Fungal benzene carbaldehydes: occurrence, structural diversity, activities and biosynthesis

Contents

• 1. Introduction

• 2. Occurrence, biological and pharmacological activities
  • 2.1. Simple benzene carbaldehydes
  • 2.2. Alkylated benzene carbaldehydes
  • 2.3. Meroterpenoids
  • 2.4. Benzophenones
  • 2.5. Spirocyclic benzene carbaldehydes
  • 2.6. Miscellaneous benzene carbaldehydes

• 3. Formation of benzene carbaldehydes and their involvement in the biosynthesis of fungal metabolites
  • 3.1. Direct releasing from backbone enzymes
  • 3.2. Modification by tailoring enzymes
  • 3.3. Spontaneous reactions

• 4. Conclusions and future perspectives

• 5. Conflicts of interest

• Acknowledgements

• References

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Abstract

Covering: up to April 2020

Fungal benzene carbaldehydes with salicylaldehydes as predominant representatives carry usually hydroxyl groups, prenyl moieties and alkyl side chains. They are found in both basidiomycetes and ascomycetes as key intermediates or end products of various biosynthetic pathways and exhibit diverse biological and pharmacological activities. The skeletons of the benzene carbaldehydes are usually derived from polyketide pathways catalysed by iterative fungal polyketide synthases. The aldehyde groups are formed by direct PKS releasing, reduction of benzoic acids or oxidation of benzyl alcohols.

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Huomiao Ran

Huomiao Ran received her Bachelor's degree in 2013 from Hainan University and obtained her Master's degree in 2016 from Nanjing Agricultural University. She is currently a PhD student at the Philipps-Universität Marburg. Her research focuses on pathway elucidation of fungal secondary metabolites and characterisation of the involved enzymes under the supervision of Prof. Shu-Ming Li.

Shu-Ming Li

Shu-Ming Li is full professor of Pharmaceutical Biology and Biotechnology at the Philipps-University in Marburg, Germany. He studied pharmacy and received his Bachelor's and Master's degrees from Beijing University, China. Shu-Ming Li was awarded in 1992 his PhD in natural product chemistry by the Rheinische Friedrich-Wilhelms-University in Bonn, Germany. He has served as an associate professor of Pharmaceutical Biology at the Heinrich-Heine-University in Düsseldorf. Li's group is interested in the biosynthesis of secondary metabolites in bacteria and fungi.

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1. Introduction

Benzene carbaldehydes, from the simplest benzaldehyde to structural features in relatively complex molecules, are widely distributed in ascomycetes and also found in basidiomycetes (Table 1 and Fig. 1). Their producers include terrestrial, sponge-associated, marine- and mangrove-derived, plant endophytic and pathogenic fungi. The compounds from this family exhibit diverse biological and pharmacological properties. Cytotoxic, antibacterial and antifungal activities have been detected for a large number of benzene carbaldehydes, followed by anti-inflammatory and antioxidant activities (Table 2 and Fig. 2). Since the first report on flavoglaucin and auroglaucin in the fungus Aspergillus glaucus in 1934,¹ at least 185 structures including 36 alkylated, 59 prenylated (meroterpenoids) and 30 both alkylated and prenylated derivatives have been described in the literature. 146 of them were isolated from ascomycetes, 32 from basidiomycetes and only three from both ascomycetes and basidiomycetes (Fig. 1). Aspergillus strains with 49 metabolites are clearly the dominant producers of benzene carbaldehydes, followed by Pestalotiopsis, Stachybotrys and Penicillium with 14, 13 and 13 metabolites, respectively (Table 1). Reports on the elucidation of their biosynthetic pathways in fungi have accumulated tremendously in recent years, especially on the backbone assembly by iterative polyketide synthases and the formation of the aldehyde group via different routes. The benzene carbaldehydes act as critical intermediates or end products of various biosynthetic pathways. Furthermore, key pathway-specific enzymes have also been characterized. Up to April 2020, more than 140 publications deal with the producers, isolation and structural elucidation, biological activities and applications as well as biosynthetic origin and pathways of benzene carbaldehydes. However, no systematic review on this natural product family is available in the literature. Therefore, we summarize these data in the present review to fill this gap.

Table 1 Taxonomic distribution of fungal benzene carbaldehydes

Fungal genera	Simple derivatives	Alkylated derivatives	Meroterpenoid derivatives	Benzophenone derivatives	Spirocyclic derivatives	Miscellaneous derivatives	Total
Ascomycetes
Aspergillus	6	29	4	1	7	2	49
Pestalotiopsis	—	10	1	—	—	3	14
Stachybotrys	—	—	13	—	—	—	13
Penicillium	4	5		1	3	—	13
Acremonium	—	—	8	—	—	—	8
Fusarium	—	—	7	—	—	—	7
Torrubiella	—	—	7	—	—	—	7
Colletotrichum	—	—	6	—	—	—	6
Paraphaeosphaeria	—	6	—	—	—	—	6
Pyricularia	—	5	—	—	—	1	6
Trichoderma	—	5	—	—	—	—	5
Diaporthe	—	—	—	—	—	4	4
Epicoccum	1	—	—	—	—	2	3
Neonectria	—	—	3	—	—	—	3
Chaetomium	1	2	—	—	—	—	3
Ascochyta	—	1	—	—	1	1	3
Daldinia	—	—	—	2	—	—	2
Hymenoscyphus	—	2	—	—	—	—	2
Lasiodiplodia	—	—	—	—	—	2	2
Pestalotia	—	—	—	2	—	—	2
Pyrenula	—	2	—	—	—	—	2
Nalanthamala	—	—	2	—	—	—	2
Zopfiella	—	2	—	—	—	—	2
Amniculicola	—	1	—	—	—	—	1
Cordyceps	—	1	—	—	—	—	1
Diplodia	1	—	—	—	—	—	1
Gelasinospora	—	1	—	—	—	—	1
Phaeomoniella	1	—	—	—	—	—	1
Phoma	1	—	—	—	—	—	1
Sordaria	—	1	—	—	—	—	1
Seiridium	1	—	—	—	—	—	1
Talaromyces	1	—	—	—	—	—	1
Basidiomycestes
Hericium	—	—	7	—	—	—	7
Heterobasidion	—	—	4	—	—	—	4
Albatrellus	—	—	3	—	—	—	3
Bjerkandera	3	—	—	—	—	—	3
Stereum	—	—	3	—	—	—	3
Bondarzewia	—	1	1	—	—	—	2
Clitocybe	—	—	—	—	—	2	2
Gloeophyllum	2	—	—	—	—	—	2
Peniophora	2	—	—	—	—	—	2
Sarcodontia	—	—	—	—	—	2	2
Tyromyces	2	—	—	—	—	—	2
Russula	—	—	2	—	—	—	2
Agrocybe	1	—	—	—	—	—	1
Fomitiporia	—	—	—	—	—	1	1
Phlebiopsis	1	—	—	—	—	—	1

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Fig. 1 Taxonomic distribution of different fungal benzene carbaldehyde classes.

