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DOI: 10.1039/C0MD00241K (Review Article) Med. Chem. Commun., 2011, 2, 229-245

Natural products targeting telomere maintenance

Jack Li-Yang Chen a, Jonathan Sperry a, Nancy Y. Ip b and Margaret A. Brimble *a
aDepartment of Chemistry, University of Auckland, 23 Symonds Street, Auckland, New Zealand. E-mail: m.brimble@auckland.ac.nz
bDepartment of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China

Received 30th November 2010 , Accepted 28th January 2011

First published on 28th February 2011

Abstract

Telomeres are repetitive sequences of DNA found at the ends of chromosomes which determine and restrict the number of replications a cell can undertake. In the majority of cancer cells, telomerase has been found to maintain the length of telomeres, conferring cell immortality and prevention of cell senescence. With the ready availability of assays to detect telomerase activity, numerous telomerase inhibitors have been discovered from a variety of natural sources. This article gives an outline of these natural product-based telomerase inhibitors and their inspiration for analogue design.

1. Introduction

1.1 The importance of telomeres and telomerase

Telomerase 1–6 is an enzyme crucial for the immortality of tumour cells, and has recently emerged as a promising target for the treatment of cancer.7Telomerase activity has been found in 80–85% of tumour cell lines8 in essentially all types of cancer, while its activity in the majority of normal cells is non-existent.9 Its recognition as a plausible target for the treatment of cancer 20 years ago has stimulated a tremendous amount of ongoing research in this area and the field is still rapidly growing.7,10–13 Compared with traditional anti-cancer agents which interact with targets such as tubulin and topoisomerases I and II,14telomere maintenance represents an exciting and novel strategy for which broader spectrum anti-cancer activity is expected, together with less undesired cytotoxicity. There are currently no pharmaceuticals on the market that target telomeres or telomerase, although a number of promising compounds are currently undergoing clinical trials (e.g.GRN163L).7

Telomeres are DNA-protein complexes that cap the ends of human chromosomes and are essential for the preservation of chromosome integrity.15,16 These structures consist of an overhang of non-coding DNA, present to allow for loss of genetic material following successive DNA replications. This loss of telomere length is due to the inability of DNA polymerase to fully replicate all the material up to the end of duplex DNA. This ‘end-replication problem’ means that normal somatic cells can only replicate a finite number of times, after which the telomeres become critically shortened and the cells cease to divide.17,18 In cancer cells, telomere length is maintained by the enzyme telomerase, allowing the cells to bypass this replicative crisis and achieve cell immortality.19 The prevalence of telomerase activity in all types of cancer, combined with its non-expression in the majority of normal cells, infers that selective telomerase inhibitors have the potential to be relatively safe, broad spectrum anti-cancer agents.

1.2 Possible biological targets

Greater understanding into the function of telomeres and telomerase over the last 15 years has led to the emergence of numerous possible targets for telomerase inhibition.8,12 Conceptually, the simplest is direct inhibition of the enzyme telomerase. Within the telomerase complex, there are two major components, an RNA template20 termed human telomerase RNA (hTR) and an RNA-dependent DNA polymerase known as human telomerase reverse transcriptase (hTERT). The role of hTR is to capture the end of a telomere by complementary interactions, while hTERT acts as the catalytic domain of telomerase and utilises the RNA template to extend telomere length. One can thus envisage either inhibition of hTR binding or direct inhibition of hTERT. One disadvantage of this approach is the time lag between drug administration and clinical response.19 The need to wait for telomeres to shorten to a critical length following successive replications means sustained treatment with this type of inhibitor would probably be required, increasing the risk of side-effects. Therefore, there is a belief that these direct telomerase inhibitors will likely be used in combination therapy.

More recently, the discovery that telomere-disrupting agents can also inhibit telomerase activity has led to intensive research into G-quadruplex stabilisers.21–24 One major advantage of these telomere disrupting agents is that rapid onset of cell death is possible.8 These telomere-disruptors interact with the TTAGGG repeats of telomeres and stabilise these structures into higher-order structures called G-quadruplexes. The formation of these structures prevents the binding of telomerase on the ends of telomeres and also hinders the ability of the telomeres to ‘cap’ and protect the ends of chromosomes. This loss of chromosomal integrity is recognised by the cells and triggers entry of the cell into senescence or apoptosis. Shelterin proteins such as TRF1, TRF2 and Pot1 are also required to obtain the correct quaternary structure of telomeres,25,26 and thus also present potential biological targets for anti-cancer activity.

Other ways to inhibit telomerase include blocking the expression of hTR or hTERT by targeting their mRNA, or indirect inhibition by targeting proteins which affect their correct assembly or protein folding.8 One example of this indirect inhibition of telomerase activity is the targeting of the c-myc gene, itself able to form G-quadruplexes and known to be a positive regulator of hTERT expression.27 Immunotherapy and gene-based therapies are also being investigated for their potential as future telomerase-based anti-cancer agents.7

1.3 Detection of telomerase activity

By far the majority of reports use an in vitro PCR-based method known as the telomere repeat amplification protocol (TRAP) to measure telomerase activity.28 In this assay, cell extracts with positive telomerase activity (from a specific cell line) are incubated together with a DNA primer sequence (substrate) and the resulting products are amplified by PCR (using Taq polymerase) before being analysed by electrophoresis and visualised. While IC50 values for telomerase inhibition as determined by the TRAP assay are used throughout this review, any comparisons made between different research groups must be done with caution due to the variation in protocols employed, which include the use of different cell lines and substrate primers. There is also evidence that the IC50 values determined for several G-quadruplex ligands have been overestimated due to the inhibition of Taq polymerase used in the PCR step.29 The development of the TRAP assay, including its numerous variants30 and alternatives are summarised in a recent review by Fajkus.31

1.4 Sources of inhibitors of telomerase and telomere function

The discovery of novel telomerase inhibitors have come from in silico screening, structure-based design and the screening of natural products.8 While both in silico screening32 and structure-based design21,33 have had their success stories, natural products34–36 continue to be a rich source of telomerase inhibitors. This review will discuss inhibitors of telomerase that have been derived from natural sources, as well as their inspiration for analogue design. The importance of telomerase in conferring cell immortality and prevention of cell senescence has triggered an immense amount of research in this area, with novel telomerase inhibitors continually being discovered. These inhibitors show large variations in their chemical structure, and have been isolated from various terrestrial and marine sources.

