus). The duplication of nuclei without complete egg cell division indicated that the mechanism of action might be related to microfilament disruption. Further studies showed that geodiamolides A (80) and H (83) have anti-proliferative activities against human breast cancer cell lines; they act by disorganising the actin filaments of T47D and MCF7 cancer cells while retaining the normal microtubule organisation. Compared to tumour cells, normal cells lines (primary culture human fibroblasts and BRL3A rat liver epithelial cells) were not affected by the treatment, indicating the biomedical potential of these compounds.¹⁰⁷ Geodiamolides L (84), O (85), and R (86) have been isolated from the marine sponge Cymbastela sp. (Motupore and Madang, Papua New Guinea). The serine residues of geodiamolides L (84), O (85), and R (86) have not been found previously in this family of compounds.¹⁰⁸ The cytotoxic peptide geodiamolide TA (87) was identified from the marine sponge Hemiasterella minor Kirkpatrick (Sodwana Bay, South Africa).¹⁰⁰ Neosiphoniamolide A (88) was isolated from the sponge Neosiphonia superstes (Banc Eponge Region, South of New Caledonia)¹⁰⁹ and shown to inhibit the growth of the fungi Piricularia oryzae and Helmintbosporium gramineum with an IC₉₀ value of 5 ppm.

Three cytotoxic depsipeptides, seragamides A, D, and E (89–91), have been isolated from the sponge Suberites japonicus (Seragaki and Manza, Okinawa Islands). Seragamide A (89) promoted the polymerisation of G-actin and stabilised F-actin filaments.¹¹⁰

The plakohypaphorines A–F (92–97) were isolated from the Caribbean sponge Plakortis simplex (Berry Island, Bahamas).^21,111 Plakohypaphorine E (96) was the first naturally occurring triiodinated indole, while plakohypaphorine F (97) is a unique metabolite because it possesses both chlorine and iodine atoms on the indole nucleus. Plakohypaphorines A–F (92–97) were evaluated for antihistaminic activity on isolated guinea pig ileum. Plakohypaphorines B (93), C (94), and D (95) produced significant concentration-dependent reductions of histamine-induced contractions. Under the same conditions, plakohypaphorine E (96) was much less active, and its inhibitory effect showed no concentration dependence, while plakohypaphorines A (92) and F (97) were completely inactive. Although calculations of pA₂ values indicated a non-competitive antagonistic effect, the histamine antagonism of 93–95 was specific because these molecules did not affect acetylcholine- and BaCl₂-induced contractions. The antihistaminic activities of 92–97 appeared to be connected to the number and nature of halogen atoms on the aromatic nucleus. Indeed, only the diiodinated analogues proved to be consistently active, regardless the relative position of the halogen atoms. Interestingly, the removal of one of the iodine atoms (in 92), the addition of a further iodine atom (in 96), and the substitution of an iodine atom with a chlorine atom (in 97) caused dramatic decays in the antihistaminic activity. The methanol extract of the Mediterranean tunicate Aplidium conicum (Sardinia, Italy) was also shown to contain plakohypaphorine A (92).¹¹² Topsentiasterol sulphate with iodinated side chain 98 was isolated from the marine sponge Topsentia sp. (Vang Fong Bay, Vietnam).¹¹³ Plakohypaphorine E (96) was also isolated from the Caribbean sponge Plakortis simplex (The Coast of Bahama).¹¹⁴ Iodinated metabolites 99 and 100, derived from the tyrosine, have been isolated from the Caribbean sponge Iotrochota birotulata (Little San Salvador Island, Bahamas).¹¹⁵ I. birotulata was reported to contain significant amounts of iodine (0.12–1.21%)¹¹⁵ together with comparable quantities of bromine (0.16–2.66%).¹¹⁶ Hence, this supported the association of the iodometabolites with reports of high iodine contents in sponge tissues.¹¹⁵

Chemical investigation of the marine sponges Agelas linnaei and A. nakamurai (Peniki E Island, Seribu Islands, Northwest Java, Indonesia) afforded the first iodinated tyramine unit-bearing pyrrole alkaloids, agelanesins B (101) and D (102); they exhibited cytotoxic activities against L5178Y mouse lymphoma cells with IC₅₀ values of 9.25 and 13.06 μM, respectively.¹¹⁷ It is challenging to identify why this Agelas sponge incorporates iodine into the agelanesins instead of bromine; this may be due to the amount of iodide present in seawater, as its level is far below other halogens such as bromide and chloride. Despite the low concentration of iodide, all known haloperoxidases are effective in oxidizing iodide, unlike chloride.¹¹⁸ The biosynthesis of iodinated metabolites seems to be related to the capability of organisms to concentrate iodine from seawater rather than to the presence of a specific peroxidase.¹¹⁵ Two unprecedented phosphorus-containing iodinated polyacetylenes, phosphoiodyns A (103) and B (104), were isolated from the Korean marine sponge Placospongia sp. (near Tong-Yong city in the South Sea, Korea). Phosphoiodyn A exhibited potent agonistic activity on human peroxisome proliferator-activated receptor delta (hPPARδ) with an EC₅₀ of 23.7 nM.^119,120 The acetylenic acids with one (105 and 106) or two (107 and 108) iodine atom(s) were isolated from the marine sponges Suberites mammilaris and S. japonicus (Cheju Island, Korea). The methylated compounds 107 and 108 exhibited strong NO inhibitory effects on RAW264.7 cells. In contrast, methylated 105 and 106 were inactive in RAW264.7 cells, but highly active in BV2 microglia cells.¹²¹ Placotylene A (109), a new inhibitor of the receptor activator of nuclear factor-B ligand (RANKL)-induced osteoclast differentiation, and placotylene B (110), a regioisomer of placotylene A, were isolated from the Korean marine sponge Placospongia sp. (near Tong-Yong city in the South Sea, Korea). Placotylene A (109) displayed inhibitory activity against RANKL-induced osteoclast differentiation at 10 μM, while placotylene B (110) did not show any significant activity up to 100 μM.¹²² 6′-Iodoaureol (111) was isolated from the Andaman Sea sponge Smenospongia sp. (PP Island, Krabi Province, Thailand); it is the first reported iodo–sesquiterpene hydroquinone.¹²³

