Analogues of the marine alkaloids oroidin, clathrodin, and hymenidin induce apoptosis in human HepG2 and THP-1 cancer cells

Abstract

The marine alkaloids clathrodin, oroidin, and hymenidin, which were isolated from Agelas sponges, possess diverse biological activities. Herein, we describe the design of a library of their analogues and the evaluation of their apoptosis-inducing activities against the human hepatocellular carcinoma HepG2 and acute monocytic leukaemia THP-1 cell lines. The screening of the complete library of 96 compounds using the HepG2 cell line allowed us to determine key structural elements and physicochemical properties that are responsible for the apoptosis-inducing activity. The indole-based compounds 24c, 28c, 29c, and 34cwere found to be the most potent inducers of apoptosis in HepG2 and THP-1 cell lines with EC 50 values in the low micromolar range. Cell cycle analysis assays confirmed that compounds 24c, 28c, 29c, and 34c induce the apoptosis of THP-1 cells at 25 mM, which highlights these oroidin analogues as interesting candidates for further evaluation of their anticancer activity.

Design, synthesis and biological evaluation of 4,5-dibromo-N-(thiazol-2-yl)-1H-pyrrole-2-carboxamide derivatives as novel DNA gyrase inhibitors

“…We have recently designed several structural classes of analogues of marine alkaloids based on clathrodin, hymenidin and oroidin, isolated from sponges of the genus Agelas, and evaluated their voltage-gated sodium channel modulatory activity [26][27][28][29], inhibition of biofilm formation [30], antimicrobial activity [31], and pro-apoptotic activity in HepG2 and THP-1 cell lines [32]. The similarity of oroidin and its analogues to the known pyrrolamide-based inhibitors [17,18] stimulated us to evaluate selected oroidin analogues from our library for E. coli DNA gyrase inhibition.…”

Synthesis and Biological Evaluation of 2‐Aminobenzothiazole and Benzimidazole Analogs Based on the Clathrodin Structure

“…), a 2‐aminoimidazole alkaloid originally isolated from a Caribbean sea sponge, Agelas clathrodes , was used in this study as a versatile starting point. Clathrodin per se has previously been reported to possess cytotoxic effects , but more interestingly its analogs have shown promising antimicrobial , proapoptotic and voltage‐gated sodium channel blocking effects.…”

Marine alkaloid oroidin analogues with antiviral potential: A novel class of synthetic compounds targeting the cellular chaperone Hsp90

“…As marine alkaloids clathrodin, hymenidin, and oroidin (Figure ) possess a potentially unstable double bond between the pyrrolamide and 2‐aminoimidazole moieties, we designed and synthesized several libraries of their conformationally restricted analogues . Among them, we prepared a library of 4,5,6,7‐tetrahydrobenzo[1,2‐ d ]thiazol‐2‐amine derivatives in which the imidazole ring was isosterically replaced by the thiazole ring (Figure , class I ; Table S1, compounds 2 , 5–11 ) .…”

“…Clathrodin and oroidin are pyrrole‐2‐aminoimidazole alkaloids isolated from sponges of the genus Agelas and were initially shown to display voltage‐gated sodium channel modulatory activity and inhibition of bacterial biofilm formation, respectively. Recently, we have designed and synthesized several structural series of conformationally restricted oroidin analogues and reported their biological activities including voltage‐gated sodium channel modulatory activity, inhibition of bacterial biofilm formation, induction of apoptosis in THP‐1 and HepG2 cell lines, DNA gyrase inhibition and antimicrobial activity …”