2. Telomerase inhibitors from microbial sources

Inhibitors of telomerase have been isolated from a variety of bacterial and fungal sources. The most well-known of these compounds is telomestatin (vide infra), renowned for its nanomolar activity and for bringing to light G-quadruplex structures as a valid target for telomerase inhibition. While most of these compounds have only been isolated in the last two decades, the rubromycin family of antibiotics (vide infra) have been known since the 1950s. However, their anti-telomerase activity was only demonstrated recently following the discovery of telomerase as a biological target, and the development of suitable assays for determining telomerase activity.

2.1 Rubromycins and purpuromycin

The rubromycins38 (Fig. 1) were first isolated as red pigments from Streptomyces collinus by Brockmann and Renneberg in the 1950s and 1960s.39–41 These compounds feature aromatic COMPOUND LINKS

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Download mol file of compoundnaphthoquinone and isocoumarin ring systems, and in the case of β- and γ-rubromycin, the structural motifs are fused by a (S)-configured 5,6-spiroacetal.42 In the 1970s, an array of closely related pigments were isolated which included the purpuromycins43,44 from Actinoplanes ianthinogenes; griseorhodins A, C from Streptomyces californicus45,46 and griseorhodin G from S. griseus.47
The rubromycin family and their telomerase inhibition (IC50 values from the TRAP assay).37
Fig. 1 The rubromycin family and their telomerase inhibition (IC50 values from the TRAP assay).37

In 2000, Hayashi et al.37 demonstrated the potent anti-telomerase activity of these compounds with β-, γ-rubromycin and purpuromycin all displaying IC50 values of ∼3 μM in a modified TRAP assay. In contrast, α-rubromycin possesses substantially decreased inhibitory activity (IC50 > 200 μM), indicating the essential role of the spiroketal moiety as the key pharmacophore for telomerase inhibition. The closely related griseorhodins A and C were also shown to exhibit comparable inhibition with IC50 values of 6–12 μM. While the roles of the quinone moieties have not been investigated as yet, the fact that neither α-rubromycin nor COMPOUND LINKS

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Download mol file of compoundnaphthoquinone exhibited telomerase activity at >200 μM suggests that the presence of the quinone moiety in itself is not sufficient to produce anti-telomerase activity. The rubromycins have been shown to bind to telomerase competitively with respect to the substrate primer, which could represent binding to the hTR and/or TERT subunits.37

Despite the interesting biological activity and structural novelty of the rubromycins, the first total synthesis of this family was only achieved in 2007, that being the synthesis of (±)-γ-rubromycin by Kita48 using two aromatic Pummerer-type reactions. A concise formal synthesis was achieved shortly after by Brimble49 using a Sonogashira reaction and acid-mediated spiroketalisation.

2.2 UCS1025A

UCS1025A and B (Fig. 2) were first isolated as novel antibiotics by Yamashita et al. in 2000 from the fungus Acremonium sp.50,51 UCS1025A exhibited antiproliferative activity against a number of cancer cell lines including epidermoid carcinoma (A431, IC50 = 55 μM) and breast cancer (MCF-7, IC50 = 21 μM), while UCS1025B exhibited no activity at 100 μM. UCS1025A was recently demonstrated to be a potent inhibitor of telomerase with an IC50 of 1.3 μM in a TRAP assay52 although the exact mechanism of action is as of yet undetermined.
UCS1025A and UCS1025B.
Fig. 2 UCS1025A and UCS1025B.

Elegant total syntheses of UCS1025A have been achieved by Danishefsky53 and Hoye54 while other synthetic studies have been performed by Christmann55,56 and Snider.57

2.3 Chrolactomycin

Chrolactomycin (Fig. 3) is a novel anti-tumour antibiotic isolated by Yamashita and co-workers from Streptomyces sp. 569N-3.58 Its antiproliferative activity was later attributed to its inhibition of telomerase by use of a novel assay based on a yeast strain possessing shortened telomeres59 and it was shown to possess an IC50 of 0.5 μM in the TRAP assay. Nakai and co-workers believe that the exo-methylene group is essential for its biological activity, and may act as a Michael acceptor to form a covalent bond with the sulfhydryl group of a cysteine residue near the active site of telomerase, thereby causing irreversible inhibition of the enzyme.59 No total synthesis has been reported to date.
Chrolactomycin.
Fig. 3 Chrolactomycin.

2.4 Diazaphilonic acid

Diazaphilonic acid is an azaphilone with telomerase inhibitory activity, isolated from the fungus Talaromyces flavus in 1999 by Tabata (Fig. 4).60 It features a pyranoquinonoid core and is a dimer of COMPOUND LINKS

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Download mol file of compoundmitorubrinic acid, a metabolite isolated from the fungus Penicillum rubrum.61Diazaphilonic acid completely inhibited telomerase activity at 50 μM (TRAP assay) and also inhibited DNA PCR amplification with an IC50 of 2.6 μg mL−1. Diazaphilonic acid has not been synthesised as yet, whereas COMPOUND LINKS

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Download mol file of compoundmitorubrin has been synthesised by Whally62 and Porco63 and COMPOUND LINKS

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Download mol file of compoundmitorubrinic acid by Pettus.64
The related azaphilones diazaphilonic acid, mitorubrin and mitorubrinic acid.
Fig. 4 The related azaphilones diazaphilonic acid, COMPOUND LINKS

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2.5 Alterperylenol

Alterperylenol is an orange-red antifungal pigment first isolated in 1983 by Okuno65 from the plant pathogen Alternaria sp. (Fig. 5). In 1998, Togashi and co-workers showed this fungal metabolite to selectively inhibit telomerase activity with an IC50 of 30 μM in the TRAP assay, with no inhibition of the homologous viral reverse transcriptase.66 The same assay on the structurally related altertoxin I exhibited no activity against telomerase even at 1 mM, clearly demonstrating the importance of the enone for biological activity. There has been not reported total synthesis to date.
Alterperylenol and altertoxin I.
Fig. 5 Alterperylenol and altertoxin I.