2.1.3. Cnidaria. The first reported halometabolite, 3,5-diiodotyrosine (1), was isolated from the coral Gorgonia cavolii in the late nineteenth century.^13,124,125 Iodovulone-I (112), an unprecedented iodinated marine prostanoid with antitumor activity, was isolated from the soft coral Clavularia viridis Quoy and Gaimard (Okinawa Islands).^126,127 Iodinated prostanoids iodovulone II, iodovulone III, iodovulone IV, 12-O-acetyliodovulone II, 12-O-acetyliodovulone III, 10,11-epoxyiodovulone II, and 10,11-epoxyiodovulone I (113–119) were isolated as minor constituents from C. viridis (Ishigaki, Okinawa Islands).¹²⁸ Iodovulone II (113) showed cytotoxic activity against human T lymphocyte leukemia (MOLT-4), human colorectal adenocarcinoma (DLD-1), and human diploid lung fibroblast (IMR-90) cells with IC₅₀ values of 0.52, 0.6, and 4.5 μg mL⁻¹, respectively. Bioassay-directed fractionation of the CH₂Cl₂–MeOH extract of C. viridis (Green Island, Taiwan) has also afforded iodovulones II (113) and III (114). Iodovulone II (113) exhibited cytotoxicity against human prostate (PC-3) and colon (HT29) cancer cells with IC₅₀ values of 3.9 and 6.5 μM, respectively. Iodovulone III (114) exhibited cytotoxicity against PC-3 and HT29 cancer cells with IC₅₀ values of 6.7 and 10.0 μM, respectively.¹²⁹ Iodinated prostanoids 7-acetoxy-7,8-dihydroiodovulone I (120) and 7-acetoxy-7,8-dihydroiodovulone II (121) were isolated from C. viridis (Ishigaki, Okinawa Islands). Compound 120 demonstrated cytotoxic activity against MOLT-4, DLD-1, and IMR-90 cells with IC₅₀ values 0.5, 0.6, and 4.5 μg mL⁻¹, respectively.¹³⁰ The first iodine-containing briaranes to be found in nature were the dichotellides A–E (122–126) from the South China Sea gorgonian Dichotella gemmacea (Meishan Island, Hainan Province, China). Dichotellide C (124) showed marginal activity against human pancreatic (SW1990) cancer cells (IC₅₀, 45.0 μM).¹³¹ Four naturally produced organoiodides, fragilisinins I–L (127–130), were isolated from the South China Sea gorgonian Junceella fragilis (Meishan Island, Hainan province of China). Fragilisinin J 128 exhibited potent antifouling activities at nontoxic concentrations with EC₅₀ values of 11.9 μM.¹³²

Novel eight-membered heterocycles named hicksoanes A–C (131–133)¹³³ were isolated from the Red Sea gorgonian Subergorgia hicksoni (Gulf of Aqaba, Eilat, Israel). Hicksoanes A–C (131–133) showed antifeeding activities against goldfish at natural concentrations of 10.0 μg mL⁻¹. The biosynthesis of hicksoanes A–C (131–133) proceeds presumably under the participation of haloperoxidases and nonribosomal peptide biosynthetic machinery. Both haloperoxidases producing hypohalogenic acid as the actual halogenating agent and NADH-dependent halogenases transforming the substrate so that the halide ion may be used directly as a nucleophile have been proposed to catalyse the reaction.¹³⁴ An unusual structure containing a combination indole–oxazole–pyrrole unit, breitfussin A (134), was isolated from the hydrozoan Thuiria breitfussi (Bjørnøya, Bear Island, Norway).¹³⁵

2.1.4. Tunicates (ascidians). A chemical investigation of the Mediterranean ascidian Ciona edwardsii (Bay of Naples, Meta di Sorrento, Punta Gradelle, Italy) has been performed, leading to the isolation of the tyrosine derivative iodocionin (135), which was shown to possess significant and selective activity against lymphoma cells with an IC₅₀ of 7.7 μg mL⁻¹.¹³⁶ A non-cytotoxic triphenylpyrrolo-oxazinone, lukianol B (136), was isolated from a tunicate (the lagoon of Palmyra Atoll).¹³⁷ Recently, Fuente and co-workers screened about 2000 marine natural products to identify structurally novel human aldose reductase (h-ALR2) inhibitors.¹³⁸ They reported that lukianol B (136) was the most potent one among the compounds tested; its h-ALR2 inhibitory activity (IC₅₀ = 0.6 μM) was six-fold more potent than that of the known ALR inhibitor sorbinil. The therapeutic effects of h-ALR2 inhibitors for some degenerative complications of diabetes such as neuropathy, nephropathy, and retinopathy are well recognised. Therefore, lukianol B (136) can be regarded as a new lead to develop therapeutic agents for the treatment of these disorders. The total synthesis of lukianol B (136) has been achieved using N-benzenesulfonyl-3,4-dibromopyrrole as a common starting material. The key developed synthetic strategy is the combined bromine-directed lithiation and palladium-catalysed cross-coupling of N-benzenesulfonyl-3,4-dibromopyrrole to produce 3,4-diarylpyrrol-2-carboxylates.¹³⁹ The nucleoside 56 was isolated from an ascidian Diplosoma sp. (Hateruma, Okinawa Islands), and its structure was successfully determined by spectroscopic and chemical analysis; 56 was found to inhibit the division of fertilised sea urchin eggs.¹⁴⁰ 56 and 59 were also isolated from two unrelated marine organisms, the ascidian Diplosoma sp. and the alga Hypnea valendiae, respectively.⁷² 58 is an iodinated tyramine derivative that constitutes one of the main components isolated in several samples of tunicates of the genus Didemnum (Barrang Lompo, Indonesia).^73,74 Iodinated phenethylamine (137) and the corresponding phenethylamine urea 138 were isolated from the tunicate Didemnum sp. (Northwest end of Cocos Lagoon, Guam); 137 showed in vitro activity against the yeast Candida albicans and was mildly cytotoxic against tumour cell line L1210 with an IC₅₀ of 20 μg mL⁻¹.¹⁴¹ 5′-Deoxy-3-iodotubercidin (59) and 60 were identified from the ascidian Didemnum voeltzkowi (Apo Reef, Philippines).¹⁴² An Australian species of ascidian, Aplidium sp., has yielded three iodinated L-tyrosine derivatives 139–141.¹⁴³ The study of an aqueous extract from the ascidian Didemnum rubeum (Reef & Islands of Chuuk Atoll, Micronesia) permitted the isolation of the previously reported diiodo-tyramine derivatives 137 and 138 together with the iodo-tyramine derivatives 142–148.¹⁴⁴ Polyandrocarpamide B (149) was isolated from the marine ascidian Polyandrocarpa sp. (Siquijor Islands, Philippines).¹⁴⁵ Plakohypaphorine A (92) was isolated from the methanol extract of the Mediterranean tunicate Aplidium conicum (The coast of Sadinia, Italy).¹⁴⁶

