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. 2021 Mar 19;12(4):625–630. doi: 10.1021/acsmedchemlett.1c00024

Semisynthetic Derivatives of the Verticillin Class of Natural Products through Acylation of the C11 Hydroxy Group

Chiraz Soumia M Amrine †,‡, Andrew C Huntsman §, Michael G Doyle †, Joanna E Burdette ∥, Cedric J Pearce ⊥, James R Fuchs §,*, Nicholas H Oberlies †,*
PMCID: PMC8040035  PMID: 33859802

Abstract

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The verticillins, a class of epipolythiodioxopiperazine alkaloids (ETPs) first described 50 years ago with the discovery of verticillin A (1), have gained attention due to their potent activity against cancer cells, noted both in vitro and in vivo. In this study, the complex scaffold afforded through optimized fermentation was used as a feedstock for semisynthetic efforts designed to explore the reactivity of the C11 and C11′ hydroxy substituents. Functionality introduced at these positions would be expected to impact not only the potency but also the pharmacokinetic properties of the resulting compound. With this in mind, verticillin H (2) was used as a starting material to generate nine semisynthetic analogues (4–12) containing a variety of ester, carbonate, carbamate, and sulfonate moieties. Likewise, verticillin A succinate (13) was synthesized from 1 to demonstrate the successful application of this strategy to other ETPs. The synthesized compounds and their corresponding starting materials (i.e., 1 and 2) were screened for activity against a panel of melanoma, breast, and ovarian cancer cell lines: MDA-MB-435, MDA-MB-231, and OVCAR3. All analogues retained IC50 values in the nanomolar range, comparable to, and in some cases more potent than, the parent compounds.

Keywords: Verticillin, semisynthetic analogues, epipolythiodioxopiperazine alkaloids, fungal metabolites, prodrug

In 2019, it was estimated that over 1.7 million cases of cancer were diagnosed in the United States alone. Currently, cancer is predicted to result in over 600 000 deaths annually, making it the second leading cause of death in the country.1 Despite significant advances in both the detection and treatment of the disease, some types of cancer, such as triple-negative breast cancer and ovarian cancer, remain extremely difficult to treat.2 With this in mind, there is still a need for drug discovery and development efforts to tackle this problem. One possible method to address this is to reconsider known compounds that have shown promising anticancer activity but for one reason or another have also faced challenges in overcoming the hurdles associated with modern drug development.

The origins of >60% of the current FDA-approved anticancer drugs can be traced back to natural products.3,4 What may be less obvious from that often cited statistic is that a staggering 47% of the small-molecule drugs approved between 1981 and 2019, including 41% of new anticancer agents, were semisynthetic derivatives of those natural products.5 The value of these semisynthetic analogues6,7 lies in their ability to retain the scaffolds afforded by nature, complete with their complex ring architectures and stereochemical diversity.8,9 Exploiting these naturally engineered scaffolds frequently expedites the study of structure–activity relationships (SARs)10−12 and has the potential to facilitate more rapid drug development by improving drug properties, including solubility, overcoming challenges like drug resistance,13 and supplying material on larger scales.14−17 Examples of semisynthetic analogues that have gained FDA approval for cancer therapy, such as taxotere,18,19 ixabepilone,20−22 and the camptothecin derivatives irinotecan (also known as CPT-11)23,24 and topotecan,17,25,26 serve as both validation and inspiration for the application of semisynthetic approaches to other potent natural products.