2.6 CRM646-A

The novel phenol glucuronides CRM646-A and -B were first isolated as heparinase inhibitors from the soil dwelling fungus Acremonium sp. MT70646 (Fig. 6).67CRM646-A was later shown to exhibit telomerase activity in a dose-dependent manner from 3.2 μM68 (TRAP assay) without inhibiting PCR amplification. CRM646-A was also found to inhibit the homologous viral reverse transcriptase in a similar concentration range, suggesting that it may act as a general inhibitor of RNA-dependent DNA polymerases. The only synthetic study reported is the total synthesis of CRM646-A and -B by Yu and co-workers.69
CRM646-A and -B.
Fig. 6 CRM646-A and -B.

2.7 Thielavin B

Thielavin A and B were first isolated in 1981 by Takahashi and co-workers from the fungus Thielavia terricola70 and their structures shown to be structurally related to polyphenolic depsides (Fig. 7).71 In 2001, thielavin B was shown using TRAP assays to be a moderate inhibitor of telomerase with inhibition beginning at 32 μM, without affecting DNA polymerase.72 The authors suggest that the phenolic hydroxyl groups, similar to that found in other telomerase inhibitors, such as epigallocatechin gallate and alterperylenol, may be important for its biological activity. No total synthesis has been reported to date.
Thielavins A and B.
Fig. 7 Thielavins A and B.

2.8 Telomestatin

Telomestatin is one of the most potent telomerase inhibitors known to date, and has been extensively studied due to its novel molecular architecture and remarkable selectivity for G-quadruplex structures (Fig. 8).33,73 Its isolation by Shin-ya74 in 2001 from Streptomyces analatus initiated the acceptance of G-quadruplex structures as a valid biological target for telomerase inhibition. Telomestatin was initially reported to possess an IC50 of 5 nM using a TRAP assay, although this is now believed to be an overestimation due to the interference of G-quadruplex stabilisers with the PCR step of the assay.29 It has been found that the IC50 value can vary greatly from 58 nM to 600 nM, depending on the primer sequence used during the assay.30 Recently, Takahashi75 has reported that the unnatural (S)-stereoisomer of telomestatin exhibits a four-fold increase in activity against telomerase.
Telomestatin and its enantiomer.75
Fig. 8 Telomestatin and its enantiomer.75

Telomestatin possesses an unprecedented macrocyclic array containing seven oxazole rings and one COMPOUND LINKS

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Download mol file of compoundthiazoline, which has been shown to overlap efficiently with G-quadruplex structures. Studies in vitro have demonstrated that telomestatin binds to the human telomeric sequence d[T2AG3]4 with 2[thin space (1/6-em)]:[thin space (1/6-em)]1 stoichiometry,76 and with high selectivity for intramolecular over intermolecular binding and for G-quadruplex structures over duplex DNA.77,78 These telomeric G-quadruplexes are poor substrates for telomerase and bring about the steady shortening of the telomeres. In addition to the strong binding to telomeric overhangs, telomestatin was also shown to induce the dissociation of TRF279 and POT1,80,81telomere-specific binding proteins involved in the capping of telomeres. This ability to facilitate telomere uncapping results in a loss of protection for the telomere ends and triggers more rapid induction of apoptosis than a simple telomerase inhibitor. There is therefore conjecture for telomestatin to be classified as a ‘telomere disrupting agent’ rather than a ‘telomerase inhibitor.’ Numerous studies against a number of cancer cells lines have demonstrated telomestatin to be an effective anti-proliferative agent against multiple myeloma,82 leukemia,83 neuroblastoma,84 human medulloblastoma and atypical teratoid/rhabdoid85cell lines in vitro and in a xenograph mouse model in vivo.86

The first total synthesis of telomestatin was achieved by Takahashi et al. in 2006,87 which also served to assign the absolute stereochemistry of the thiazoline as (R). Other synthetic studies towards telomestatin have been performed by Shin,88 Vedejs,89 Chattopadhyay,90 and Pattenden.91 The potent activity of telomestatin has also inspired several groups to synthesise other macrocyclic analogues in the search for a more potent and/or more accessible telomerase inhibitor.

Examples include the cyclo[n]pyrroles (Fig. 9) synthesised by Bowers et al. as expanded porphyrin analogues to telomestatin, where the macrocycle containing six pyrroles was found to exhibit the strongest binding with the human telomere repeat sequence d(T2AG3)4.92 Nagasawa's work on macrocyclic polyoxazoles included the synthesis of C2-symmetric hexaoxazoles with amine and guanidine side chains.93 These macrocycles possess the central planar pharmacophore for π–π stacking with the guanine tetrads and also the cationic side chains to facilitate binding to the G-quadruplex structure via interaction with the phosphate groups. Potent binding of both these derivatives was found using TRAP assays (IC50 ≈ 20 nM) in addition to strong inhibition of the telomerase positive HeLa cells. Nagasawa subsequently synthesised a macrocyclic heptaoxazole which was demonstrated to bind selectively to single stranded over double stranded DNA and exhibited cytotoxicty towards HeLa cells with an IC50 of 2.2 μM.94 In response to previous reports of the 2[thin space (1/6-em)]:[thin space (1/6-em)]1 stoichiometry of telomestatin binding G-quadruplexes, Nagasawa also synthesised a series of hexaoxazole dimers with varying linker lengths, although the resulting affinity for telomeric DNA was found to be comparable to that of the hexaoxazole monomers.95


Telomestatin inspired analogues. The most potent member of each respective class is shown.
Fig. 9 Telomestatin inspired analogues. The most potent member of each respective class is shown.

Two hexaoxazoles HXDV and HXLV-AC synthesised by Pilch (Fig. 9) also displayed 2[thin space (1/6-em)]:[thin space (1/6-em)]1 ligand–quadruplex stoichiometry, thus providing further insight into their mode of binding.96 Both HXDV and HXLV-AC exhibited sub-μM activity against RPMI 8402 human lymphoblast and KB3-1 human oral carcinoma cells. Rice has also reported the synthesis of rapidly-accessible macrocyclic pyridyl polyoxazoles, with one exhibiting an IC50 of 0.18 μM against RPMI 8402 cells and possessing in vivo activity against a human breast cancer xenograft in mice.97 The potent activity of telomestatin has also provided impetus for the synthesis of polyoxazole analogues by Marson98 and Chattopadhyay99,100 although no biological data was disclosed.

Recently, Moody and co-workers described an efficient formal synthesis of telomestatin using rhodium carbene methodology to construct the oxazole rings.101 The authors demonstrated the involvement of monovalent cations in the binding of several telomestatin precursors to terminal G-quadruplexes.