Table 2 Biological activities of benzene carbaldehydes

Substance class	Biological activities	Compounds
Simple derivatives	Antiviral activity	—
	Antifungal activity	1,^1554,^1569,^1216,^2219,^2521,^2722,^2823 ^28
	Antibacterial activity	1,^1554,^15716,^1719 ^25
	Antioxidant activity	1,^1552,^15816 ^19
	Anti-inflammatory activity	2 ^8 and 3 ^159
	Anti-insect activity	1,^1554,^16020 ^26
	Phytotoxic activity	2 ^3
	Cytotoxic activity	4,^1619,^1310,^1416 ^18
	Enzyme inhibitors, activators and receptors	2,^1623,^16316 ^19
	Anti-nociceptive activity	2 ^8
	Anti-angiogenic activity	2 ^8
	Positive modulation of GABAergic neuromodulation	2 ^158
Alkylated derivatives	Antiviral activity	53,^4979,^4980 ^49
	Antifungal activity	24–29,^3141,^3542,^3546,^4682 ^64
	Antibacterial activity	32,^3541–44,^3546,^4656,^5657,^5660,^55,5662,^5679,^4981,^6482,^6489 ^40
	Antioxidant activity	30,^3256,^53,5457,^53,5458,^5360,^5362,^53,5473,^5375,^5276 ^52
	Anti-inflammatory activity	33,^3634,^3756,^36,56,5757,^56,5760,^5662,^5670,^3771,^3775 ^36,56
	Anti-insect activity	47–50 ^47
	Phytotoxic activity	41,^4449,^16451 ^48
	Cytotoxic activity	28,^3132,^3541–44,^3552,^3554,^5073,^6278,^6379,^4980,^4981,^6482,^6484–86,^6989 ^40
	Enzyme inhibitors, activators and receptors	45,^4556,^5863 ^58
	Immunomodulatory activity	40 ^43
	Antifouling activity	36 ^39
	Antimalarial activity	85,^6986 ^69
Meroterpenoid derivatives	Antiviral activity	119,^87134,^92135,^92137,^93138 ^93
	Antifungal activity	98,^7999,^79112,^79126 ^79
	Antibacterial activity	98,^7999,^79112,^91113,^91126,^91127,^78,79,91131,^91132,^91133,^78136,^91146 ^95
	Antioxidant activity	—
	Anti-inflammatory activity	126,^87127,^87132,^87136 ^87 and 141 ^87
	Anti-insect activity	—
	Phytotoxic activity	90,^7695,^7797,^3898,^7999 ^79
	Cytotoxic activity	97,^3899,^78127,^78129,^92131–134,^92136 ^92
	Enzyme inhibitors, activators and receptors	98,^7899,^78114,^85127,^78134,^78133 ^78
	Neuritogenic activity	106–111,^83,84116 ^86
Benzophenone	Antibacterial activity	153 ^100
	Enzyme inhibitors, activators and receptors	154 ^101
	Anti-inflammatory activity	149 ^97 and 150 ^97
	Cytotoxic activity	153 ^100
Spirocyclic derivatives	Antioxidant activity	155,^104157–160 ^105
	Cytotoxic activity	160,^106162–164 ^107
Miscellaneous derivatives	Antiviral activity	169 ^49 and 171 ^34
	Antifungal activity	165,^108166,^108179,^113180,^113182,^21183 ^21
	Antibacterial activity	167,^109182,^21183 ^21
	Anti-inflammatory activity	171,^34175–178 ^112
	Anti-insect activity	168 ^47
	Phytotoxic activity	168 ^48 and 170 ^4
	Cytotoxic activity	179,^113180,^113181 ^114

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Fig. 2 Bioactivity distribution of fungal benzene carbaldehydes.

2. Occurrence, biological and pharmacological activities

2.1. Simple benzene carbaldehydes

In this review, merely slightly modified like hydroxylated, halogenated, methylated and/or ethylated benzaldehydes are classified as simple benzene carbaldehydes accounting for 23 members (Fig. 3). Despite their simple structures, these compounds also exhibit broad biological and pharmacological activities such as antifungal (eight compounds), antibacterial and cytotoxic activities (Table 2). Hydroxylated and methoxylated simple benzaldehydes are also natural products of plant origin.² Eleven simple fungal benzene carbaldehydes were isolated from ascomycetes and eight from basidiomycetes (Fig. 1). The main producers are members of the genera Aspergillus, Penicillium and Bjerkandera (Table 1).

Fig. 3 Structures of simple aldehydes 1–23.

The simplest member of this family is benzaldehyde 1 without other additional substituents. It is one of the most industrial used chemicals and can be found as a preservative in cosmetics and food as well as in personal care and select car detailing products. Its 4-hydroxylated derivative 2 was identified in plants² and a wide range of fungi such as the plant pathogens Botryosphaeria obtusa³ and Phaeoacremonium chlamydosporum,⁴ the endophytic fungi Aspergillus sp. YL-6 ⁵ and Penicillium thiomii⁶ as well as the brown-rot fungi Tyromyces palustris and Gloeophyllum trabeum.⁷ In addition to phytotoxicity,³2 also possesses anti-angiogenic,⁸ anti-inflammatory⁸ and anti-nociceptive⁸ activities.

Compounds 3–8 are hydroxylated, methoxylated or chlorinated benzaldehyde derivatives. The dihydroxylated benzaldehyde, protocatechuic aldehyde 3, was identified in the aforementioned brown-rot basidiomycetes T. palustris and G. trabeum.⁷ 2,5-Dihydroxylated benzaldehyde 4 and 6-formylsalicylic acid 15 were metabolites of Penicillium patulum.⁹ Biosynthetic study on the white-rot fungus Bjerkandera adusta led to the identification of compounds 1, 5, 7 and 8.¹⁰ Another congener syringaldehyde 6 was obtained from the plant endophytic fungus Phoma sp. YN02-P-3.¹¹

To understand the preventive mechanism of the root rot biocontrol fungus Phlebiopsis gigantea, its chemical constituents were investigated, leading to identification of o-orsellinaldehyde 9 with inhibitory activity against the pathogenic fungi Heterobasidion occidentale and Fusarium oxysporum, and the saprotrophic fungus Penicillium canescens¹² as well as cytotoxic activity against the human carcinoma cell line Hep 3B and the lung fibroblast cell line MRC-5.¹³ The highly decorated and cytotoxic 2,4-dihydroxy-3,5,6-trimethylbenzaldehyde 10 was obtained from the deep sea-derived fungus Aspergillus sydowi.¹⁴o-Orsellinaldehyde derivatives 11–14 were identified as biosynthetic precursors in genetically manipulated fungal strains.^15,16 The dialdehyde flavipin 16 from Aspergillus,¹⁷Chaetomium^18,19 and Epicoccum^20,21 species was well documented for its antibacterial,¹⁷ antifungal,²² antiproliferative¹⁸ and antioxidant¹⁹ activities as well as inhibitory effect on α-glucosidase, even more potential than the clinically used drug acarbose.¹⁹

Benzene carbaldehydes 17 and 18 carrying ethyl groups were isolated from a marine mangrove endophytic fungus.²³ Gladiolic acid 19 from Penicillium gladioli^24,25 and cyclopaldic acid 20 from Seiridium cupressi²⁶ are hemiacetal lactones and differ from each other just in a hydroxyl group. Chemical investigation on a co-culture broth extract of two marine mangrove pathogenic fungi led to the isolation of the hydroxylated benzaldehyde 21 with both ethyl ether and ester bonds.²⁷ The two antifungal benzene carbaldehydes 22 and 23 with O-prenyl moieties have been isolated from Peniophora polygonia and were demonstrated to strongly inhibit the growth of the aspen decay fungus Phellinus tremulae.²⁸

2.2. Alkylated benzene carbaldehydes

Alkylated derivatives with 66 structures, i.e. more than one-third of the known benzene carbaldehydes, constitute one of the largest classes. In comparison to the simple benzene carbaldehydes, members from this class contain an additional unmodified or modified alkyl chain, which is attached in most cases (94%) to the ortho-position of the formyl group. With the exception for 35 from the basidiomycete Bondarzewia montana, all these fungal products are salicylaldehyde derivatives from ascomycetes (Fig. 1). Their main producers belong to the genera Aspergillus and Pestalotiopsis with 29 and 10 metabolites, respectively (Table 1 and Fig. 1). In addition to their main activities like antibacterial, antifungal and cytotoxic activities, most group members also exhibit anti-inflammatory and antioxidant effects, which were observed only for few members from other classes (Table 2).

