Synthesis and anticancer activity of epipolythiodiketopiperazine alkaloids

Abstract

The epipolythiodiketopiperazine (ETP) alkaloids are a highly complex class of natural products with potent anticancer activity. Herein, we report the application of a flexible and scalable synthesis, allowing the construction of dozens of ETP derivatives. The evaluation of these compounds against cancer cell lines in culture allows for the first expansive structure–activity relationship (SAR) to be defined for monomeric and dimeric ETP-containing natural products and their synthetic cognates. Many ETP derivatives demonstrate potent anticancer activity across a broad range of cancer cell lines, and kill cancer cellsviainduction of apoptosis. Several traits thatbode well for the translational potential of the ETP class of natural products includeconcise and efficient synthetic access, potent induction of apoptotic cell death, activity against a wide range of cancer types, and a broad tolerance for modifications at multiple sitesthat should facilitate small-molecule drug development, mechanistic studies, and evaluation in vivo.

Pretrichodermamide C and N-methylpretrichodermamide B, two new cytotoxic epidithiodiketopiperazines from hyper saline lake derived Penicillium sp.

“…These metabolites possess a broad spectrum of biological activities, including antibacterial, antiviral and antifungal activities (Witiak and Wei, 1990;Gardiner et al, 2005;Borthwick, 2012). Several naturally occurring ETPs, such as gliotoxin (antitumor activity) (Cole and Cox, 1981), chaetocin (antimyeloma activity) (Isham et al, 2007), and acetylaranotin (pro-apoptotic activity) (Neuss et al, 1968;Choi et al, 2011) have attracted considerable attention in recent years due to their pronounced cytotoxic activities against various human cancer cell lines (Dubey et al, 2013;Boyer et al, 2013;Reece et al, 2014). The essential structural element of ETPs responsible for the observed biological properties is attributed to the sulfur moiety in the oxidized disulfide form and/or the reduced dithiol form (Chai and Waring, 2000).…”

Role of gliotoxin in the symbiotic and pathogenic interactions of Trichoderma virens

“…The anti-cancer effects of this reactive compound warrant further examination as ETPs and ETP-like alkaloids have exhibited potent anti-cancer roles via induction of apoptosis (Boyer et al, 2013). However, negative effects on non-cancerous cells are a concern.…”

Quantitative Modeling of Bis(pyridine)silver(I) Permanganate Oxidation of Hydantoin Derivatives: Guidelines for Predicting the Site of Oxidation in Complex Substrates

“…1,2 As illustrated in Figure 1, the diketopiperazine substructure of these alkaloids is commonly adorned with a polysulfane motif that is known to be essential to their biological activity, 3 including the potent anticancer activity of both natural and designed ETP derivatives. 4,5 The combination of their fascinating molecular architecture and biological activity has prompted significant interest in chemical synthesis of ETPs. 6,7 One of our laboratories has developed a general strategy for conversion of complex diketopiperazines to the corresponding epipolythiodiketopiperazines in the context of several synthetic campaigns.…”

“…6,7 One of our laboratories has developed a general strategy for conversion of complex diketopiperazines to the corresponding epipolythiodiketopiperazines in the context of several synthetic campaigns. 2,4,6 A critical step in our approach to stereo-, regio-, and congener-specific sulfidation of complex diketopiperazines is the C–H hydroxylation of the diketopiperazine heterocycle. In particular, our discovery of the bis(pyridine)silver (I) permanganate 8 promoted oxidation of diketopiperazines has enabled the chemical synthesis of various epipolythiodiketopiperazines.…”