The verticillins, fungal metabolites and key members of the epipolythiodioxopiperazine alkaloids (ETPs)27−29 isolated from cultures of Verticillium sp., Penicillium sp., and Gliocladium sp.,30 for example, represent an attractive class of compounds for the application of this strategy. These intricate natural compounds are characterized by their dimeric pyrroloindoline cores, cis-fused five membered rings, and the sulfur bridges across their diketopiperazine rings (Figure 1).31 Verticillin A (1), the parent compound and arguably the most widely studied of the class, was first isolated in 1970.32 Although this compound has shown very promising in vitro and in vivo activity against a variety of cancer cell lines,33−36 the relatively low availability of the compound through culture from natural sources has hampered its development. Over the past decade, however, interest in 1 and related compounds has dramatically increased from both a biological and chemical perspective. In fact, the creative efforts of Movassaghi and others have recently established elegant total syntheses of (+)-11,11′-dideoxyverticillin A and a number of related compounds including (+)-gliocladin C, (+)-chaetocin, and bionectin.37−39 These syntheses, however, are clearly not trivial, and despite their efforts, the production of the quantities of material necessary for thorough biological evaluation via synthetic means remains a significant challenge. Adding to this challenge is the potential need for subsequent structural modification and optimization to explore SARs and overcome limitations associated with their drug properties, in particular, their poor solubility, potentially increasing the complexity of these efforts. Indeed, a recently reported nanoencapsulated version of verticillin A (1), which has enhanced solubility, showed statistically significant results in a murine model of ovarian cancer.34 Our own interest in these compounds has led to methods to more efficiently increase the production of various members of the verticillin class.40 With quantities of these compounds in hand, semisynthesis has ultimately become an option to further explore the unique properties of these compounds.

Figure 1.

Figure 1

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Structures of symmetric (verticillin A (1) and verticillin H (2)) and asymmetric (Sch 52901 (3)) analogues biosynthesized by Clonostachys rogersoniana (strain MSX59553).40

Subsequent analysis of the structure of compounds in this class suggested the C11/C11′ hydroxy substituents as the most appropriate and accessible functional groups for semisynthetic functionalization. This was further supported by findings from the initial characterization papers for 1(41) and the structurally related verticillin D,42 which both showed that acetylation of one of these “central” alcohols could be accomplished upon treatment of the natural compounds with acetic anhydride and pyridine. To explain the observed selectivity for monofunctionalization, Gloer and colleagues specifically suggested a potential “conformational bias” that precluded a subsequent reaction at the C11′ position.42

With this in mind, verticillin H (2) was selected as the primary substrate for the present study. This was based on (1) the optimized production of the compound upon culturing of Clonostachys rogersoniana (strain MSX59553), a fungal strain demonstrating enhanced biosynthesis of various verticillin analogues,40,43 and (2) the symmetric nature of the substitution at the C13/C13′ positions on the diketopiperazine rings of this natural product (Figure 1). This symmetry was expected to simplify the purification and data analysis of the anticipated monofunctionalized products by avoiding the likely formation of two very closely related regioisomeric products, as would be obtained from an unsymmetrical substrate such as Sch 52901 (3).

In an effort to confirm the reactivity of the C11/C11′ alcohols, 2 was first treated with an excess of acetic anhydride under conditions similar to those previously reported.41,42 As expected, the acetylation reaction proceeded smoothly, resulting in the acylation of only a single alcohol moiety to generate compound 4. The formation of the monoacetylated product could easily be confirmed via analysis of the 1H NMR spectrum, which indicated desymmetrization of the aromatic protons through apparent doubling of the diagnostic peaks between 6.5 and 8.0 ppm (Figure 2 and Figure S1). Data from the heteronuclear single quantum correlation (HSQC) and heteronuclear multiple bond correlation (HMBC) nuclear magnetic resonance (NMR) experiments were both supportive of monoacylation at the C11 alcohol in 4 (Figures S2 and S3). LC/MS analysis of the reaction mixture failed to show any evidence of bis-acetylation. Attempts to acylate both the C11 and C11′ alcohols utilizing the more reactive acetyl chloride also failed, likewise resulting primarily in the formation of the monoacetylated product and demonstrating the high barrier to reactivity at the second alcohol position (e.g., C11′).

Figure 2.