2.1.5. Mollusc. The bioassay-guided separation of the aqueous ethanol extract of the viscera of the gastropod Turbo marmorata (Okinawa Islands) resulted in the isolation of two toxins, turbotoxins A (150) and B (151), which were isolated as bis-trifluoroacetates.^147,148 The structures were determined by spectral analysis and confirmed by organic synthesis to be diiodotyramine derivatives. Turbotoxins A (150) and B (151) exhibited acute toxicities against ddY mice, with LD₉₉ values of 1.0 and 4.0 mg kg⁻¹, respectively.¹⁴⁷ The structure–toxicity relationship of the turbotoxins was examined, demonstrating that the iodine atoms and trimethylammonium groups were important for their acute toxicities. Turbotoxin A (150) inhibited acetylcholinesterase with an IC₅₀ of 28 μM.¹⁴⁸ X-Ray crystallographic studies of complexes of acetylcholinesterase with small molecules such as decamethonium bromide, tacrine, and edrophonium bromide indicated that an aromatic gorge exists at the bottom of the active site. Currently, no data exists on the relationships between the toxicity and affinity to acetylcholinesterase of turbotoxin analogs; however, the benzyl group might be stacked against the aromatic gorge to increase its toxicity. Preliminary neuropharmacological experiments on turbotoxin A (150) indicated that it does not interact with the peripheral nervous system. The toxin iodomethyltrimethylammonium chloride (152) was found in the viscera of the green turban shell Turbo marmorata (Ishigaki, Okinawa Islands).¹⁴⁹ A cytotoxic cyclodepsipeptide, doliculide (153), was isolated from the sea hare Dolabella auricularia (Mie Prefecture, Japan).¹⁵⁰ It contained a 15-carbon polyketide unit, glycine, and a unique D-amino acid and was regarded as a metabolite of mixed peptide–polyketide biogenesis. Notably, the doliculide (153) possesses a structurally novel polyketide moiety and exhibits potent cytotoxicity against HeLa-S₃ cells with an IC₅₀ of 0.001 μg mL⁻¹.¹⁵⁰ The first total synthesis of doliculide (153) has been achieved;¹⁵¹ the key synthetic step was the construction of the stereogenic centres of a 15-carbon polyketide-derived dihydroxy acid moiety by a combination of the Evans aldol reaction and the Barton deoxygenation reaction. Furthermore, artificial congeners of doliculide (153) were synthesised, and their structure–cytotoxicity relationships were examined.¹⁵²

The iodinated furanones 76 and 77 were isolated from the sea hare Aplysia parvula and its host plant Delisea pulchra (Sydney, New South Wales, Australia).¹⁵³ The results indicated that the distribution and level of D. pulchra metabolites in A. parvula are consistent with the role of acquired chemical defences against predators.

2.1.6. Bacteria. The iodoalkaloid 3,6-diiodocarbazole (154) was isolated from the marine cyanobacterium Kyrtuthrix maculans (Ping Chau, Hong Kong, China).¹⁵⁴ The synthesis of the iodocarbazole was achieved by direct iodination of carbazoles by an N-iodosuccinimide and N-iodosuccinimide–silica gel system.¹⁵⁵ Tasihalides A (155) and B (156), which possess novel cage structures, have been isolated from an assemblage of a marine cyanobacterium belonging to the genus Symploca and an unidentified red alga (Short Drop-off, Palau).²⁰ The presence of iodine was confirmed by the UV/vis spectrum, which showed an n–σ* transition at 253 nm characteristic of this halide. The closest structural relatives to tasihalides A (155) and B (156) are tricyclic synthetic compounds that have been prepared from cembrane diterpenes treated with electrophiles.¹⁵⁶ This suggested that tasihalides A (155) and B (156) arise from a halogenation-initiated cyclisation of an oxygenated cembrane diterpene. Such haloperoxidase-mediated electrophilic cyclisations have recently been demonstrated in vitro using bromoperoxidases cloned from red algae.¹⁵⁷

A slightly halophilic myxobacterial strain, Paraliomyxa miuraensis SMH-27-4 (Brush Vegetation, Arai-Hama Beach, Miura Peninsula, Kanagawa Prefecture, Japan), was isolated. This slowly growing myxobacterium produces the antibiotic depsipeptide miuraenamide B (157), which inhibits NADH oxidase with an IC₅₀ value of 50 μM.^158,159 Miuraenamide B (157) selectively inhibits the fungus-like phytopathogen Phytophthora capsici at a minimum dose of 0.025 μg per disk and has no effect on bacteria. Several polyketide–peptide hybrid-type metabolites that resemble the miuraenamides have been isolated from marine sponges and a mollusc (e.g., geodiamolides, seragamides, and doliculide). The true producers of these metabolites could be unknown halophilic myxobacteria and/or related microorganisms.^158,159

2.2. Terrestrial organisms

2.2.1. Actinomyces. The calicheamicins (CLMs) α₂^I (158), α₃^I (159), β₁^I (160), γ₁^I (161), and δ₁^I (162)^160–163 are a class of enediyne antibiotics derived from the terrestrial bacterium Micromonospora echinospora (chalky soil, Kerrville, Texas, USA), with CLM γ₁^I (161) being the most notable. It is extremely toxic to all cells, and a CD33 antigen-targeted immunoconjugate N-acetyl dimethyl hydrazide CLM was developed and marketed as targeted therapy against the non-solid tumour cancer acute myeloid leukemia (AML).¹⁶⁴ CLM γ₁^I (161) is one of the most potent known antitumor agents; its extremely potent cytotoxic properties led to its development as an antibody drug conjugate (ADC, Mylotarg®) against a certain type of leukemia. Introduced in 1996, Mylotarg® ushered in a new era of cancer chemotherapy that now constitutes one of the most active areas of cancer research and has already resulted in several promising drug candidates in the pipeline.^165–167

