Bispidine moiety-driven simplified eleutherobin analogues: Synthesis and biological evaluation

Abstract

In the present research, the bispidines were used as a scaffold for the design of new inhibitors of protein-protein interaction with potential antitumor activity. Molecular modeling investigation was performed and optimum symmetrical structures demonstrating strong affinity to the taxane binding site in tubulin were determined. The target structures were analyzed retrosynthetically and produced accordingly. A Mannich-type reaction with urotropine and subsequent ring-opening N-acylation constitute the two key steps in the synthetic pathway. The modification options for C9 position in diazabicyclo[3.3.1]nonanes are discussed. The cytotoxicity of the synthesized bispidine derivatives was evaluated on colon cancer HCT116, pulmonary adenocarcinoma A549 and prostatic adenocarcinoma PC-3 cell lines. Three of the obtained compounds showed cytotoxic activity with IC₅₀ as low as 7.5–15.6 μM.