Three New Strategies to the Synthesis Of Structurally Diverse Dipyrrolobenzodiazepines. Bioactivity Evaluation

Abstract

Simple and efficient strategies have been developed for the synthesis of three structurally diverse dipyrrolo[1,2-a : 2′,1′-c][1,4]benzodiazepine (DPBD) derivatives. Firstly, two-component reaction between 4-aroylpyrrolo[1,2-a][1,4]benzodiazepines and electron-deficient internal alkynes in different conditions was applied to obtain isomeric geminal and vicinal DPBDs (gem and vic). Secondly, multicomponent synthesis from 2-pyrrolylbenzylamine, arylglyoxal monohydrates and same alkynes led to the formation of other vicinal DPBDs (vic’). These transformations could be conducted under mild and metal-free conditions to provide a number of dipyrrolo[1,2-a : 2′,1′-c][1,4]benzodiazepine derivatives in moderate to good yields. The in vitro biological activity of title compounds have been tested. Further physicochemical and pharmacokinetic computations also demonstrated the drug-like characteristics of synthesized compounds. The cytotoxic activity IC₅₀ 27.59 (KB cell culture) as well as molecular docking with bromodomain-containig protein 4 (BRD4) indicated the importance of dipyrrolobenzodiazepine moieties in the development of potential anticancer agents.