Biosynthetically, alkylated benzene carbaldehydes are derivatives of aromatic polyketides with different numbers of malonyl-CoA as extension units.^29,30 Their alkyl chains differ consequently from each other by numbers of C₂ units. Thus, the members of this class can be conveniently subdivided according to the length of the side chains, i.e. C₃-, C₅-, C₇-, C₉- and C₁₁-alkylated benzene carbaldehydes.

2.2.1. C₃-alkylated benzene carbaldehydes. 12 benzaldehyde derivatives 24–35 bear modified C₃-alkyl chains (Fig. 4). Six of them, sporulosaldeins A–F 24–29, were identified in the endophytic fungus Paraphaeosphaeria sp. F03.³¹24–26 carry an acetonyl group at C6 with different oxidative levels on the C3 substituents. It was proposed that cyclisation between the acetal group on the benzene ring and the ketal group of the side chain in the dialdehyde 26 leads to the formation of two chromene aldehydes 27 and 28 as well as one chromane aldehyde 29. The structurally similar redoxcitrinin 30 with two additional methyl groups at C5 and C1′, was obtained from a marine-derived Penicillium strain and acts as a precursor in citrinin biosynthesis.^32,33 Investigation on the secondary metabolites of two Pestalotiopsis species resulted in the isolation of the salicylaldehyde derivative 31 carrying a propanic acid residue and its methyl ester 32, respectively.^34,35 The two prenylated chromene-5-carbaldehydes, 33 from the marine-derived fungi Eurotium cristatum³⁶ and 34 from Aspergillus sp. SF-5976,³⁷ display significant anti-inflammatory effect.

Fig. 4 Structures of C₃-alkylated aldehydes 24–35.

The only basidiomycete-derived metabolite in this group is the dihydroxylated aldehyde 35 from the rare white-rot fungus Bondarzewia montana.³⁸ An alkenyl substitution at the meta-position to the formyl group differs clearly from the ortho-position of other members 24–34 from ascomycetes.

2.2.2. C₅-alkylated benzene carbaldehydes. Compounds 36–46 are C₅-alkylated metabolites with a formyl group at the ortho-position (Fig. 5). Two 2,4-dihydroxy-3-methylbenzaldehydes 36 and 37 with a modified C₅-alkyl chain were obtained from the deep sea-derived fungus Aspergillus versicolor SCSIO 41502.³⁹ Chemical investigation of another marine fungus Zopfiella marina BCC 18240 resulted in the isolation of salicylaldehyde derivative 38 with a pentan-diene carboxylic acid residue.⁴⁰ Its derivative 39 with a 1,3-pentan-diene moiety has also been isolated as a key biosynthetic intermediate of sordarial.⁴¹ A set of oxidation products of 39 with 3′,4′-dihydroxyl group (40–44) were identified in several ascomycetes. Sordariol 40 with an immunosuppressive activity was isolated from Sordariol macrospora,⁴²Gelasinospora heterospora⁴³ and G. longispora⁴³ and then identified in the same biosynthetic pathway with 39.⁴¹ Its isomer, agropyrenol 41, was isolated as a phytotoxin from the plant pathogen Ascochyta agropyrina var. nana.⁴⁴ Its absolute configuration was determined as 3′R and 4′R by the Mosher ester method. Three additional 3′R,4′R-dihydroxylated polyketide analogues with adjunct prenyl unit or saturated alkyl chain, vaccinol G 42, heterocornols A 43 and F 44, were obtained from the marine sponge-associated fungus Pestalotiopsis heterocornis.³⁵ Bioactivity tests with 41–44 showed their cytotoxic and antibacterial potentials against human cancer cell lines and Gram-positive bacteria, respectively. The benzofuran aldehyde 45 with a saturated C₅-alkyl residue was isolated from the entomopathogen Cordyceps annullata.⁴⁵ It exhibits potent agonistic activity towards the cannabinoid receptors CB1 and CB2. Moreover, the antifungal and antibacterial metabolite anguillosporal 46 with an ethyl and a branched C₆-alkyl chain was isolated from the freshwater fungus Anguillospora (also known as Amniculicola) longissima CS-869-1A.⁴⁶

Fig. 5 Structures of C₅-alkylated aldehydes 36–46.

2.2.3. C₇-alkylated benzene carbaldehydes. This benzene carbaldehyde class includes more than 30 structures (47–78) and shares a salicylaldehyde scaffold mostly with a modified C₇-alkyl chains. The majority (56–78) bears an additional dimethylallyl (C₅) moiety or structural feature derived thereof. Various modifications on the alkyl chains are found for derivatives without a prenyl moiety (47–55, Fig. 6).

Fig. 6 Structures of C₇-alkylated aldehydes 47–55.

Four salicylaldehydes with a dihydroxyheptyl moiety 47–50 and their oxidised dicarbonyl derivative 51 were obtained from the rice pathogen Magnaporthe grisea.^47,48 Two similar metabolites, heterocornol B 52 and pestalol D 53, were isolated from Pestalotiopsis heterocornis and Pestalotiopsis sp. AcBC2, respectively.^35,49 Ginsenocin 54 with a substituted 2H-pyran ring resulted from cyclisation on the C₇-alkylatd chain was identified as an anti-tumour metabolite in the endophytic fungus Penicillium melinii Yuan-25.⁵⁰ It shows potent cytotoxicity with IC₅₀ values ranging from 0.49 to 5.03 μg mL⁻¹ to six cell lines including MKN45, LOVO, A549, MDA-MB-435, HepG2 and HL-60. Pyrenulafuran 55, a 2H-benzofuran derivative, was isolated from the cultured lichen mycobionts of Pyrenula sp.⁵¹

The majority of the C₇-alkylated benzene carbaldehydes are 3,6-dihydroxybenzaldehydes with a dimethylallyl moiety at C3 (56–78, Fig. 7). These compounds belong to the groups of flavoglaucins and auroglaucins and were obtained from different Aspergillus/Eurotium species including several mangrove-derived strains. One of the notable features is the presence of a complete saturated (56) or unsaturated (57–63) C₇-alkyl chains at C6 of the benzene ring. This set of compounds show broad bioactivities e.g. antioxidant,^52–54 antibacterial^55,56 and anti-inflammatory activities^56,57 as well as binding affinity to human opioid or cannabinoid receptors.⁵⁸

Fig. 7 Structures of C₇-alkylated and at C3 prenylated aldehydes 56–78.

In the cases of 64 and 65, the alkyl residues are further modified by hydroxylation. Compound 64 with a 3′,6′-dihydroxyhepta-1′,4′-dienyl moiety was identified in the fruit-associated fungus Aspergillus amstelodami.⁵⁵ The C3′-hydroxylated analogue 65 was isolated from the gorgonian-derived fungus Eurotium sp.⁵⁹

The alkyl chain has cyclised with the C5-hydroxyl group to a 2H-benzopyran in 66–69, to a dihydrobenzopyran in 70–73, and to a benzofuran ring in 74–76, respectively. A spontaneous intramolecular cyclisation of 65 to an enantiomer pair 66/67 with a 2H-chromene skeleton was observed when it was dissolved in CDCl₃.⁶⁰ Their derivatives 68 and 69 with an additional C4′ hydroxylated group were identified in a gorgonian-derived fungus Eurotium sp. as well.⁶⁰ Two chromane-5-carbaldehyde isomers, 70 and 71, with opposite configurations of the C4′ hydroxyl group, were characterized from the Antarctic marine-derived fungus Aspergillus sp. SF-5976 and proven to have anti-inflammatory activity.³⁷ Investigation on the chemical constituents of the mangrove endophytic fungus Eurotium rubrum led to the identification of compounds 72–76 and eurotirumin 77 with a cyclopentabenzopyran ring system.⁶¹ Among them, chaetopyranin 73 exhibits cytotoxic activity toward several tumour cell lines,⁶² while compounds 75 and 76 show antioxidant activity.⁵² The anti-proliferative prenylated benzene carbaldehyde 78 with a rare endo peroxide bond was isolated from the mangrove-derived fungus Aspergillus sp. AV-2.⁶³

Two rare examples of C5-prenylated and C₇-alkylated salicylaldehydes, pestalols B 79 and C 80 (Fig. 8), were obtained from the mangrove endophytic fungus Pestalotiopsis sp. AcBC2 and show stronger anti-influenza virus activity than the non-prenylated precursor 53.⁴⁹ The dimethylallyl moiety in 79 was further modified by adjunction of two hydroxyl groups in 80.