The total synthesis of CLM γ₁^I (161) has been achieved,¹⁶⁸ and an account of the reasoning and reduction to practice of a highly convergent total stereospecific synthesis of CLM γ₁^I (161) was provided. The key finding was the use of a very mild promoter system to allow for the coupling of trichloroacetimidate with advanced calicheamicinone-like accepters.¹⁶⁹

The enediyne antibiotic CLM γ₁^I (161) was targeted to DNA by a novel aryltetrasaccharide comprised of an aromatic unit and four unusual carbohydrates. CLMs bind with DNA in the minor groove, where they then undergo a reaction analogous to the Bergman cyclisation, generating a diradical species. Like all enediynes, this diradical (1,4-didehydrobenzene) then abstracts hydrogen atoms from the deoxyribose (sugar) backbone of DNA, resulting in strand scission.¹⁷⁰ The core metabolic pathway for the biosynthesis of this molecule resembles that of other characterised enediyne compounds and occurs via a polyketide synthase pathway.¹⁷¹ The specificity of the binding of CLM to the minor groove of DNA was demonstrated to be due to the aryltetrasaccharide group of the molecule.^172,173

The headspace extracts from Streptomyces chartreusis (Braunschweig, Germany) contain methyl 2-iodobenzoate (163), an iodinated volatile.

2.2.2. Insects. Several insects contain monoiodohistidine (MIH), 2-iodohistidine (164), and 4-iodohistidine (165) has been obtained from the cuticles of locusts.² 2-(or 4)-Iodohistidine, (164) or (165), respectively, have been found in several insects such as the squash bug, house fly, mosquito, dragonfly, and cockroach.^174,175

2.2.3. Higher animals. Organoiodines are rare in higher animals, however, several such compounds have been identified. 3-Mono-iodo-4-hydroxyphenylpyruvic acid (166) and 3,5-di-iodo-4-hydroxyphenylpyruvic acid (DIHPPA, 167) were isolated from rat thyroid glands.^176,177 4-Iodohistidine, phosphoriodohistidine (PIH, 168), thyroxine [O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-L-tyrosine, T4, 169], and 3,5,3′-triiodothyronine (T3, 170) were extracted from beef heart mitochondria.^178,179 4-Iodohistidine (165) was the product of the limited iodination of histidine,¹⁸⁰ and PIH (164) was a possible intermediate of oxidative phosphorylation in a rapid ³²P-labeling experiment.¹⁸¹ Thyroxine (169) and 3,5,3′-triiodothyronine (170) have been also shown to be present in butanol extracts of normal rat liver, kidney, and heart.¹⁸² MIH (164 or 165) and diiodohistidine (DIH, 171) were identified from thyroidal iodoproteins and their peripheral metabolites in rats.¹⁸³ The deiodination behaviour of DIH (171) in the presence of rat liver and kidney homogenates was studied qualitatively in terms of time course with thin layer chromatography and paper chromatography compared with the known course of DIT (1) metabolism. In contrast to DIT (1), the split of iodine from DIH (171) depended neither on the amount of homogenate nor the time course. In order to more precisely examine the mode of deiodination from DIH (171) and MIH (164 or 165), they were labelled with ¹³¹I, and the metabolisms of DIH (171) and MIH (164 or 165) were found to be considerably different. DIH (171) was deiodinated enzymically and non-enzymically, while MIT (78) resisted rapid metabolism and was deiodinated slowly in the body.^184,185 2-Iodohexadecanal (2-IHDA, 172) is present in horse, dog, and rat thyroids.¹⁸⁶ Studies have indicated that 172 serves as a mediator of some of the regulatory actions of iodide on the thyroid gland.^187,188 Pereira et al.¹⁸⁶ demonstrated the formation of iodolipids by the incorporation of iodine into proteins and lipids of horse thyroid slices. The authors identified the major thyroid iodolipid to be 2-IHDA (172). The biosynthesis of 172 likely involves the addition of iodine to the vinyl ether group plasmenylethanolamine. This iodolipid mimics the main regulatory effect of iodide on thyroid metabolism: the inhibition of H₂O₂ production by adenylyl cyclase. 2-Iodohexadecan-1-ol (2-IHDO, 173) was also detected in these studies; it formed later than 2-IHDA (172), and thyroid cells converted exogenous 2-IHDA (172) into 2-IHDO (173) in a time-dependent manner. The ratio of 2-IHDO/2-IHDA increased with H₂O₂ production and decreased as a function of iodide concentration. Aldehyde-reducing activity was detected in subcellular fractions of horse thyroid. As no formation of 2-iodohexadecanoic acid could be detected, the reduction into the biologically inactive 2-IHDO (173) was determined to be a major metabolic pathway of 2-IHDA (172) in dog thyrocytes.¹⁸⁹

(2R)-(+)- and (2S)-(−)-2-IHDA (172) were synthesised¹⁹⁰ in five steps and 62% overall yield from chiral enol ethers via the iodocyclisation and chromatographic separation of the resulting diastereomeric 1′-iododioxanes. The absolute configurations were assigned through chemical correlation and by application of Mosher's method to the esters obtained by methanolysis of (2R)- and (2S)-2-IHDA followed by derivatisation. Moreover, the biosynthesis and inhibitory activity have been shown to be unstereoselective.¹⁹¹

Another α-iodoaldehyde, 2-iodooctadecanal (174), was also detected in rat and dog thyroids, where it was even more abundant than 2-IHDA (172).¹⁸⁶ 6-Iodo-5-hydroxy-eicosatrienoic acid, δ-lactone (175) and 5-iodo-4-hydroxydocosapentaenoic acid, γ-lactone (176) have been identified in the thyroid gland of dogs.¹⁹² The transformation of arachidonic acid and docosahexaenoic acid with lactoperoxidase, iodide, and hydrogen peroxide into 175 and 176 in vitro suggested that this pathway may operate in vivo with thyroid peroxidase.³

Although the thyroid gland has been known to exist for hundreds of years, the first report linking cretinism and hypothyroidism to the destruction of this gland was published in 1888.¹⁹³ The existence of hormones containing iodine as a normal constituent of the thyroid gland was foretold by Baumann in 1895.¹⁹⁴ The first report of the isolation of thyroxine (169) from mammalian thyroid gland was published in 1915,¹⁹⁵ followed by later publications identifying the related iodinated tyrosines (170) and 3,5-diiodothyronine (177).^196,197 However, it was Kendall^195,198,199 in 1919 who first isolated the hormone 169 via alkaline hydrolysis of hog thyroid glands and named the compound, ‘thyroxine.’ Kendall successfully isolated 7 g of crystalline thyroxine (169). Later, Harington and co-workers^196,200,201 employed an enzymatic hydrolysis to liberate thyroxine (169) from hog thyroid glands and correctly reported its empirical formula to be C₁₅H₁₁O₄NI₄. They also reported the correct structure of the isolated thyroxine (169) based on extensive analysis and subsequent independent chemical synthesis. Similar structural elucidation results on thyroxine (169) were also obtained by Foster et al.,²⁰² who employed an acid hydrolysis following a brief enzymatic digestion of the hog thyroid gland. The stereochemistry of this α-amino acid was determined to be L-series by Canzanelli et al.,²⁰³ who found similar optical rotations for two L-thyronines prepared by the conversion of natural thyroxine (169) isolated from thyroid gland and synthesised from L-tyrosine.