Figure 2

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Comparison of the 1H NMR spectra in CDCl3 (500 MHz) of verticillin H (2, top) and the acetylated analogue 4. The reaction was monitored via 1H NMR by tracking the asymmetry that appeared mainly in the aromatic region (δH 6.5–8.0) through acylation of the alcohol at the C11 position.

Having successfully acylated the C11 position, however, the strategy for the further modification of 2 shifted to the introduction of alternative groups that would demonstrate the versatility of reactivity at this position and would be predicted to affect the physicochemical properties of the molecule, specifically through manipulation of the solubility and relative stability. This was anticipated to include several ester derivatives with various substitution patterns and carbonate, carbamate, and sulfonate analogues. On the basis of the diagnostic NMR shifts of the aromatic protons during the previous reaction and the small scale on which subsequent reactions would initially be carried out, these acylation reactions could be run in NMR tubes and monitored by tracking the desymmetrization of the aromatic protons. After a simple workup, the crude reaction mixtures would then be purified utilizing high-performance liquid chromatography (HPLC) and monitored for key signals in the MS data.

Using this approach, a series of four additional ester analogues (compounds 5–8, Table 1) were generated, demonstrating the ability to produce both straight-chain and more sterically encumbered branched-chain derivatives. Despite the higher degree of steric congestion, pivaloyl derivative 7 was obtained in comparable or even better yield compared with the other ester analogues. This result suggests that whereas the conformation of the monoacetylated derivatives presumably precludes further reaction at the C11′ position, there is no significant size limitation for the initial acylation event. Perhaps the most practical of these four examples, however, is the succinate analogue 8, formed through the addition of 2 to succinic anhydride. The introduction of the succinic acid moiety is a commonly employed strategy for prodrug development and was expected to have an appreciable impact on the solubility (relative to the parent natural product) given that the terminal carboxylic acid would be deprotonated at physiological pH.44 Similar to the esters, carbonate 9 was generated upon the treatment of 2 with ethyl chloroformate. Analogous to the use of acid chlorides and ethyl chloroformate, 4-fluorobenzenesulfonyl chloride was also utilized to prepare sulfonate 10. Carbamates 11 and 12, however, were generated through a two-step procedure involving initial acylation with carbonyldiimidazole and subsequent treatment with the desired amine precursors for the formation of the carbamates.45 This two-step, one-pot procedure provides excellent versatility for this type of semisynthetic approach, as the reactive imidazole carboxylic esters derived from secondary alcohols have previously been shown to be incapable of reacting with a second equivalent of the alcohol, thereby facilitating selective carbamate formation through the addition of a potentially wide-range of amine substrates. Specifically, the secondary and tertiary carbamates 11 and 12 showcase that both primary and secondary amines can be utilized in this case, exemplifying the side-chain variability that could be introduced to further explore the SAR and the impact on solubility.

Table 1. Synthesis of Verticillin Analogues 4–13.

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As previously noted, the 1H NMR spectra of ester derivatives 4–8 and 13, carbonate 9, sulfonate 10, and carbamates 11 and 12 were similarly characterized by a notable doubling of signals that illustrated the loss of symmetry of the starting material. A distinct singlet peak in the range between 6.73 and 7.11 ppm was observed in all 1H NMR spectra and was found to represent H-11. The deshielded nature of this peak compared with H-11′ (∼5 ppm) of the same molecule, or of H-11/11′ in the parent compounds (also ∼5 ppm), further confirms the linkage of the new groups to OH-11. As expected, in addition to the doubling of the peaks in the 1H NMR spectra, doubling of peaks could also clearly be observed in the 13C NMR spectra for each analogue (Figures S1, S4–S9, and S12–S14, Supporting Information).