3. Telomerase inhibitors from plant sources

The majority of known telomerase inhibitors are derived from plant sources. Many of these compounds, such as COMPOUND LINKS

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Download mol file of compoundgambogic acid and berberine, have been used for centuries in traditional Chinese or ayuvedial medicine. Others are derived from well known foods and ingested by many on a daily basis, such as epigallocatechin gallate from green tea, COMPOUND LINKS

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Download mol file of compoundallicin from garlic and flavonoids from a variety of fruits and vegetables. These plant derived inhibitors of telomerase also encompass a wide range of molecular structures, including alkaloids, xanthones, sesquiterpene lactones, terpenoids and various polyphenols. While these plant metabolites possess anti-telomerase activity, it is important to note that several of these compounds are also known to interact with a range of other biological targets, and thus their cytotoxic activity may be due to factors in addition to their anti-telomerase activity.

3.1 Cephalotaxus alkaloids

The Cephalotaxusalkaloids are a family of potent antileukemia alkaloids isolated from the powdered leaves and stems of the Asian coniferous evergreen trees Cephalotaxus sp.102,103 Cephalotaxine is the parent member of this family and is the most abundant alkaloid constituent of these extracts, although it has been found to be biologically inactive (Fig. 10).104 The complex C-3 ester derivatives homoharringtonine (HHT), deoxyharringtonine, homodeoxyharringtonine and anhydroharringtonine have been found to exhibit potent activity against a number of cancer cell lines including leukemia, lymphoma and epidermoid carcinoma cells.105,106 Recently, more than 20 novel Cephalotaxusalkaloids have been isolated by various groups.107
The Cephalotaxusalkaloids with IC50 values against human leukemia HL-60 cells.108
Fig. 10 The Cephalotaxusalkaloids with IC50 values against human leukemia HL-60 cells.108

Clinical trials were first conducted in China in the 1970s on total Cephalotaxusalkaloids and showed promising results against patients with leukemia.109 This prompted the initiation of phase I110 clinical trials with HHT in the United States followed by a number of phase II trials in patients with acute, promyelocytic and chronic myelogenous leukemia as well as solid tumours and myelodysplastic syndrome.111HHT was chosen as the initial lead due to its in vivo activity and ready supply. However, poor toxicity profiles and multidrug resistance (MDR)112 have hampered further development of these alkaloids, though these compounds are still considered promising for the treatment of hematologic malignancies.

The Cephalotaxusalkaloids have been shown to exhibit their biological activity via inhibition of protein synthesis,113 however, there is also recent evidence that these C3-ester derivatives of cephalotaxine may be exhibiting apoptotic activity by inhibition of telomerase activity. Anti-telomerase activity has been reported with COMPOUND LINKS

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Download mol file of compoundharringtonine114 and also with HHT, which has been suggested to induce apoptosisviareduction of telomerase activity115 and down-regulation of hTERT transcription.116

The chemical synthesis of the Cephalotaxusalkaloids has received a tremendous amount of attention since the 1970s.107,117 While numerous syntheses of cephalotaxine has been achieved, successful elaboration to the biologically active C-3 ester derivatives have been limited due to steric problems encountered with the hindered coupling partners. Numerous medicinal chemistry studies have been conducted on the Cephalotaxusalkaloids and this has been extensively summarised in a review by Lee et al.107 Recently, studies by Gin et al. of a variety of analogues against HL-60 tumour cells suggest that the 2′-hydroxyl group on the acyl chain is required for in vivo activity.108 The authors also demonstrated a higher susceptibility of HHT towards MDR (resistance index 125), possibly due to its relatively low lipophilicity (clogP = 0.95). This opens up the potential for overcoming multi-drug resistance by design and modification of the acyl chain of the Cephalotaxusalkaloids.

3.2 Berberine

Berberine (Fig. 11) is an isoquinoline alkaloid, isolated from the roots and stem-bark of many plants, including Berberis vulgaris chinensis (Coptis or goldenthread).118 It has a decorated history in Chinese, Indian and Middle Eastern traditional medicine for a wide range of indications, from use as an anti-inflammatory to the treatment of diarrhoea. Recent studies have demonstrated that berberine possesses a wide range of biological properties, including anti-microbial, anti-diabetic, anti-inflammatory and anti-depressant activity.119
Berberine, 9-O- and C13-substituted derivatives of berberine and coralyne.
Fig. 11 Berberine, 9-O- and C13-substituted derivatives of berberine and coralyne.

COMPOUND LINKS

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Download mol file of compoundBerberine chloride has been shown to demonstrate anti-cancer activity with moderate inhibition of telomerase (IC50 = 75 μM, TRAP assay)120,121 and possessed an IC50 of 35 μM against U937 human leukemia cells.122 The anti-telomerase activity of berberine appears to be due to its interaction with G-quadruplexes (preference for G-quadruplexes over duplex DNA), with suggestions that this compound stabilises, rather than inducesG-quadruplex formation.123 Beck and co-workers have synthesised C13-substituted analogues of berberine which also show selectivity for quadruplex over duplex DNA124 and Neidle and co-workers have synthesised C13-substituted analogues which exhibited binding to G-quadruplex structures but failed to display significant anti-telomerase activity.123 However, Neidle was able to show that coralyne, a planar synthetic analogue of berberine famous for its antileukemic properties,125 possessed comparable anti-telomerase activity to berberine.