Fig. 8 Structures of C₇-alkylated at C5 prenylated aldehydes 79 and 80.

2.2.4. C₉- and C₁₁-alkylated benzene carbaldehydes. Only three C₉- and six C₁₁-alkylated benzene carbaldehydes are until now reported (Fig. 9). All of the known members from these classes are salicylaldehyde derivatives from ascomycetes. The two antibiotics albiducins B 81 and A 82 were isolated from the ash tree-associated saprotrophic fungus Hymenoscyphus albidus.⁶⁴ Hydroxylation at C5, 82versus81, enhances the antimicrobial and cytotoxic activities. Another C₉-alkylated salicylaldehyde 83 with modifications of the alkyl chain by one keto and two methyl groups was found to be one of the common secondary metabolites in Penicillium species and as a key precursor in the asperfuranone biosynthetic pathway (see Section 3.1.2 for details).^65–68

Fig. 9 Structures of C₉- and C₁₁-alkylated aldehydes 71–89.

Two reports described the identification of C₁₁-alkylated benzene carbaldehydes. Bioassay-guided constituent investigation of the wood-decay fungus, Hypocrea (syn. Trichoderma) sp. BCC 14122, resulted in the isolation of the C₁₁-alkylated salicylaldehyde 84, gentisaldehyde 85, its isomer 86 with a cis-configured double bond and two benzofuran derivatives 87 and 88.⁶⁹85 with an additional phenolic hydroxyl group shows stronger cytotoxicity against tumour cell lines KB, BC and NCI-H187 than its non-hydroxylated analogue 84. In 2018, a C7′-hydroxylated congener 89 was obtained from the marine-derived fungus Zopfiella marina. It shows antibacterial activities against Mycobacterium tuberculosis and Bacillus cereus.⁴⁰

In summary, alkylated benzene carbaldehydes with 66 members contribute not only significantly to the structural diversity, but also to the broad biological activities. They exhibit all the described activities for benzene carbaldehydes with antibacterial, antioxidant, anti-inflammatory and cytotoxic activities as their remarkable features (Table 2).

2.3. Meroterpenoids

Meroterpenoids are hybrid natural products of terpene and other pathways.⁷⁰ They generally contain a start molecule from the polyketide, alkaloid or shikimate pathway, which is connected with a prenyl moiety of various chain lengths. The attachment of the prenyl moiety to different core structures is usually catalysed by prenyltransferases.⁷¹ Several related reviews on meroterpenoids have been published previously.^70–74

Since the first report on benzaldehyde-containing meroterpenoids by Ellestad et al. in 1969,⁷⁵ at least 86 metabolites from this class have been isolated from fungal strains. These include structures carrying a dimethylallyl moiety already discussed above, e.g. the simple aldehydes 22 and 23 (2.1), the C₃-alkylated benzene carbaldehydes 34 and 35 (2.2.1) and the C₇-alkylated derivatives 56–80 (2.2.3).

Therefore, meroterpenoids belong to one of the major benzene carbaldehyde classes and contribute significantly to the structural diversity of these natural products. More than 30% of the mentioned products were isolated from basidiomycetes and 66% from ascomycetes (Fig. 1). The majority of the fungal meroterpenoids have a C₅, C₁₀ or C₁₅ terpenoid chain, which is usually connected to meta-position of the formyl group and ortho-position of at least one hydroxyl group or structural feature derived thereof.

2.3.1. Meroterpenoids derived from C₅- and C₁₀-prenylated precursors. Meroterpenoids 90–111 are benzaldehyde derivatives with a C₅- or C₁₀-terpenoid chain (Fig. 10). Fomannoxin 90, a benzene carbaldehyde from the shikimate pathway with a fused isoprenyl dihydrofuran, was suggested to be involved in the pathogenicity of the root rotting fungus Heterobasidion annosum sensu lato.⁷⁶ Compounds 91–93 were isolated and characterized as key intermediates in the fomannoxin biosynthesis.⁷⁶ It was proposed that the prenylated precursor 93 was oxidatively cyclised to benzofuran 92 and subsequently reduced to 91 and 90. Grapevine disease-guided study led to the isolation of three rare acetylenic benzene carbaldehydes 94–96 from the plant pathogenic strain Stereum hirsutum.⁷⁷ Sterehirsutinal 95 exhibits a high phytotoxicity and inhibits 100% of the plant callus growth at 500 μM. Another dimethylallyl-carrying benzene carbaldehyde, montadial A 97, was isolated from the polypore Bondarzewia montana and shows strong cytotoxic activities against tumour cells L1210 with MIC of 10 μg mL⁻¹ and HL60 with MIC of 5 μg mL⁻¹.³⁸

Fig. 10 Structures of meroterpenoids 90–111.

Representatives of the geranylated (C₁₀) meroterpenoids are colletorin B 98 and its chlorinated derivative colletochlorin B 99. They were obtained from several fungi like Nectria galligena,⁷⁸Fusarium sp.⁷⁹ and Cephalosporium diospyri.⁸⁰98 and 99 display moderate herbicidal, antifungal and antibacterial activities against Chlorella fusca, Ustilago violacea and Fusarium oxysporum as well as Bacillus megaterium, respectively.⁷⁹ They are also regarded as potential drugs for the treatment of Alzheimer's disease due to the inhibitory activities towards β-glucuronidase and acetylcholinesterase (AChE).⁷⁸ Five structurally-related metabolites with a modified geranyl residue (100–104) were isolated from Colletotrichum nicotianae. Colletochlorins A 101 and C 103 are chlorinated derivatives of colletorins A 100 and C 102, respectively.⁸¹ Phytotoxicity tests against Ambrosia artemisifolia and Sonchus arvensis with 100 and 101 as well as their analogues indicated the importance of the stereochemistry at the hydroxylated geranyl chain and the enhancing effect of chlorination.⁸² Six fatty acid esters hericenones C–H 106–111 bearing a 6′-carbonyl geranyl moiety, were isolated, together with their proposed precursor 105, from the edible mushroom Hericium erinaceum.^83,84109–111 can be considered as cyclisation products of 106–108, respectively.

2.3.2. Meroterpenoids derived from C₁₅-prenylated precursors. Benzene carbaldehydes carrying an unmodified or modified farnesyl (C₁₅) moiety with 35 members build the largest group within meroterpenoids (Fig. 11). Compound 112, a C3-farneylated o-orsellinaldehyde 9, can be considered as prototype of these metabolites.

Fig. 11 Structures of meroterpenoids 112–146.