Iodolipids in calf thyroid slices have been characterised as iodinated free fatty acids and neutral lipids.²⁰⁴ The suppression of iodine organification as well as phospholipase A₂ strongly inhibits their formation, whereas the inhibition of prostaglandin synthesis increases lipid iodination, suggesting a correlation with arachidonic acid metabolism.²⁰⁵ The transformations of arachidonic and docosahexaenoic acids into iodolactones by the action of lactoperoxidase, iodine and hydrogen peroxide have been demonstrated in vivo.^205,206 Lactoperoxidase catalyses the transformation of 5,8,11,14-eicosatetraenoic and 4,7,10,13,16,19-docosahexaenoic acids to iodolactones. The major lactones formed in this reaction are the δ-lactone of 6-iodo-5-hydroxy-eicosatrienoic acid (175) and the γ-lactone of 5-iodo-4-hydroxydocosapentaenoic acid (176).²⁰⁴ Two other ω-lactones, 178 and 179, have also been detected by GC-MS.^192,204 Pereira et al.¹⁸⁶ demonstrated the formation of iodolipids (the ω-lactone of 14-iodo-15-hydroxy-eicosa-5,8,11-trienoic acid (178) and the ω-lactone of 15-iodo-14-hydroxy-eicosa-5,8,11-trienoic acid (179)) by incorporating iodine into proteins and lipids from horse thyroid slices. The authors identified the major thyroid iodolipid to be 2-IHDA (172). The biosynthesis of this iodolipid likely involves the addition of iodine to the vinyl ether group of plasmenylethanolamine. δ-Iodolactones decreases epidermal growth factor-induced proliferation and inositol-1,4,5-trisphosphate generation in porcine thyroid-follicles.²⁰⁷

Thyroxine (169) and other iodinated compounds tyrosine (170) and 3,5-diiodothyronine (177) have been isolated from numerous ascidians, sponges, gorgonians, marine algae, and insects.^2,11,208,209

2.2.4. Human. Iodine is considered as an essential mineral in the human body. MIH (164 or 165) and DIH (171) have been identified from thyroidal iodoproteins and their peripheral metabolites in normal man.¹⁸³ MIH (164 or 165) and DIH (171) were identified from the urine of patients with congenital goitrous hypothyroidism.²¹⁰ 3,5-Diiodotyrosine (1) has been shown to be the result of the second stage of iodine incorporation into the amino acid tyrosine in the thyroid gland. The action of the enzyme thyroid peroxidase on tyrosine in the presence of iodine first produces 3-iodotyrosine, which is the precursor to 3,5-diiodotyrosine (1). Two 3,5-diiodotyrosine molecules then combine in the presence of this same enzyme to generate 3,5,3′,5′-tetraiodothyronine, commonly known as thyroxine (169).¹²⁵

Thyroxine (T4, 169) is an essential hormone produced by the thyroid gland, which is located in the necks of humans just below the larynx. The thyroid gland utilizes iodine, primarily from food (e.g., seafood, bread, and salt), to produce T4 along with small amounts of 3,5,3′-triiodothyronine (T3, 170) in a ratio of about 99.9 : 0.1. T3 exhibits most of the physiological activity and it is primarily produced by the deiodination of T4 in tissues other than the thyroid gland. T3 has a much shorter half-life (less than two days) compared to T4. The thyroid hormones T4 and T3 are the only two endogenous hormones that contain iodine atoms. Thyroid hormones regulate a variety of metabolic processes and play a critical role in normal growth and development, carbohydrate metabolism, oxygen consumption, and maturation of the central nervous system and bone. Indeed, these hormones are required for the normal function of nearly all tissues.¹⁹³

For decades, the biosynthesis of thyroxine (169) has been the subject of continued investigation, and the precise mechanism of this interesting biochemical process is not yet fully understood. The coupling of two 3,5-diodotyrosine (DIT, 1) molecules to form thyroxine (169) was first suggested as early as 1927 by Harington and Barger.²⁰⁰ Subsequently, in 1939, von Mutzenbecher²¹¹ reported that the incubation of a basic solution of DIT (1) produced a small amount of thyroxine (169). Two possible mechanisms, intra- and intermolecular coupling processes catalysed by the enzyme thyroid peroxidase (TPO), were subsequently proposed for the in vivo formation of thyroxine (169) in the thyroid gland.^212–215 Later studies indicated that peptide-linked DIT (1) within thyroglobulin (TGB) is more likely the precursor of thyroxine (169).^216,217 It is generally believed that thyroxine (169) is formed via oxidative free radical coupling^214,215 of the phenol groups from two units of DIT (1) with the loss of a three-carbon unit, which was later reported to be pyruvic acid by Johnson and Tewkesbury.²¹⁴ Subsequently, other groups identified the three-carbon unit, which is lost in the transformation of DIT (1) into thyroxine (169), as alanine,²¹⁸ serine,²¹⁹ hydroxypyruvic acid,²²⁰ and dehydroalanine.^221,222 For some time, dehydroalanine was favoured as the lost three-carbon unit in the biosynthesis of thyroxine (169). However, Sih and co-workers²²³ recently showed that the three-carbon unit lost in this coupling process is in fact aminomelonic acid semialdehyde and further suggested that both intra- and inter-molecular mechanisms could be operating in the biosynthesis of thyroid hormones.