Further studies by Gu and co-workers have shown that C9-substituted derivatives containing amino121 or aza-aromatic126groups significantly increase the binding affinity of these compounds with G-quadruplexes, resulting in increased anti-telomerase activity. Naasani also demonstrated how a novel application of COMPARE informatics was used to screen their database to identify other berberine-like compounds with potent telomerase activity.122

Wilairat and co-workers have shown inhibition of telomerase activity in Plasmodium falciparum by berberine in the TRAP assay, suggesting berberine and its derivatives may have potential as a novel type of anti-malarial agent.127

3.3 COMPOUND LINKS

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Download mol file of compoundBerbamine

COMPOUND LINKS

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Download mol file of compoundBerbamine (Fig. 12) is a dimeric tetrahydroisoquinoline alkaloid, isolated together with berberine from Berberis vulgaris (barberry).118 It has been shown to exhibit anti-telomerase activity in human leukemia HL-60 cells with only 5% telomerase activity remaining following treatment with 10 μM COMPOUND LINKS

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Download mol file of compoundberbamine for 24 h.128 The synthesis of COMPOUND LINKS

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Download mol file of compoundberbamine derivatives as anti-leukemia agents have been reported by Yu and co-workers.129
Berbamine.
Fig. 12 COMPOUND LINKS

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3.4 COMPOUND LINKS

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Download mol file of compoundCryptolepine

COMPOUND LINKS

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Download mol file of compoundCryptolepine is an indoloquinoline alkaloid (Fig. 13) first isolated in 1929 by Clinquart from the roots of Cryptolepis triangularis, a shrub native to the Belgian Congo.130 It has also been isolated from C. sanguinolenta, a plant long used by West and Central African traditional healers for the treatment of fevers and malaria.131 Though known more for its antimalarial activity, COMPOUND LINKS

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Download mol file of compoundcryptolepine has been shown to induce activity against a broad spectrum of biological targets exhibiting anti-microbial activity, anti-hyperglycemic activity and anti-cancer activity.132 Though its mechanism of action is not completely understood, it was recently found to interact with G-quadruplexes and to exhibit moderate anti-telomerase activity with an IC50 of 9.4 μM.133
The indoloquinoline alkaloid cryptolepine.
Fig. 13 The indoloquinoline alkaloid COMPOUND LINKS

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Gu and co-workers have synthesised cyptolepine analogues as telomerase inhibitors and shown that the 5-N-methyl is crucial for its telomerase activity.134 Other analogue studies of COMPOUND LINKS

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Download mol file of compoundcryptolepine with regards to telomerase activity have been performed by Zhou135 and Neidle,136 and extensive SAR studies performed on COMPOUND LINKS

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Download mol file of compoundcryptolepine against a variety of different biological targets have been summarised by Ablordeppey.131

3.5 Gambogic acid

COMPOUND LINKS

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Download mol file of compoundGambogic acid belongs to a family of caged xanthones possessing a unique 4-oxa-tricyclo[4.3.1.03,7]dec-2-one scaffold and is isolated from the gamboge resin of the Garcinia hurburyi tree (Fig. 14).137 This resin has been used as a traditional Chinese medicine for centuries, and its structure was first elucidated in 1965,138 although its absolute configuration was only recently determined by Kinghorn.139 COMPOUND LINKS

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Download mol file of compoundGambogic acid has shown promising in vitro and in vivo activity against a number of different cancer cell lines, including human leukemia, gastric carcinoma, lung carcinoma, breast cancer, hepatoma and pancreatic cancer, among others.137 Several mechanisms for the anti-cancer activity have been proposed and studies have shown that the induction of apoptosis may be due to the reduction in telomerase activity. Several reports have shown that human reverse transcriptase (hTERT) activity is reduced by both the down-regulation of hTERT transcriptionvia inhibition of the transcription activator c-myc,140,141 and by the inhibition of the phosphorylation of Akt, which downregulates the activity of hTERT in a post-translational manner.142 Both the crude extract gamboge and COMPOUND LINKS

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Download mol file of compoundgambogic acid have been tested in China in clinical trials against cancer.137
Gambogic acid.
Fig. 14 COMPOUND LINKS

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Several SAR studies for anti-tumour activity against a number of different cell lines have found the α,β-unsaturated ketone, the caged bridgecore and the isoprenyl side chains to be essential for apoptotic activity, whereas the C-6 phenol and the carboxylic acid functionality can tolerate modification. These results are summarised in a review by Han and Xu.137

3.6 Tanshinone I and IIA

The tanshinones are diterpenoidortho-quinones (Fig. 15) isolated from danshen, one of the most widely used drugs in Chinese traditional medicine obtained from the dried root of the Chinese red-rooted sage Salvia miltiorrhiza.143 Both tanshinone I and IIA have recently been found to exhibit anti-tumour effects against a variety of different cancer cell lines.144 While several molecular targets have been implicated for its anti-tumour activity, its exact mechanism of action is still uncertain. Studies have shown that tanshinone I also inhibits both hTERT expression and telomerase activity.145 For tanshinone IIA, studies have shown decrease of telomerase activity in HL60 and K562 cells and induction of apoptosis against leukemia cell lines.146 Tanshinone IIA has also been shown to be stronger than COMPOUND LINKS

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Download mol file of compoundtamoxifen in both in vitro and in vivo assays against human breast cancer.147
Examples of diterpenoidortho-quinones isolated from danshen.
Fig. 15 Examples of diterpenoidortho-quinones isolated from danshen.

Tanshinone IIA has been synthesised by a number of groups including Cai using a radical cyclisation process,148 Danheiser using a photochemical aromatic annulation strategy,149 Snyder and Lee by an ultrasound-promoted [4 + 2] cycloaddition150 and by Kakisawa using a Diels–Alder approach.151,152

3.7 Epigallocatechin gallate (EGCG)

Epigallocatechin-3-gallate (EGCG) is the major polyphenolic constituent of green tea, derived from the dried leaves of the plant Camellia sinensis.153 It has been shown to interact with a large variety of molecular targets.154 In 1998, EGCG was found to reversibly and directly inhibit telomerase with an IC50 of ≈ 1 μM in a TRAP assay, deeming it the most potent telomerase inhibitor in a series of tea catechins (Fig. 16).
The major polyphenolic constituents of green tea.
Fig. 16 The major polyphenolic constituents of green tea.

EGCG has been shown to bind competitively at the active site of human telomerase reverse transcriptase (hTERT) with respect to the RNA substrate primer155 and also to decrease expression of hTERT mRNA.157 Green tea, polyphenol extracts from tea and EGCG have all been found to be useful for the prevention and treatment of a variety of ailments including prostate,158,159 breast, cervical and esophageal cancers. The results of these clinical trials are summarised in reviews by Mukhtar,160 Gescher161 and Afzal.162

The first enantioselective synthesis of (−)-epigallocatechin-3-gallate was achieved by Li and Chen163 in 2001 using methodology previously developed by Ferreira.164,165 The exciting anti-telomerase activity of EGCG also inspired Tsuruo and co-workers to synthesise a series of COMPOUND LINKS

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Download mol file of compoundchromone analogues to investigate the pharmacophore and overcome the poor stability of EGCG.156 A series of analogues was synthesised (represented by MST-199), in which the ester linkage was exchanged for an amide linkage for increased stability (Fig. 17). The authors found that the 3,4-hydroxy groups on each of the B and D rings were essential for anti-telomerase activity, while the hydroxyl groups on the original chromane system (AC fragment) were dispensable. Tsuruo simplified the structures further to improve their accessibility and found that a series of N,N′-(phenylene)dibenzamide analogues (MST-295, MST-312) also retained anti-telomerase activity. A dideoxy-EGCG analogue has also been synthesised by Furuta166 and shown to preserve its potent inhibition of viral reverse transcriptase, confirming Tsuruo's findings that the hydroxyl substituents in the A-ring are not required for biological activity.