During a screening programme for interacting agents with mammalian CNS receptors, three farnesylated benzene carbaldehydes, LL-Z1272 β 112, ovinal 114 and scutigeral 115, were isolated from an extract of the edible mushroom Albatrellus ovinus by bioassay-guided fractionation of the crude extracts.⁸⁵ The antibiotic LL-Z1272 α 113, a chlorinated derivative of 112, was isolated from the ascomycete Fusarium sp.⁷⁵

Three benzene carbaldehydes 116–118 bear a hydroxylated farnesyl moiety. Parvisporin 116 was isolated from the culture broth of Stachybotrys parvispora F4708 and demonstrated to have a weak neuritogenic activity.⁸⁶ Its analogues chlorocylindrocarpol 117 and cylindrocarpol 118 were later obtained from the sponge-derived fungus Acremonium sp.⁸⁷ Recently, stachybonoids A–C 119–121, with a benzopyran ring after cyclisation of the farnesyl chain with the salicylic hydroxyl group, were isolated from the crinoid-derived fungus Stachybotrys chartarum 952.⁸⁸ Compound 119 exhibits an inhibitory activity against the replication of dengue virus.

Asperugin B 122 and A 123, two phthalaldehydes, carrying an intact O-farnesyl moiety were identified as metabolites of a mutated strain of Aspergillus rugulosus.⁸⁹ Their derivatives 124 and 125 were obtained from a genetically engineered A. nidulans strain as biosynthetic intermediates of aspernidine A 186 (see 3.1.1. for details).⁹⁰

Structurally, 126–134 are meroterpenoids with a substituted cyclohexone ring by cyclisation within a modified farnesyl chain. To counter antibiotic-resistance bacteria, Mogi et al. screened hundreds of natural products and identified a unique set of active natural products LL-Z1272 β 112, ε 126, δ 127, γ 132, ζ 133, which were isolated originally from Fusarium sp.^75,91 Chlorination determines the biological activities. The non-chlorinated derivatives 112 and 126 are active against cytochrome bd, while the chlorinated derivatives 127, 132 and 133 are potent inhibitors of cytochrome bo and trypanosome alternative oxidase.⁹¹126 shows very strong antifungal activity against Eurotium repens.⁷⁹ Compounds 127 and 133 display moderate inhibitory activity towards the enzymes AChE and β-glucuronidase as well as toxicity towards human lung fibroblasts.⁷⁸

Chemical investigation of the bioactive metabolites in the pathogenic fungus Verticillium hemipterigenum and the sponge-derived fungus Acremonium sp. led to the isolation of deacetylchloronectrin 128,^87,92 the glycoside vertihemipterin A 129,⁹² cylindrol B 130,⁸⁷ 8′-hydroxyascochlorin 131,⁹² compounds 132 and 133 ^87,92 as well as ilicicolin E 134.⁹² Compounds 129 and 131–134 possess remarkable cytotoxicity to several cell lines such as KB, BC-1, NCI-H187 and vero with IC₅₀ values ranging from 0.36 to 19 μg mL⁻¹.⁹² Two meroterpenoids with a tetrahydrofuran ring at the modified farnesyl chain, ascofuranol 135 and ascofuranone 136, were obtained also from the fungi Verticillium hemipterigenum and Acremonium sp.^87,92135 has antiviral potential and cytotoxicity,⁹¹ while 136 shows significant anti-inflammatory activity.⁸⁷

Eight phenylspirodrimane derivatives 137–144 were identified in the fungus Stachybotrys chartarum.^88,93 In their structures, a decahydronaphthalene ring system and a fused spiroketal feature are formed within the farnesyl chain. Stachybonoid A 141 exhibits moderate anti-inflammatory activity by inhibiting the production of nitric oxide in lipopolysaccharide-activated RAW264.7 cells with an IC₅₀ value of 27.2 μM.⁸⁸ Stachybotrysins A 137 and B 138 display antiviral activity.⁹³ Kampanol C 145, a pentacyclic meroterpenoid, was obtained from Stachybotrys kampalensis Hansf.⁹⁴ Dicarbaldehyde backbone makes it extremely unstable in CD₂Cl₂, but reasonable stable in acetone. Pestalotiopen A 146 was isolated from the Chinese mangrove-endophytic fungus Pestalotiopsis sp. as an ether of altiloxin A derived from a farnesyl moiety and a highly substituted benzene carbaldehyde (cyclopaldic acid). It shows moderate antibacterial activity against Enterococcus faecalis.⁹⁵ The rare acetylenic spirodioxolactone ochroleucin A₁147 was obtained from the mushrooms Russula ochroleuca and R. viscida after treatment with aqueous KOH. The labile chromogen undergoes easily rearrangement into the isomeric dilactone ochroleucin A₂148 (Fig. 12).⁹⁶

Fig. 12 Structures of meroterpenoids 147 and 148.

Taking together, meroterpenoid benzene carbaldehydes contain usually C₅-, C₁₀-, C₁₅-prenyl moiety or structures derived thereof. Antiviral, antifungal, antibacterial, phytotoxic and cytotoxic activities were determined for many members of this substance class. Furthermore, six compounds act as enzyme inhibitors, activators or receptors (Table 2).

2.4. Benzophenones

Natural products of this class share a diarylketone skeleton, which can be further modified by hydroxylation, methylation, methoxylation, halogenation or prenylation (Fig. 13). Six such substances were identified in fungi. They are usually oxidative ring opening products of anthrones (see Section 3.2.3 for details).

Fig. 13 Structures of benzophenones 149–154.

Daldinals A 149 and B 150, benzophenones with two bilateral methoxyl groups, differ from each other by just a hydroxyl or methoxyl group and were isolated from the fungus Daldinia childiae with anti-inflammatory activity.⁹⁷ The diversity of this group is increased by prenylation on the benzene ring, like the metabolites 151–154. Arugosins I 151 and H 152 with a dimethylallyl moiety at C2 are key intermediates in the shamixanthone biosynthesis and were isolated from the endophytic fungi Penicillum sp. JP-1 and Emericella nidulans var. acristata, respectively.^98,99 Co-cultivation of a marine-derived fungus Pestalotia sp. with a unicellular antibiotic-resistant bacterium led to the identification of a chlorinated benzophenone derivative, pestalone 153.¹⁰⁰ It shows antibiotic activity against resistant bacteria and moderate cytotoxicity. Its demethylated analogue 154 has been reported for Chrysosporium sp. with inhibitory activity against testosterone-5α-reductase.¹⁰¹

2.5. Spirocyclic benzene carbaldehydes

10 spirocyclic benzene carbaldehydes have been found in different Aspergillus, Eurotium and Penicillum species (Fig. 14). The spirocyclic derivatives 155–160 are presumably head-to-tail [4 + 2] Diels–Alder reaction products between the diene feature of a prenylated C₇-alkyl benzene carbaldehyde and an enone group of a prenylated diketopiperazine derived from cyclo-Trp-Ala. 155 and 156 have an olefinic bond at C1′ and 156 carries an additional dimethylallyl chain at C6.

Fig. 14 Structures of spirocyclic benzene carbaldehydes 155–164.

Cryptoechinuline D 155 and 7-isopentenylcryptoechinuline D 156 were first reported in 1976 from Aspergillus amstelodami and isolated later from the mangrove endophytic fungus Eurotium rubrum.^102–104 Eurotinoids A–C 157–159 and dihydrocryptoechinulin D 160 were recently identified as enantiomeric pairs in the marine-derived fungus Eurotium sp. SCSIO F452.¹⁰⁵ Compounds 157 and 158 represent two “meta”, while 159 and 160 “ortho” structures, regarding the relative position of the aryl-alkyl substitute to the spiro centre. With the exception for 156, all of the spirocyclic compounds exhibit antioxidant activity.¹⁰⁵ Compound 160 also displays cytotoxic activity against two tumour cell lines.¹⁰⁶

Four spiroketal benzene carbaldehydes have been until now reported. Cristaldehyde B 161, a spiro dichromene derivative, was isolated from the crinoid-associated fungus Eurotium cristatum.³⁶ Peniciketals A–C 162–164 with two spiroketal features were isolated from the saline soil-derived fungus Penicillium raistrichii and show a selective cytotoxity against HL-60 cell line.¹⁰⁷

2.6. Miscellaneous benzene carbaldehydes

More than 20 fungal benzene carbaldehydes with naphthalene, chromanone or other skeletons cannot be grouped in the classes described above and are listed in this section (Fig. 15). They are usually events of strong rearrangements.