The first synthesis of (±)-thyroxine (169) was achieved by Harington and Barger²⁰⁰ in 1927 in eight steps starting from 4-methoxyphenol. The synthesis began from 4-methoxyphenol, which was coupled with 3,4,5-triiodonitrobenzene. The nitro group was subsequently reduced to give the corresponding aniline derivative. The amine group was then converted to a nitrile via diazotisation, which upon reduction with anhydrous stannous chloride gave 3,5-diiodo-4-(4′-methoxyphenoxy) benzaldehyde. The arylaldehyde derivative was further reacted with hippuric acid in the presence of fused sodium acetate and treated with sulphuric acid in ethanol to afford a cinnamic ester derivative. The olefin in ester was reduced using red phosphorous in hydrochloric acid, which also hydrolyzed the benzamide and ethyl ester groups. The resulting product was treated with iodine and potassium iodide in aqueous ammonium hydroxide solution to afford (±)-thyroxine (169). This synthesis gave a racemic hormone for comparison with the material isolated from the thyroid gland and ultimately paved the way for the structural confirmation of thyroxine (169). Harington²²⁴ also prepared L-thyroxine via optical resolution starting from (±)-3,5-diiodothyronine (177), which was synthesised and converted to the corresponding N-formyl derivative by treatment with formic acid. This derivative was then resolved using L-1-phenylethylamine to give the corresponding 3,5-diiodo-L-thyronine derivative. Hydrolysis of the 3,5-diiodo-L-thyronine derivative and subsequent iodination afforded L-thyroxine in its natural form, again confirming the stereochemistry of the lone chiral centre.

The persistent interest in thyroid iodolipids is related to speculations about their role in thyroid metabolism and regulation. It has been suggested that they could play a role in the transport of iodide or be intermediates in thyroxine (169) formation. Alternatively, their formation might result from the nonspecific binding of oxidised forms of iodine and could thus play a protective role in scavenging excess iodine released by thyroid peroxidase.^186,206 It has also been suggested that iodolipids could be mediators of the Wolff–Chaikoff effect and other inhibitory effects of iodide on the thyroid gland such as the inhibition of iodide transport, adenylate cyclase activation, and hormone secretion.^186,225

2.2.5. Miscellaneous. Metaquat (1,1′-dimethyl-3,3′-bipyridinium diiodide, 180) was isolated from an arrow poison (the poison is produced by squeezing chilli leaves, bark and a root crop) used by the Southeast Asian Orang Mentawai Tribe (The inhabitants of Siberut, an island in the Mentawaiarchipelago, west of Sumatra); the description of the effect of the arrow poison is similar to that of curare, which has a strong muscle relaxing effect. Metaquat (180) is isomeric with the common herbicide paraquat (1,1′-dimethyl-4,4′-bipyridinium).²²⁶

Iodomethane (2) was also emitted from fungi,²²⁷ rice paddies,^228–233 and oat plants.²³³

3 Abiotic sources

3.1. Volcanos

Early studies of volcanic gases and the presence of organoiodines are well documented.^2,3,8 A recent study of volcanoes (Kuju, Satsuma Iwojima, Mt. Etna) revealed an extraordinarily large array of organoiodines including CH₃I, 2,^234,235 CH₂ClI 36, and CH₃CH₂I 3.²³⁵

3.2. Sediment and soils

Abiotic soils can also produce CH₃I 2;²³⁶ iodomethane 2 is emitted from wetlands²³⁷ and peatlands.²³⁸ Furthermore, the presumed natural halogenation of humic material occurs in Baltic Sea marine sediments, leading to brominated and iodinated phenolic units in high-molecular-weight matter.²³⁹

3.3. Atmosphere

CH₃I 2 is often detected in the oceanic atmosphere.^22–42 Diiodomethane 3 is a more significant source of iodine in the atmosphere than CH₃I 2.⁴²

3.4. Seawater

Iodomethane (CH₃ I, 2) has been detected in the oceans and in the air over oceans. Measurements have indicated that the oceans are the major source of CH₃I 2, the concentration of CH₃I 2 has been observed to be 1000 times higher in water near kelp (Laminaria digitata) beds than in the open ocean.

Volatile organoiodine compounds (VOIs) are the main carrier of iodine from the oceans to the atmosphere, and the sea surface is the source of the short-lived VOIs. CH₂I₂ 3, CHClI₂ 181, and CHI₃ 2 were identified in a series of laboratory experiments. These VOIs are produced from the reaction of marine dissolved organic matter with hypoiodous acid/molecular iodine, which are formed at the sea surface when ozone reacts with dissolved iodide. The presence of dissolved iodide, dissolved organic matter and ozone could lead to the sea surface production of CH₂I₂ 3, CHClI₂ 181, and CHI₃ 2. As such, this process could provide a ubiquitous source of iodine to the marine atmosphere.²⁴⁰ Recent studies have confirmed the oceanic presence of chloroiodomethane (CH₂ClI, 36),^{31,35–37,39,40,42,48–51,53,59,241–244} bromoiodomethane (BrCH₂I, 8),^35,37,243 dibromoiodomethane (CHBr₂I, 5),²⁴³ and dichloroiodomethane (Cl₂CHI, 182).²⁴³

3.5. Miscellaneous

Natural combustion sources such as biomass fires and other geothermal processes account for a wide range of organohalogens. Biomass combustion also accounts for some CH₃I 2.^245–247

4 Biological significance

More interesting is the possible biological significance of iodinated products. The presence of iodine atoms in compounds causes significant changes in their physico-chemical characteristics, increasing their reactivity and changing the conformation of biological membranes. Novel natural iodinated products have been discovered and evaluated for their biological activity. It seems certain that some possess anticancer, antifungal and/or antibacterial properties. Halogens play an important role in both biogenic and abiogenic natural processes. Recent studies have indicated a chemical defensive role for iodine-containing metabolites in many marine invertebrates. Many marine and terrestrial organisms use organoiodines for chemical defence (feeding deterrents, irritants, or pesticides) or in food gathering.²⁴⁸ It seems clear that natural organoiodine compounds play an essential role in the survival of organisms, and the ability of the organism to synthesise such compounds for chemical defence and food gathering has evolved over time under the stress of natural selection.²⁴⁹

5 Halogenases and biological halogenation

Nature has developed a series of exquisite methods to introduce halogens into organic compounds. Most of the relevant enzymes are oxidative and require either hydrogen peroxide or molecular oxygen as a co-substrate to generate reactive halogens for catalysis.²⁵⁰ For many years, the only known halogenases were the haloperoxidases, although we now have a much better understanding of enzymatic halogenation. Halogenated natural products are widely distributed in nature, and some of them show potent biological activities. The incorporation of halogen atoms in drug leads is a common strategy to modify molecules in order to vary their bioactivities and specificities. Chemical halogenation, however, often requires harsh reaction conditions and results in unwanted byproduct formation. It is thus of great interest to investigate the biosynthesis of halogenated natural products and the biotechnological potential of halogenating enzymes.²⁵¹