Epigallocatechin gallate derivatives by Tsuruo.156
Fig. 17 Epigallocatechin gallate derivatives by Tsuruo.156

3.8 COMPOUND LINKS

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Download mol file of compoundQuercetin and related flavonoids

The flavonoid family of natural products encompass a broad class of secondary plant metabolites found throughout the plant kingdom, including commonly ingested fruits and vegetables such as red onion, and also tea and red wine.167 While being famous for their anti-oxidant properties, they have also been shown to interact with numerous biological targets,168 exhibiting anti-inflammatory, anti-microbial and anti-cancer properties, among others.169

COMPOUND LINKS

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Download mol file of compoundQuercetin (Fig. 18) is a flavonoid generally regarded as a protein tyrosine kinase inhibitor, and widely used as such as a biological tool.170 There have been reports of COMPOUND LINKS

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Download mol file of compoundquercetin reducing telomerase activity and down-regulation of hTERT gene expression in hepatocarcinoma (HepG2 cells),171 lung cancer cell lines172 and gastric cancer cell lines173 and it has been the subject of a recent patent describing COMPOUND LINKS

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Download mol file of compoundisoflavone derivatives for telomerase inhibition.174 However, there have also been contrasting reports of COMPOUND LINKS

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Download mol file of compoundquercetin possessing no inhibition of hTERT mRNA expression in a malignant melanoma cell line175 and no inhibition of telomerase activity in human nasopharyngeal cancer cells in culture.176


Flavonoids exhibiting anti-telomerase activity.
Fig. 18 Flavonoids exhibiting anti-telomerase activity.

COMPOUND LINKS

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Download mol file of compoundGenistein (Fig. 18) has also been studied for its anti-telomerase activity against a number of different cell lines including melanoma,177 head and neck,178 prostate,179,180 neuroblastoma181 and breast cancer.182 These reports have suggested disturbances in the translocation of hTERT to the nucleus178 and inhibition of hTERT expression179,180,182 as modes of anti-telomerase activity. Other flanovoids that have been reported to exhibit anti-telomerase activity include COMPOUND LINKS

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Download mol file of compoundapigenin177 and COMPOUND LINKS

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Download mol file of compoundwogonin.185

Several SAR studies have been performed on COMPOUND LINKS

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Download mol file of compoundquercetin related flavonoids, though there is still little understanding about a clear relationship with regards to apoptotic and anti-proliferative activity. While most agree that the presence of the carbonyl at C4 and the C2–C3 olefin are crucial, the requirements for A- and B-ring substitution has been more difficult to interpret.186 An extensive review on the chemistry and structure–activity-relationship of COMPOUND LINKS

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Download mol file of compoundquercetin has been published by López-Lázaro,186 and more recently by Hirpara.187

The biological profile of COMPOUND LINKS

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Download mol file of compoundquercetin is limited by its poor solubility, as its soluble conjugates generally have greatly decreased activity. As such, QC12 (Fig. 19) has been synthesised as a water soluble prodrug and has been subjected to phase I clinical trials.183 d'Alarcao and co-workers have synthesised COMPOUND LINKS

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Download mol file of compoundquercetin analogues possessing 3- and 5-linked inositol 2-phosphate moieties via a succinate diester linkage. The 5-linked COMPOUND LINKS

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Download mol file of compoundquercetin analogue was found to exhibit comparable antiproliferative activity against human colon adenocarcinoma and human glioblastoma cells, indicating this modification did not diminish its biological activity.184


Soluble derivative of quercetin by Kerr183 and d'Alarcao.184
Fig. 19 Soluble derivative of COMPOUND LINKS

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Download mol file of compoundquercetin by Kerr183 and d'Alarcao.184

Menichincheri188 identified a tetrahydroxyflavone (boxed, Fig. 20) as a potent inhibitor of telomerase using a novel Flash-Plate assay which was designed to facilitate high throughput screening. SAR studies on this lead compound established the catechol A ring to be essential for anti-telomerase activity, while the hydroxyl groups on ring B were required to maintain low micromolar activity.


Flavone analogues with circles highlighting the differences from lead compound (boxed).
Fig. 20 COMPOUND LINKS

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Download mol file of compoundFlavone analogues with circles highlighting the differences from lead compound (boxed).

Zhu and co-workers189 have combined 2-pyridine moieties with simple flavones to synthesise a series of derivatives and tested them for telomerase activity. Potent low micromolar anti-telomerase activity was observed for several compounds, together with potent Taq polymerase inhibition. Docking simulations of a 2-chloropyridine flavone (Fig. 21) with the ATP binding site of telomerase demonstrated efficient binding with the telomerase active site.


A 2-chloropyridine flavone derivative (Zhu).189
Fig. 21 A 2-chloropyridine flavone derivative (Zhu).189

3.9 COMPOUND LINKS

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Download mol file of compoundResveratrol

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Download mol file of compoundResveratrol (Fig. 22) was first isolated in 1940 from the roots of white hellbore (Veratrum grandiflorum O. Loes)190 and was later determined to be a phytoalexin.191 It has since been isolated from a variety of biological sources including peanuts (Arachis hypogeal), legumes (Cassia sp.) and grapes (Vitis vinifera).192 In 1992, COMPOUND LINKS

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Download mol file of compoundresveratrol was implicated as the active ingredient causing the cardioprotective effects of red wine,193 stimulating an explosion of interest into its potential health benefits. It has since been shown to be beneficial for a wide range of ailments, including heart disease, diabetes, pathological inflammation and cancer.194,195
Resveratrol.
Fig. 22 COMPOUND LINKS

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Download mol file of compoundResveratrol has been demonstrated to interact with a large variety of molecular targets,192 and in 2006, was shown by Lanzilli and co-workers to inhibit telomerase activity (IC50 ≈ 85 μM, TRAP assay).196 Interestingly, Lanzilli also observed interference of the translocation mechanism of hTERT, with up-regulated levels of hTERT in the cytoplasm and reduced levels in the nucleus.