Fig. 15 Structures of miscellaneous aldehydes 165–185.

Bioactivity-guided fractionation led to isolation of two volatile benzaldehyde derivatives 165 and 166 from an extract of the basidiomycete Sarcodontia crosea (syn. S. setosa).¹⁰⁸ They exhibit weak activity against several phytopathogenic fungi including Leptosphaeria maculans and Botrytis cinerea. A biphenyl carbaldehyde 167 with antibacterial activity was obtained from the endophytic fungus Pestalotiopsis zonata.¹⁰⁹

Two C₆-alkylated salicylaldehydes, pyricuol 168 and pestalol E 169, were obtained from Magnaporthe grisea and Pestalotiopsis sp., respectively.^47,49,110 Pyricuol 168 shows a strong nematicidal activity and killed 94.5% of Caenorhabditis elegans at 400 ppm over 24 h. Obviously, the hydroxymethyl group at C3′ in 168 enhances the nematicidal activity, compared to its C₇-alkylated analogues 47–50.⁴⁷ Compound 169 carrying a sulfonic group at C4′ shows inhibitory activity against influenza A and swine flu viruses.

Agropyrenal 170 and vaccinal A 171, two naphthalene carbaldehydes, were isolated from the phytopathogen Ascochyta agropyrina var. nana and the endogenic fungus Pestalotiopsis vaccinii, respectively.^34,44 Compound 171 displays anti-enterovirus and anti-inflammatory activities. Three 4/2-chromanone carbaldehydes 172–174 were obtained from the basidiomycetes Fomitiporia punctata and Clitocybe illudens.^4,111 Four unusual 2,3-dihydro-1H-indene benzaldehydes bearing a 1,4-benzodioxan moiety, diaporindenes A–D 175–178, were identified in the endophytic fungus Diaporthe sp. SYSU-HQ3.¹¹² They possess significant anti-inflammatory activity against nitric oxide production.

Depsidones 179–181 share a characteristic seven-member ring formed by ester and ether bonds between two benzene rings. They were isolated from the endophyte Botryosphaeria rhodina and the endophytic fungus BCC 8616.^113,114 Botryorhodines A 179 and B 180 show cytotoxic and antifungal activities, while compound 181 exhibits only cytotoxic activity.

Secondary metabolite investigation of the endophytic fungus Epicoccum sp. resulted in the isolation of a tetracyclic aromatic benzene carbaldehyde 182 and a 2-phenylbenzofuran carbaldehyde 183, which show potent antibacterial and significant anti-phytopathogenic activities.²¹ It was proposed that epicoccolides A 182 and B 183 are presumably formed from two molecules of flavipin 16via an unsymmetrical benzoin condensation, which undergoes further modification.²¹ Two benzene carbaldehydes were identified in the genetically manipulated strains. Compound 184 with a diphenylmethane skeleton, probably derived from o-osellinaldehyde 9, was isolated from a non-reducing polyketide (NR-PKS) heterologous expression host.¹¹⁵ Moreover, deletion of the down-regulator in Aspergillus nidulans led to the discovery of compound 185, a hemiacetal ether from two 3-methylosellinaldehyde 11 molecules.¹¹⁶

3. Formation of benzene carbaldehydes and their involvement in the biosynthesis of fungal metabolites

In the last years, significant progress has been achieved for the understanding of the formation of fungal benzene carbaldehydes. While some of them are formed by direct releasing from non-reducing polyketide synthases (NR-PKSs) with a terminal reductive domain or from highly reducing PKSs (HR-PKSs) by involvement of additional enzymes, other derivatives are formed via modification by tailoring enzymes, e.g. oxidoreductases and NRPS-like enzymes.

3.1. Direct releasing from backbone enzymes

Fungal benzene carbaldehydes are often generated by NR-PKSs with acetyl-CoA as the start and malonyl-CoA as the extender unit. The start unit initiates precursor for polyketide synthesis, while the extender units elongate the polyketide backbone to completion.¹¹⁷ The number of extender units determines the length of the polyketide size. A set of grouped catalytic domains control the incorporation of changed or unchanged C₂-units into the polyketide backbone. A minimal fungal PKS consists of a ketosynthase (KS), an acyltransferase (AT), and an acyl carrier protein (ACP). Most PKSs also contain accessory domains, such as β-ketoacyl reductase (KR), dehydratase (DH), enoyl reductase (ER), product template (PT), C-methyltransferase (CMeT) and terminal reductase (R).^29,118

3.1.1. Releasing from non-reducing polyketide synthases. The R domain in NR-PKSs is often used as chain releasing mechanism to form an aldehyde by NAD(P)H-dependent reduction. In the case of aspernidine A 186 biosynthesis, the responsible pkf cluster was identified in the genome of Aspergillus nidulans.⁹⁰ Gene deletion experiments confirmed the function of the involved genes. The simple o-osellinaldehyde 9 is released from the NR-PKS PkfA by its C-terminal R domain (Fig. 16) and further converted to aspernidine D 124 with a farnesyl moiety by the UbiA-like prenyltransferase PkfE. Additional tailoring enzymes catalyse hydroxylation, reduction and methylation steps to form the final meroterpenoid 186.

Fig. 16 Genetic organisation of the pkf gene cluster in A. nidulans and the simplified postulated biosynthetic pathway of aspernidine A 186 (modified after Yaegashi et al.⁹⁰). SAT: starter unit, ACP transacylase, CYP: cytochrome P450, SDR: short-chain dehydrogenase, PT: prenyltransferase, DH: dehydrogenase, NR-PKS: non-reducing polyketide synthase.

Similarly, 3-methylosellinaldehyde 11 and redoxcitrinin 30 were detected as the direct releasing products of the NR-PKSs TropA and CitS with R domains (Fig. 17 and 18). In comparison to PkfA, TropA (also known as Tspks1) and CitS (also known as PksCT) contain an additional CMeT domain for methylation during the polyketide chain elongation leading to the formation of the dimethylated benzene carbaldehydes 11 and 30. Heterologous expression of the intronless tropA in the fungal host Aspergillus oryzae led to the identification of the benzaldehyde 11.¹⁶ Gene deletion and heterologous expression experiments demonstrated stipitatic acid 187 as the final product of the trop cluster (Fig. 17). Cox and He reported the reconstruction of the biosynthetic gene cluster (BGC) for citrinin 190 from Monascus ruber in A. oryzae.³³ The iterative NR-PKS gene citS codes for a redoxcitrinin synthase. Expression of citS alone led to low production of the ketoaldehyde 30 evidently released from the PKS by its terminal reductive R domain. Coexpression of citA coding for a serine hydrolase with citS resulted in a much higher titre of 30. This indicates that cooperation of CitA with the R domain of CitS serves as the release machinery in the native strain (Fig. 18).

Fig. 17 Genetic organisation of the trop gene cluster in T. stipitatus and the simplified postulated biosynthetic pathway of stipitatic acid 187 (modified after Davison et al.¹⁶). SAT: starter unit, ACP transacylase, DC: decarboxylase, CYP: cytochrome P450, MO: monooxygenase. Hyd: hydrolase, Tra: transport, DH: dehydrogenase, DO: dioxygenase, TF: transcription factor, NR-PKS: non-reducing polyketide synthase.