A large and diverse series of halogenated natural products exists. In many of these compounds, the halogen is important to biological activity and bioavailability. Enzymes capable of halogenating all kinds of different chemical groups from electron-rich to electron-poor and from aromatic to aliphatic have been characterised. Given that synthetic halogenation reactions are not trivial transformations, and that halogenated molecules possess pharmaceutical usefulness, further research on halogenating enzymes will be worthwhile.²⁵²

5.1. Haloperoxidases

The first halogenating microbial enzyme (fungal chloperoxidase) was discovered and described in 1959.²⁵³ Haloperoxidases including Heme-Fe-vanadium haloperoxidase and vanadium bromoperoxidases have been found in marine organisms.²⁵⁴

5.1.1. Heme-containing haloperoxidases. The prototypical heme-dependent haloperoxidase is a fungal enzyme from Caldariomyces fumago.^255–257 Mammalian heme-dependent haloperoxidases are also known. In particular, a haloperoxidase in thyroid epithelial cells is responsible for a remarkable series of posttranslational oxidative modifications of tyrosyl residues in the protein thyroglobulin.²⁵⁸ The reaction mechanism of heme-dependent haloperoxidases is likely parallel to that of haem enzymes.^259,260 The halide ion is oxidised to ferric hypohalite in the active site by ferryl-oxo species. This species is generated in turn by the binding of hydrogen peroxide to the ferric resting state, which is followed by halide addition and finally the release of the hypohalous acid.²⁵²

5.1.2. Vanadium-containing haloperoxidases. Vanadium-dependent haloperoxidases (V-HPOs) contain a vanadate prosthetic group and utilize hydrogen peroxide to oxidize a halide ion into a reactive electrophilic intermediate. These metalloenzymes have a large distribution in nature; they are present in macroalgae, fungi, and bacteria, but have been exclusively characterised in eukaryotes.²⁵⁰ V-HPOs catalyse the oxidation of halides (chloride, bromide, and iodide) by hydrogen peroxide. Iodine uptake and the production of iodo-organic compounds by marine algae are thought to involve vanadium-dependent iodoperoxidases. Iodoperoxidases catalyse the oxidation of iodines and are named according to the most electronegative halide that they can oxidize; chloroperoxidases (CPOs) can catalyse the oxidation of chloride as well as bromide and iodide, bromoperoxidases (BPOs) react with bromide and iodide, and iodoperoxidases (IPOs) are specific to iodide.²⁶¹

5.2. Flavin-dependent halogenases (FADH₂-dependent halogenases)

The understanding of the enzymatic incorporation of halogen atoms into organic molecules has increased during the last few years.²⁶² Most known enzymatic halogenase reactions are oxidative, but more and more different strategies are being discovered in the marine environment. A novel type of halogenating enzymes, flavin-dependent halogenases, has been identified as a major player in the introduction of chloride and bromide into activated organic molecules. Flavin-dependent halogenases require the activity of a flavin reductase for the production of reduced flavin, which is required by the actual halogenase. A number of flavin-dependent tryptophan halogenases have been investigated in some detail, and the first three-dimensional structure of a member of this enzyme subfamily, tryptophan 7-halogenase, has been elucidated. This structure suggests a mechanism involving the formation of hypohalous acid, which is used inside the enzyme for the regioselective halogenation of the respective substrate. The introduction of halogen atoms into non-activated alkyl groups is catalysed by non-heme Fe^II α-ketoglutarate- and O₂-dependent halogenases. Examples of the use of flavin-dependent halogenases for the formation of novel halogenated compounds in vitro and in vivo promise a bright future for the application of biological halogenation reactions.²⁶³ The elucidation of the three-dimensional structure of FADH₂-dependent halogenases has led to the understanding of the reaction mechanism, which involves the formation of hypohalous acids. Unactivated carbon atoms were found to be halogenated by nonheme iron and α-ketoglutarate- and O₂-dependent halogenases. The reaction mechanism of this type of halogenase involves the formation of a substrate radical.²⁶⁴

5.3. Non-heme Fe^II/α-ketoglutarate-dependent halogenases

Radical halogen species can be exploited to allow the halogenation of unactivated aliphatic carbon centres.^252,265 The Fe^II in halogenases is liganded by two histidine residues, α-ketoglutarate and chloride. An interesting aspect of α-ketoglutarate-dependent halogenases is the number of halogen transfers that can be carried out by one active site.

5.4. Methyl halide transferases

In this reaction mechanism, the halide reacts as a nucleophile with an SAM cofactor to displace S-adenosylhomocysteine.²⁶⁶ Whether this reaction is biologically relevant in the formation of methyl halides remains to be determined.²⁶⁷

5.5. Biological iodogenation

Several new enzymes capable of bioiodogenation have been identified. For example, one species of the marine phytoplankton Navicula produces CH₂I₂ 3 and ClCH₂I 36 via an iodoperoxidase (IPO), an enzyme capable of oxidizing iodide but not bromide or chloride.³⁵ A vanadium-dependent IPO has been purified and characterised from the brown alga Saccorhiza polyschides²⁶⁸ and isolated from the brown algae Phyllariopsis brevipes,²⁶⁹ Laminaria saccharina, L. hyperborea, L. ochroleuca, and Pelvetia canaliculata.^270–272 One enzyme specific for the oxidation of iodide and another that could oxidize both iodide and bromide were separated from the sporophytes of the brown alga L. digitata and purified to electrophoretic homogeneity.²⁶¹ Other studies of L. digitata and L. saccharina indicated the presence of IPO.^273–275 The marine microalga Porphyridium purpureum,²⁷⁶ the alga Ascophyllum nodosum,²⁷⁷ and the Arctic green algae Acrosiphonia sonderi and Enteromorpha compressa have high IPO activities.²⁷⁴ Two peroxidase enzymes²⁷⁸ that catalyse the iodination of tyrosine are horseradish peroxidase (HRP) and lactoperoxidase (LPO).²⁷⁹ The latter enzyme is dominant in the iodination of tyrosine in mammals. A recent study analysing gene expression in the brown alga Laminaria digitata shed light on how V-BrPOs and vanadium-dependent iodoperoxidases are up-regulated upon defence elicitation.²⁸⁰ Vanadium-dependent iodoperoxidases in Laminaria digitata, have a novel biochemical function diverging from brown algal bromoperoxidases.²⁸¹

An electrifying development was the utilisation of the halide/peroxidase/hydrogen peroxide chemical system by humans and other mammals to generate active halogen (HOCl and HOBr) in order to destroy microorganisms. Human white blood cells (eosinophils and neutrophils) contain myeloperoxidase, which rapidly forms active halogen in the presence of chloride, bromide, or iodide, and hydrogen peroxide, resulting in the death of bacteria, fungi, and even tumour cells though halogenation reactions.^282–284 Thus, it would appear that biohalogenation is an integral component of our immune system.