An efficient synthesis to this simple natural product has been recently published by Marra with an overall yield of 71%.197 A method for the synthesis of methylated resveratrol and analogues has also been reported, but no biological testing on these compounds have been conducted.198 The exciting biological profile of reservatrol has also stimulated synthetic studies by Snyder into resveratrol-based oligomers (e.g.pallidol, Fig. 23)199 synthesised by plants in response to environmental stress and has allowed access to a large number of these more complex polyphenols for which only limited biological/clinical studies have been performed.200,201 Nicolaou and Chen have completed the total synthesis of the resveratrol-derived polyphenols hopeanol and hopeahainol A, but did not confirm the reported cytotoxicity of hopeanol.202


The resveratrol-based oligomers pallidol and hopeanol.
Fig. 23 The resveratrol-based oligomers pallidol and hopeanol.

3.10 COMPOUND LINKS

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Download mol file of compoundHelenalin

COMPOUND LINKS

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Download mol file of compoundHelenalin (Fig. 24) is a naturally occuring sesquiterpene lactone commonly found in Arnica montana, a flower used since the 16th century for the treatment of injuries such as sprains and dislocations.203 It has since been observed to show anti-neoplastic, anti-microbrial, anti-inflammatory and anti-tumour activity among others. COMPOUND LINKS

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Download mol file of compoundHelenalin contains the α-methylene-γ-butyrolactone and α,β-unsaturated cyclo-pentenone Michael acceptor moieties, capable of accepting intracellular nucleophiles such as thiols, (thus acting as irreversible inhibitors of enzymes/proteins) and this has long been postulated to be important for its various biological activities.204–206
Helenalin and its derivatives, with IC50 values against human epidermoid carcinoma (HEp-2).204
Fig. 24 COMPOUND LINKS

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Download mol file of compoundHelenalin and its derivatives, with IC50 values against human epidermoid carcinoma (HEp-2).204

COMPOUND LINKS

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Download mol file of compoundHelenalin is known for its anti-inflammatory activity which is thought to arise through inhibition of NF-κB, a transcription factor involved in immune response.207 In 2005, Wang reported helenalin's potent anti-telomerase activity against hematopoietic cancer cells Jurkat and HL-60 (IC50 ≈ 4 μM, TRAP assay).208 This inhibition was observed to be selective for telomerase over DNA or RNA polymerases, and was also shown to be irreversible. They also observed down-regulation of hTERT, possibly through inhibition of NF-κB, though the rapid onset of anti-telomerase activity suggests that this anti-telomerase activity is unlikely to be due to its action of hTERT alone.

Evaluation of the anti-tumour activity of COMPOUND LINKS

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Download mol file of compoundhelenalin analogues and other α-methylene-γ-lactone containing compounds against a number of different cancer cell lines have been conducted by both Hall206,209 and Lee.210

Interestingly, investigations into the SAR of the structurally related parthenin by Shah and co-workers resulted in the synthesis of a more potent perthenin analogue (Fig. 25) which was found to inhibit the expression of telomerase.211QSAR studies with respect to cytotoxic acitivity have also been performed on a large set of over 30 sesquiterpene lactones including COMPOUND LINKS

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Download mol file of compoundcostunolide, pharthenin and COMPOUND LINKS

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Download mol file of compoundhelenalin.212


Parthenin and a derivative found to inhibit telomerase expression.
Fig. 25 Parthenin and a derivative found to inhibit telomerase expression.

3.11 COMPOUND LINKS

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Download mol file of compoundCostunolide

COMPOUND LINKS

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Download mol file of compoundCostunolide (Fig. 26) is a sesquiterpene lactone first identified in 1960 from costus root oil (Saussurea lappa)213 and is commonly isolated from the stem bark of Magnolia sieboldii and from the ayurvedic medicinal plant Saussurea sp.214 It has since been shown to exhibit a variety of biological effects including anti-tumour, hepatoprotective and immunomodular properties.214COMPOUND LINKS

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Download mol file of compoundCostunolide has been shown to decrease telomerase activity (IC50 = 65 μM, TRAP assay) by reduction of hTERT mRNA215 expression, with no reduction of hTR mRNA expression.216 A survey of the SAR of sesquiterpene lactones has shown that the presence of the α-methylene-γ-lactone is essential for the observed cytotoxic activity.217
Costunolide.
Fig. 26 COMPOUND LINKS

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3.12 COMPOUND LINKS

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Download mol file of compoundAllicin and COMPOUND LINKS

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Download mol file of compoundajoene

Garlic (Allium sativum) has been used as a herbal remedy for thousands of years by numerous cultures throughout the world. Today, garlic tablets are a popular health supplement, being recommended in many countries, and with global sales second only to Echinacea.218 A large amount of research has been conducted and has implicated garlic in a wide variety of ailments, including the prevention of coronary heart disease, immunological disorders, and cancer.219 Garlic contains a uniquely high content of organosulfur compounds, which are believed to be the source of its pharmacological activity.220

COMPOUND LINKS

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Download mol file of compoundAllicin (Fig. 27) is one such organosulfur compound, responsible for the distinctive smell of garlic, and is produced when the plant undergoes tissue damage.221 However, COMPOUND LINKS

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Download mol file of compoundallicin is not particularly stable and decomposes readily to a variety of organosulfur compounds, including E- and Z-ajoene.222 Several of these organosulfur compounds are believed to be active agents in the prevention of cancer.219 The compounds COMPOUND LINKS

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Download mol file of compoundallicin (IC50 ≈ 0.5 μM, TRAP assay)223 and COMPOUND LINKS

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Download mol file of compoundajoene have been shown to be inhibitors of telomerase activity, with Z-ajoene observed to inhibit telomerase activity (TRAP assay) and decrease telomerasehTERT mRNA levels after incubation at 10 μM for 24 h.224


Allicin and ajoene from garlic.
Fig. 27 COMPOUND LINKS

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Download mol file of compoundAllicin and COMPOUND LINKS

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Download mol file of compoundajoene from garlic.