Fig. 18 Genetic organisation of the cit gene cluster in M. ruber and the simplified biosynthetic pathway of citrinin 190 (modified after He and Cox³³). SAT: starter unit, ACP transacylase, OR: oxidoreductase, Reg: regulator, SH: serine hydrolase, Tra: transporter, NR-PKS non-reducing polyketide synthase.

3.1.2. Releasing from dual polyketide synthases. The majority of fungal PKS-derived metabolites uses only one PKS for assembling the skeleton as exemplified above. However, there are also numerous biosynthetic pathways, in which two PKSs contribute to the complex fungal products.^29,119 It was reported that the BGC of asperfuranone 192 in A. terreus contains one HR-PKS gene ateafoG and one NR-PKS gene ateafoE. Co-expression of the two PKS genes under control of a strong promoter each resulted in the formation of a shunt product 191 and the C₉-alkylated salicylaldehyde 83.¹²⁰ The HR-PKS AteafoG was demonstrated to synthesize a dimethylated C₈-chain start moiety, which is transferred to the NR-PKS AteafoE for further extension with the facilitation of AteafoC (Fig. 19).

Fig. 19 Genetic organisation of the ateafo gene cluster in A. terreus and the simplified postulated biosynthetic pathway of asperfuranone 192 (modified after Chiang et al.¹²⁰). SAT: starter unit, ACP transacylase, Reg: regulator, DH: dehydrogenasem Tra: transporter, OR: oxidoreductase, MO: monooxygenase, Oxy: oxygenase, NR-PKS: non-reducing polyketide synthase, HR-PKS: highly reducing polyketide synthase.

Yi Tang and coworkers reported a convergent model of dual PKS-containing BGC from A. niger by activation of the silent gene cluster.¹²¹ The two PKSs can function independently in parallel to form precursors which can be ultimately connected via accessory enzymes. The NR-PKS AzaA released a C₅-alkylated salicylaldehyde 193 by its R domain, which is further reduced to the intermediate 36. The precursor 194 with a pyran ring was then afforded by involvement of the monooxygenase AzaH. In parallel, 2′,4′-dimethylhexanoly CoA 195 as another precursor is synthesized by the HR-PKS AzaB and is proposed to be transferred to the C4-hydroxyl group of 194 to form the key intermediate 196. Further modifications by several tailoring enzymes led to the end product azanigerone C 197 (Fig. 20).

Fig. 20 Genetic organisation of the aza gene cluster in A. niger and the simplified postulated biosynthetic pathway of azanigerone 197 (modified after Zabala et al.¹²¹). SAT: starter unit, ACP transacylase, AT: acyltransferase, KR: ketoreductase, ACL: acyl:CoA ligase, Oxy: oxygenase, MO: monooxygenase, CYP: cytochrome P450, Reg: regulator, DH: dehydrogenase, Tra: transporter, NR-PKS: non-reducing polyketide synthase, HR-PKS: highly reducing polyketide synthase.

3.1.3. Releasing from highly reducing polyketide synthases by involvement of additional oxidoreductases. All the aforementioned fungal benzene carbaldehyde-forming enzymes belong to NR-PKS.²⁹ Recently, two examples of HR-PKSs for the involvement in the benzaldehyde biosynthesis were reported for vir and fog clusters.^122,123 Investigation on vir BGC revealed the benzaldehyde releasing mechanism from the HR-PKS with involvement of associated tailoring enzymes.¹²² Heterologous expression of virA alone led merely to an aliphatic C₁₈ product virensol C 198, which exists mostly as a pair of hemiacetals. Two short-chain reductases (SDRs) VirB and VirD catalyse dehydrogenation at C7 and C3 to β-ketone aldehyde 199. The salicylaldehyde 200 is formed after intramolecular aldol condensation between C2 and C7 and dehydration likely catalysed by VirD. The final pathway product trichoxide 201 was afforded after decoration by different tailoring enzymes (Fig. 21). The third known HR-PKS for the formation of aromatic compounds is FogA, which releases a salicyl alcohol derivative in the presence of additional oxidoreductases (see 3.2.1. for details).

Fig. 21 Genetic organisation of the vir gene cluster in T. virens and the simplified postulated biosynthetic pathway of trichoxide 202 (modified after Liu et al.¹²²). SDR: short chain reductase, Cupin: cupin-domain containing protein, CYP: cytochrome P450, OR: oxidoreductase, HR-PKS: highly reducing polyketide synthase.

3.2. Modification by tailoring enzymes

3.2.1. Alcohol oxidation by oxidoreductases. We recently identified a HR-PKS-containing fog cluster from Aspergillus ruber and proved its responsibility for the biosynthesis of the C₇-alkylated salicylaldehyde flavoglaucin 56 and congeners (Fig. 22).¹²³ Heterologous expression of four genes including fogA coding for a HR-PKS, two for SDRs FogB and FogD as well as one for the cupin-domain-containing protein FogC led to the accumulation of the alkylated salicyl alcohols 202–207, which is a prerequisite for consecutive hydroxylation and prenylation to form alcohol derivatives 208–213. Feeding experiment confirmed that the FAD-binding oxidoreductase FogF oxidises these alcohols to the final aldehyde products.

Fig. 22 Genetic organisation of the fog gene cluster in A. ruber and the simplified postulated biosynthetic pathway of flavoglaucin 56 and its congeners (modified after Nies et al.¹²³). SDR: short chain reductase, Cupin: cupin-domain containing protein, CYP: cytochrome P450, OR: oxidoreductase, PT: prenyltransferase, TF: transcription factor, HR-PKS: highly reducing polyketide synthase.

In the citrinin biosynthetic pathway, the unstable dialdehyde intermediate 189 was formed via alcohol oxidation catalysed by the nicotinamide-dependent oxidoreductase CitC (also known as Mrl7) (Fig. 18).³³ Furthermore, in the biosynthesis of aspernidine A 186, the P450 PkfB introduces a hydroxyl group on the methyl moiety to yield asoernidine E 125, which is proposed to be further oxidised by the choline dehydrogenase PkfF to a reactive dialdehyde 123 (Fig. 16).

3.2.2. Acid reduction by NRPS-like enzymes. Zhao and coworkers reported that an aryl-acid produced by a NR-PKS can be activated by a nonribosomal peptide synthase (NRPS)-like protein with an A-ACP-R domain structure and reduced to a benzene carbaldehyde.¹⁵ By cloning and heterologous expression of both cryptic NR-PKS and NRPS-like genes from Aspergillus terreus in Saccharomyces cerevisiae, they detected 5-methylorsellinic acid 214 and 5-methylosellinaldehyde 10 as the accumulated products. The purified ATEG_03630 protein can convert 214 to 10in vitro. Therefore, they proposed that the aryl-acid 214 is activated by the adenylation (A) domain of ATEG_03630 and transferred to its ACP domain. Reduction of the thioester by the R domain led to the releasing of the aldehyde product 10 (Fig. 23). Further investigation of this NRPS-like protein showed that the adenylation (A) domain acts as the first “gate-keeper” to ensure the activation and thioester formation of the correct monomer onto the ACP.¹²⁴ Abe and coworkers identified later a NRPS-like enzyme StbB, which can catalyse the reduction of a farnesylated benzoic acid agrifolic acid (also known as ilicicolinic acid B) 216 to the aldehyde LL-Z1272β (also known as ilicicolin B) 112 (Fig. 24).¹²⁵

Fig. 23 Genetic organisation of the ATEG gene cluster in A. terrus and the proposed biosynthetic pathway of 5-methylosellinaldehyde 10 (modified after Wang et al.¹⁵).

Fig. 24 Genetic organisation of the stb gene cluster in Stachybotrys bisbyi and the proposed biosynthetic pathway of LL-Z1272β 112 (modified after Li et al.¹²⁵).

