Polygodial and Ophiobolin A Analogues for Covalent Crosslinking of Anticancer Targets

Abstract

In a search of small molecules active against apoptosis-resistant cancer cells, including glioma, melanoma, and non-small cell lung cancer, we previously prepared α,β- and γ,δ-unsaturated ester analogues of polygodial and ophiobolin A, compounds capable of pyrrolylation of primary amines and demonstrating double-digit micromolar antiproliferative potencies in cancer cells. In the current work, we synthesized dimeric and trimeric variants of such compounds in an effort to discover compounds that could crosslink biological primary amine containing targets. We showed that such compounds retain the pyrrolylation ability and possess enhanced single-digit micromolar potencies toward apoptosis-resistant cancer cells. Target identification studies of these interesting compounds are underway.

The incredible story of ophiobolin A and sphaeropsidin A: two fungal terpenes from wilt-inducing phytotoxins to promising anticancer compounds

“…93,96 Monomeric ( 127 and 132 ) and dimeric ( 128 and 134 ) polygodial and ophiobolin A esters showed the same effects on human glioblastoma U373 cells, suggesting that their mode of action did not change with the dimerization. 99…”

Anticancer Activity of Natural and Semi-Synthetic Drimane and Coloratane Sesquiterpenoids

“…Recently, Maslivetc et al synthesized ethylene glycol-linked dimers of polygodial (2) (Figure 15) [69]. Antiproliferative effects of 74a and 74b were increased compared to polygodial (2).…”

“…The increased cytotoxicity of 74a and 74b is explained by the ability to crosslink antitumor targets by pyrrole formation with lysine residues. However, no crosslink adducts were identified by Maslivetc et al [69]. Antiproliferative effects of 9-epipolygodial ( 49) and the Wittig derivative 64 were investigated more intensively [67,68].…”

Polygodial, a Sesquiterpene Dialdehyde, Activates Apoptotic Signaling in Castration-Resistant Prostate Cancer Cell Lines by Inducing Oxidative Stress

“…PG also exhibits antifungal, anti-inflammatory, and anticancer activity [ 29 , 30 , 31 ]. Several studies have reported that PG and its derivatives, including isopolygodial, 9-epipolygodial (DR-P27), 1-β-(p-coumaroyloxy)-polygodial, and 1-β-( p -methoxycinnamoyl)-polygodial, exhibit anticancer activity in different cancers [ 32 , 33 , 34 , 35 ]. Dasari et al [ 30 ] reported that DR-P27 possesses superior antiproliferative efficacy compared to PG in drug resistant cancer cells.…”