Simple halogen substituents frequently afford key structural features that account for the potency and selectivity of natural products including antibiotics and hormones. For example, when a single chlorine atom on the antibiotic vancomycin is replaced by hydrogen, its antibacterial activity decreases by up to 70%. This result highlights how structure underlies the mechanisms of halogenases, the molecular machines designed by nature to incorporate halogens into diverse substrates.

Structural characterisation has provided a basis for a mechanistic understanding of the specificity and chemistry of these enzymes. In particular, the latest crystallographic snapshots of active site architecture and halide binding sites have provided key insights into enzyme catalysis. A thorough mechanistic analysis will elucidate the biological principles that dictate the specificity of these compounds, and the application of these principles to new synthetic techniques will expand the utility of halogenation in small-molecule development.²⁸⁵

6 Conclusion

The few examples of iodine-containing natural products can be grouped into five main structural classes: (1) volatile compounds having very short carbon frameworks; (2) nucleoside derivatives; (3) amino acid (tyrosine, tryptophan, and histidine) derivatives; (4) fatty acid derivatives; and (5) terpenoid derivatives. Of all the iodinated compounds, most of them (159/182) are derived from marine sources (especially marine algae, sponges, and corals).

But what is the basis for the existence of natural organoiodines? Some organoiodines function as iodine recyclers, as pheromones and hormones,¹⁹³ and as chemical defence substances such as antimicrobials,⁵⁸ anti-UVs,⁸⁷ antifeedants,^134,153 and antifoulants.¹³² To the benefit of mankind, many organoiodines display enormous biological activities that may lead to clinical drugs. Indeed, most of these promising compounds are heterocycles.⁸ There are many examples of the beneficial effects of halogen substitution in organic compounds, and excellent reviews on this topic are available.²⁸⁶ An iodinated enediyne antibiotic CLM γ₁^I (161) is two-times as active as its brominated analog CLM γ₁^Br.²⁸⁷ Likewise, iodine-substituted gomisin J derivatives are more effective than the natural product itself as HIV-1 reverse transcriptase inhibitors.²⁸⁸ The geodiamolide D 81 (iodinated) induces microfilament disruptions and is three-times more effective than geodiamolide E (brominated counterpart).¹⁰¹ Geodiamolide H 83 shows in vitro cytotoxicity against a number of human cancer cell lines; surprisingly, geodiamolide I (the brominated counterpart of 83) is completely devoid of activity.¹⁰⁶ Iodovulone II 108 shows significant cytotoxic activity against MOLT-4, DLD-1, and IMR-90 cells, while its brominated and chlorinated counterparts show no activities.¹²⁸ Hicksoanes A–C 130–133 show antifeeding activities against goldfish, and hicksoane C 133, which contains two atoms of iodine, has a higher activity than its counterparts hicksoanes A 131 and B 132, which have one iodine atom. As shown in the literature,²⁸⁹ halogenation increases antifeeding activity. Iodine substitution on aromatic rings greatly stabilises cross-strand aromatic rings in model β-hairpin peptides,²⁹⁰ as demonstrated by the interactions of the thyroid hormones 3,5,3′-triiodothyronine 166 and thyroxine 169 with the thyroid hormone receptor.

Iodogenating enzymes, which catalyse the formation of carbon–iodine bonds during the biosynthesis of iodogenated compounds, have been identified. The biological importance of iodogenating enzymes in bioiodogenation has aroused considerable interest. Meanwhile, using modern biotechnology such as combinatorial biosynthesis and directed evolution, the prospects for generating iodinated derivatives of valuable natural products appear very promising.

Traditional synthetic methods to integrate halogens into complex molecules are often complicated by a lack of specificity and regioselectivity. Nature, however, has developed a variety of elegant mechanisms for halogenating specific substrates with both regio- and stereoselectivity. An improved understanding of the biological routes toward halogenation could lead to the development of novel synthetic methods for the creation of new compounds with enhanced functions. While chemical synthesis of organohalogens can be difficult, the biological production of these compounds occurs under relatively mild conditions and often with a greater degree of specificity. Therefore an understanding of the biosynthesis of halometabolites and the enzymology of carbon–halogen bond formation in particular may provide convenient biotechnological methods for the halogenation of organic compounds.¹²⁴ Biological halogenation can provide this specificity and selectivity. However, the transfer of this technology to large-scale manufacturing and established industrial methods is yet to be realised.

Abbreviations

AML	Acute myeloid leukemia
BPO	Bromoperoxidase
CLM	Calicheamicin
CPO	Chloroperoxidase
DIT	3,5-Diiodotyrosine
DPPA	Diphenyl phosphorazidate
HRP	Horseradish peroxidase
2-IHDA	2-Iodohexadecanal
2-IHDO	2-Iodohexadecan-1-ol
IPO	Iodoperoxidase
LPO	Lactoperoxidase
MIT	Monoiodotyrosine
MIH	Monoiodohistidine
MPO	Myeloperoxidase
PIH	Phosphoriodohistidine
PKSs	Polyketide synthases
T4	Thyroxine
T3	3,5,3′-Triiodothyronine
TPO	Thyroid peroxidase
UV	Ultraviolet
VOIs	Volatile organoiodine compounds

Acknowledgements

This study was supported by the National Basic Research Program of China (973 Program, no. 2011CB915503), the National High Technology Research and Development Program (863 Program, 2012AA092104), the National Natural Science Foundation of China (no. 31270402, 21172230, 20902094, 41176148, and 21002110), the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant no. XDA11030403), and the Guangdong Marine Economic Development and Innovation of Regional Demonstration Project (GD2012-D01-001).

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