Investigation on asc cluster in Acremonium egyptiacum shows the aforementioned reduction of 216 to 112 (3.2.2) can also be catalysed by the NRPS-like enzyme AscB, which shares a 59% identity to StbB. This was observed in the biosynthesis of ascochlorin 132 and ascofuranone 136 in Acremonium egyptiacum (Fig. 25).¹²⁶ Both pathways share the same key precursor ilicicolin A epoxide 217. Cyclisation of 218 catalysed by the terpene cyclase AscF and further dehydrogenation by AscG result in the final product of the ascochlorin pathway. Hydroxylation of 217 by AscH, cyclisation by AscI and oxidation by AscJ complete the ascofuranone pathway. All genes for the ascochlorin biosynthesis are located within the asc-1 cluster, which also contains responsible genes for the common precursors. Additional genes required for the formation of ascofuranone, i.e. ascHIJ were found on the second locus asc-2 (Fig. 25).

Fig. 25 Genetic organisation of the asc gene cluster in A. egyptiacum and the simplified biosynthetic pathways of ascochlorin 132 and ascofuranone 136 (modified after Araki et al.¹²⁶). TF: transcription factor, PT: prenyltransferase, OR: oxidoreductase, Hal: halogenase, CYP: cytochrome P450, TPC: terpene cyclase, DH: dehydrogenase, PKS: polyketide synthase.

3.2.3. Reductive or oxidative cleavage of ring systems. A FAD-binding oxidoreductase CicC was proposed to catalyse a ring opening reaction, leading to the formation of the putative aldehyde intermediate 221 in the postulated cichorine 222 biosynthetic pathway (Fig. 26) in Aspergillus nidulans.¹²⁷ Analysis of the extracts from deletion strains indicated that the PKS PkbA assembled the precursor 3-methylorsellinic acid 219, which undergoes hydroxylation, methylation and lactonization to the lactone intermediate 220. However, no experimental data are till now available to support the definite CicC function and the conversion of the lactone 220 to the final lactam 222 also remains speculative.

Fig. 26 Genetic organisation of the cic gene cluster in A. nidulans and the simplified postulated biosynthetic pathway of cichorine 222 (modified after Sanchez et al.¹²⁷). Tra: transporter, OR: oxidoreductase, Reg: regulator, MT: methyltransferase, CYP: cytochrome P450, PKS: polyketide synthase.

Oxidative cleavage of chrysophanol anthrone 223 was observed in the formation of the benzophenone aldehydes 152 and 224 (Scheme 1). Subsequent intramolecular hemiacetal formation or reduction and ether formation give the dibenzooxepinones 225–228.^98,128,129 It is unclear whether enzymes are involved in the transformation.

Scheme 1 Proposed biosynthesis of dibenzooxepinones 225–228.

3.3. Spontaneous reactions

In our previous study, we observed the spontaneous oxidoreduction of the benzoquinone alcohol 229, leading to the formation of the salicylaldehyde 56, the benzyl alcohol 230 and the benzoquinone aldehyde 231.¹²³ A proposed mechanism is given in Scheme 2. Two 229 molecules can act as both oxidant and reductant to form the hydroquinone alcohol 230 and the instable benzoquinone aldehyde intermediate 231, which reacts with a third 229 molecule to form the aldehyde 56. In addition, a set of dimethyl sulfoxide (DMSO) induced oxidations of benzyl alcohol to benzaldehyde were also described in the literature.¹³⁰

Scheme 2 Proposed mechanism of benzoquinone alcohol 229 conversion to salicylaldehyde 56 (modified after Nies et al.¹²³).

4. Conclusions and future perspectives

In this review, we summarized the structural features, distribution, biological activities and applications as well as the origin and biosynthesis of benzene carbaldehydes from fungi. The topic compounds are mainly produced by ascomycetes (79%) and occasionally by basidiomycetes (17%) (Fig. 1). Approx. 51% of the ascomycetes-originated benzene carbaldehydes are from the genera of Aspergillus, Stachybotrys, Penicillium and Pestalotiopsis. For basidiomycetes, the genus of the edible mushroom Hericium contributes to approximate a fifth of benzene carbaldehydes (Table 1). The described biological activities are grouped into eleven categories with cytotoxic, antibacterial and antifungal activities as the top three (Fig. 2).

The backbones of the benzene carbaldehydes are usually originated from polyketides assembled by iterative fungal polyketide synthases, although other biosynthetic routes like shikimate or alkaloid pathways also serve as additional possibilities. The key aldehyde functional group can be formed by direct release from the polyketide chain, reduction of carboxylic acids or oxidation of benzyl alcohols. Other procedures such as oxidative ring opening also deliver aldehyde products. The simplest member of these natural products, i.e. benzaldehyde, can be decorated by hydroxylation, alkylation including methylation and ethylation, halogenation, prenylation at the benzene ring. Further modifications include oxidation, reduction and cyclisation. The majority of the compounds mentioned in this review belongs to derivatives of salicylaldehyde from the PKS pathway. Alkylated derivatives with different chain length (C₃, C₅, C₇, C₉ or C₁₁) at the ortho-position to the aldehyde group and meroterpenoids containing structural features derived from C₅, C₁₀ or C₁₅ prenyl moiety constitute the two large classes of benzene carbaldehydes. Benzene carbaldehydes are accumulated as pathway final products or serve as intermediate for more complex natural products.

As aforementioned, a number of fungal benzene carbaldehydes with interesting biological activities have been discovered in the past decades. However, the studies on structure–activity relationship have been few reported. More information on interactions of benzene carbaldehydes with biological targets will enhance the application potential of these compounds. Furthermore, it became a challenge to get new bioactive natural products under conventional laboratory culture conditions. Therefore, screening microorganisms from less explored or untapped sources, e.g. fungi from extreme environments^131–134 like saltern,¹³⁵ sulfur-rich hydrothermal vents,¹³⁶ in deep-sea segments,¹³⁷ hot springs¹³⁸ and mine area¹³⁹ becomes more important for bioactive metabolite finding. Symbiotic systems between fungi and bacteria, plants, insect, animals or invertebrate are also less studied promising sources of secondary metabolites.¹⁴⁰ Metabolite dereplication, e.g. by library-based LC-MS analysis^141,142 and comparative mass spectrometry-based metabolomics¹⁴³ have been successfully used in the past and will also play an important role in the future to accelerate novel metabolite discovery. Furthermore, the OSMAC (One Strain – Many Compounds) approach^144–146 by cultivation under different conditions and co-cultivation with other organisms has also been developed and successfully applied. However, the most putative genes and gene clusters for natural product biosynthesis still remain silent.¹⁴⁷ It can be therefore expected that reactivation of such genetic potentials by transcriptional regulator manipulation, promoter engineering and heterologous expression would deliver a large number of structures hidden the silent biosynthetic machinery.^148–150 Different new strategies have been published recently for the identification of fungal metabolites and their gene clusters, especially of large clusters. One of such approaches is the fungal artificial chromosomes and metabolic scoring (FAC-MS) strategy, which allows scientists to identify metabolites from complex mixtures after heterologous expression of clusters.¹⁵¹ Metagenomics of uncultivable microbes and reconstruction of biosynthetic pathways provide other possibilities to get new metabolites.^152–154 Elucidation of biosynthetic pathways and characterisation of key enzymes would provide another way to create designed molecules by synthetic biology.

5. Conflicts of interest

There are no conflicts to declare.

6. Acknowledgements

The researches carried out in the Li's group were funded in part by the Deutsche Forschungsgemeinschaft (DFG) Li844/11-1. H. Ran (201606850085) is a scholarship recipient from the China Scholarship Council.

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