Abstract
New analogs of nortopsentin, a natural 2,4-bis(3′-indolyl)imidazole alkaloid, in which the central imidazole ring of the natural lead was replaced by a 1,2,4-oxadiazole moiety, and in which a 7-azaindole portion substituted the original indole moiety, were efficiently synthesized. Among all derivatives, prescreened against the HCT-116 colon rectal carcinoma cell line, the two most active compounds were selected and further investigated in different human tumor cells showing IC50 values in the micromolar and submicromolar range. Flow cytometric analysis of propidium iodide-stained MCF-7 cells demonstrated that both the active derivatives caused cell cycle arrest in the G0–G1 phase. The cell death mechanism induced by the compounds was considered to be apoptotic by measuring the exposure of phosphatidylserine to the outer membrane and observed morphological evaluation using acridine orange/ethidium bromide double staining. Moreover, further tested on intestinal normal-like differentiated Caco-2 cell line, they exhibited preferential toxicity towards cancer cells.
Highlights
Natural products (NP) constitute a significant source of bioactive molecules and potential drug leads due to their high chemical diversity, biochemical specificity, binding efficiency with biological targets, and broad panel of bioactivities
Considering the successful results obtained using Marine natural products (MNP) as leads for drug discovery and the growing number of marine-derived molecules entering into clinical trials, researchers are still inspired by their scaffold for the design of new active molecules
Continuing our search for new anticancer compounds [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40], we report the synthesis of a new 1-methyl-3-[3-(1-methyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl]-1H-pyrrolo[2,3-b]pyridine nortopsentin analog 1, designed on the basis of the potent activity shown by thiazole nortopsentin analogs with a 7-azaindole portion and considering the important characteristics of the 1,2,4-oxadiazole ring found in compounds with promising biological activity
Summary
Natural products (NP) constitute a significant source of bioactive molecules and potential drug leads due to their high chemical diversity, biochemical specificity, binding efficiency with biological targets, and broad panel of bioactivities. About 60% of drugs currently on the market are of natural origin and natural products screening still plays a fundamental role in the drug discovery process [1]. Marine natural products (MNP), in particular marine sponge-derived compounds, have attracted considerable attention due to their unique biodiversity and structural differences as compared to terrestrial natural products. Among MNP or marine-derived molecules, eight compounds are currently on the market with application in different therapeutic areas and several compounds are in different phases of the clinical pipeline, showing promising anticancer activity. MNPs, while the majority are derivatives obtained through molecular lead optimization [2]. Considering the successful results obtained using MNP as leads for drug discovery and the growing number of marine-derived molecules entering into clinical trials, researchers are still inspired by their scaffold for the design of new active molecules
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