The synthesis of COMPOUND LINKS

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Download mol file of compoundallicin and its biomimetic rearrangement to ajeone and its various homologues has been reported by Block and Apitz-Castro.225 More recently, Hunter and Kaschula226 have reported a synthetic route to access COMPOUND LINKS

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Download mol file of compoundajoene analogues with retention of the central vinyl disulfide/sulfoxide core and have found comparable anti-cancer activity to the parent compound (Fig. 28). The authors found that substitution of the allyl group on the sulfoxide end did not decrease anti-cancer activity and allowed for greater chemical stability. They propose that the vinyl-disulfide group is responsible for inhibition of cancer-cell proliferation, while the sulfoxide group is required for binding onto proteins.222


Derivatives of ajoene tested for cytotoxic activity against CT-1 transformed fibroblast cells.226
Fig. 28 Derivatives of COMPOUND LINKS

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Download mol file of compoundajoene tested for cytotoxic activity against CT-1 transformed fibroblast cells.226

3.13 COMPOUND LINKS

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Download mol file of compoundOleic acid and related long chain fatty acids

Recent research by Oda and co-workers demonstrated strong inhibition of telomerase activity by simple long chain fatty acids such as COMPOUND LINKS

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Download mol file of compoundoleic acid.227 A chain length of 16 to 20 carbons and cis-configured monounsaturation were both required for significant activity, with COMPOUND LINKS

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Download mol file of compoundoleic acid (C18) found to be the most potent with an IC50 of 8.6 μM (Fig. 29). A free carboxylic acid was also found to be essential for telomerase inhibition. Using kinetic experiments, COMPOUND LINKS

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Download mol file of compoundoleic acid was found to bind competitively at the telomerase active site, a site normally occupied by the telomerase substrate primer. Correlating the differing chain lengths and position of unsaturation with the observed biological activity, the authors were able to offer some insight into the size and shape of the telomerase binding pocket using computer modelling. As the exact 3D structure of the telomerase binding site has not yet been elucidated by X-ray crystallography or NMR analysis, this information may prove important for future rational structure-based design of novel telomerase inhibitors.
Long chain fatty acids as inhibitors of telomerase.
Fig. 29 Long chain fatty acids as inhibitors of telomerase.

4. Telomerase inhibitors from marine sources

A less common source of telomerase inhibitors are marine-based organisms. In 2003, the dictyodendrin family of alkaloids were the first marine derived telomerase inhibitors to be identified. Since then, ascididemin and COMPOUND LINKS

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Download mol file of compoundmeridine and more recently the sulfated liposaccharide axinelloside A have also been identified as inhibitors of telomerase.

4.1 Dictyodendrins

Dictyodendrins A–E (Fig. 30) were isolated by Fusetani and co-workers228 and were the first marine natural products to be identified to exhibit telomerase inhibition. This family of tyramine-based alkaloids were isolated from the Japanese marine sponge Dictyodendrilla verongiformis and all its members completely inhibit telomerase activity at 50 μg mL−1. Interestingly, removal of the sulfate group resulted in no activity at this concentration.228
The dictyodendrin family of marine natural products.
Fig. 30 The dictyodendrin family of marine natural products.

Total syntheses have been reported by Tokuyama229 and Fürstner230,231 and a formal synthesis by Ishibashi.232 Other synthetic studies have been reported by Ishibashi,233 Fürstner234 and Ayats.235

4.2 COMPOUND LINKS

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Download mol file of compoundMeridine and ascididemin

COMPOUND LINKS

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Download mol file of compoundMeridine (Fig. 31) was first isolated in 1990 by Schmitz and co-workers from the ascidian Amphicarpa meridian found in Australian waters.236 The structurally related ascididemin was isolated by Kobayashi as a potent anti-leukemic compound from the Okinawan tunicate Didenum sp.237
Meridine and ascididemin.
Fig. 31 COMPOUND LINKS

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Download mol file of compoundMeridine and ascididemin.

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Download mol file of compoundMeridine and ascididemin have both been shown to stabilise G-quadruplexes and inhibit telomerase activity with IC50 values of 11 μM and >80 μM respectively.238 These alkaloids also exhibit preference for quadruplexes over DNA duplexes or single strands. A series of C- and D-ring substituted phenanthrolin-7-ones (Fig. 32) have been synthesised by Delfourne and co-workers as analogues of ascididemin and COMPOUND LINKS

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Download mol file of compoundmeridine and demonstrated an increase in cycotoxicity in 12 distinct human cancer cell lines.239QSAR studies towards anti-tumour activity have been performed by Jha, which determined the importance of the A and B rings as the pharmacophore for anti-tumour activity.240


Examples of C-ring analogues of meridine tested against bladder T24 and lung carcinoma A-427 cell lines.239
Fig. 32 Examples of C-ring analogues of COMPOUND LINKS

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Download mol file of compoundmeridine tested against bladder T24 and lung carcinoma A-427 cell lines.239

4.3 Axinelloside A

Axinelloside A (Fig. 33) is a recently isolated telomerase inhibitor isolated from the Japanese marine sponge Axinella infundibula.241 This unique highly sulfated liposaccharide inhibits human telomerase with an IC50 value of 2.0 μg mL−1, though the exact mechanism of action has not yet been elucidated. No total synthesis of axinelloside A has been reported to date.
Axinelloside A.
Fig. 33 Axinelloside A.

5. Conclusions

The importance of telomere maintenance in conferring cell immortality and prevention of cell senescence has triggered immense interest in this biological target for the treatment of cancer. Ongoing research has revealed a large number of telomerase inhibitors from natural sources displaying remarkable diversity in molecular structure. The novelty of these compounds has inspired the synthesis of numerous synthetic analogues which has assisted in determining the biologically active pharmacophore. Further work needs to be undertaken to establish the exact mode of action of many of these natural products so that a more direct comparison between the mode of action and the molecular structure requirements for binding can be established.

The prevalence of telomerase activity in the majority of cancer cells offers a tremendous opportunity for the development of a broad spectrum anti-cancer agent. Natural products continue to provide a rich source of novel bioactive compounds targeting telomere maintenance, which may soon pave the way for the development of a new class of cancer therapeutics.

6. Acknowledgements

We would like to thank the NZ Foundation for Research, Science and Technology (FRST) for its financial support through the International Investment Opportunities Fund (IIOF).

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