Synthesis of azepino[4,5-b]indoles and benzo[f][1,5]diazecine-2,8(1H,3H)diones: promising anti-cancer activity toward cervical and brain cancer

Abstract

The current manuscript comprises (i) the development of a robust protocol for the regio- and stereoselective synthesis of azepino[4,5-b]indoles with wide substrate scope, (ii) the unprecedented formation of tetrahydrobenzo[f][1,5]diazecine-2,8(1H,3H)diones via a series of oxidation reaction cascades on [4,5-b]indole derivatives and (iii) the biological evaluation of the diazecine compounds for the anti-cancer activity against HeLa and U87MG cell lines. The protocol proceeds via Lewis acid-catalyzed S_N2-type ring-opening of activated aziridines with indoles from the C-3 position, followed by base-mediated propargylation in the same pot under reflux conditions, and subsequent [Au]-catalyzed 7-exo-dig hydroarylation cyclization at room temperature. The synthetic utility of the developed strategy was further demonstrated by a number of important chemical transformations, viz, metathesis, isomerization, oxidation and reduction reactions. The exocyclic azepino[4,5-b]indole compound 6 reacts with mCPBA to furnish an unprecedented formation of 3-hydroxy-4,5,6,7-tetrahydrobenzo[f][1,5]diazecine-2,8(1H,3H)dione 11, a higher-order di-aza-heterocycle via a series of cascade reactions: Prilezhaev epoxidation, Meinwald rearrangement, Baeyer–Villiger oxidation, Witkop oxidation, followed by hydrolysis (PMBWH). Biological evaluation of our synthesized ten-membered compounds 11 revealed their superior cytotoxic activity compared to cisplatin and temozolomide, which are established marketed drugs for the treatment of cervical and brain cancers, respectively. The significance of the methodology is further demonstrated by the gram-scale synthesis of hexahydroazepino[4,5-b]indoles and the anti-cancer agent tetrahydrobenzo[f][1,5]diazecine. The formation of the products is rationalized by a plausible mechanism, and the mechanistic proposal is substantiated by computational studies (DFT). All these results are reported in the manuscript.