Having demonstrated that this approach could effectively be used to generate analogues of 2, this strategy was also extended to verticillin A (1). In this case, the succinate derivative of 1 was synthesized using the same reaction conditions previously utilized to generate 8. As anticipated, this reaction proceeded smoothly, providing the desired product 13 in 71% yield. This demonstrates that the semisynthetic strategies outlined have the potential to be applied to a range of verticillin analogues, although specific structural features in target compounds, including the nonsymmetric nature of molecules such as Sch 52901, and the presence of additional reactive functional groups would certainly affect the translation of this approach. In particular, we were intrigued by the calculated change in LogD values when using the succinic acid analogues (e.g., LogD of 2.11 vs −0.96 at pH 7.4 for 1 vs 13, respectively; see Table S11 for LogD of 1, 2, and 4–13), further supporting the notion that these modifications may dramatically modulate physicochemical properties despite the size and complexity of the natural products.46

The antiproliferative properties of all of the newly synthesized analogues were evaluated against human melanoma cancer cells (MDA-MB-435), human breast cancer cells (MDA-MB-231), and human ovarian cancer cells (OVCAR3) using techniques detailed previously (Table 2).47,48 The results showed that in nearly every case, the acylated verticillin H derivatives 4–12 performed as well as or better than the parent compound 2. The fact that activity against these cell lines was retained or even slightly improved was somewhat surprising, as the addition of pro-moieties designed to modulate the drug properties of highly potent compounds often negatively affects the potency of the parent compound in both cellular and targeted assays,49 presumably due to changes in the cell permeability or direct binding. In the case of the verticillins, the compounds themselves are known to have limited solubility,34 and the introduction of these groups may be enhancing their drug properties, including the cell permeability. In addition, little is known about their binding mode. The key feature identified in SARs is the bridged disulfide moiety.37 In this case, the introduction of these acyl substituents clearly does not affect those groups or cause a loss of potency against the cancer cell lines, despite the fact that acylation may induce a conformational change in the molecule, as evidenced by the differing reactivities of the C11 and C11′ alcohols. Overall, this study demonstrates that the extension of groups from the verticillin core not only is a viable strategy to increase the solubility or modulate drug properties, as in the case of readily cleavable ester-derived prodrugs, but also may have the potential to improve drug properties using functional groups that show greater metabolic stability, as in the case of the carbonate and carbamate derivatives. In addition to using medicinal chemistry to modulate the potency and solubility of natural-product-based drug leads, such semisynthetic analogues may be patentable, which is a current challenge in the field of natural products research.50

Table 2. Cytotoxicity of Verticillin A (1), Verticillin H (2), and Related Analogues (4–13).

  IC50 (nM)a
compound MDA-MB-231 OVCAR3 MDA-MB-435
verticillin A (1) 23 36 18
verticillin H (2) 31 229 44
4 21 96 41
5 17 25 19
6 12 105 24
7 20 72 21
8 13 133 21
9 7 137 11
10 49 79 31
11 21 68 22
12 12 19 9
13 12 33 9
taxol (control) 0.6 1.8 0.3
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a

MDA-MB-435, human melanoma cancer cells; OVCAR3, human ovarian cancer cells; MDA-MB-231, human breast cancer cells.

Acknowledgments

This research was supported by the National Institutes of Health/National Cancer Institute via grant P01 CA125066 and an ACS Medicinal Chemistry Division Predoctoral Fellowship to A.C.H. We thank Tyler Graf and Dr. Huzefa Raja from UNCG for helpful discussions.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00024.

  • Detailed experimental description of semisynthetic procedures of verticillins derivatives; fermentation, extraction, and isolation of fungal verticillins; cytotoxicity assays; complete 1H and 13C NMR data; HSQC and HMBC spectra; and LogD values (PDF)

Author Contributions

# C.S.M.A. and A.C.H. are cofirst authors. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare the following competing financial interest(s): Nicholas Oberlies is a member of the Scientific Advisory Board of Mycosynthetix, Inc.

This letter published ASAP on March 19, 2021. Corrections were made to the structures of verticillins in Figure 1, Table 1, and the Table of Contents/Abstract graphics. The corrected version reposted on March 30, 2021.

Supplementary Material

ml1c00024_si_001.pdf (2.2MB, pdf)

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