Combretastatin anlogues: synthesis and biological evaluation of new disubstituted analogues of 6-methoxy-3-(3',4',5'-trimethoxy-benzoyl)-1H-indole (BPR0L075), as potential antivascular agents

Abstract

6-Methoxy-3-(3',4',5'-trimethoxy-benzoyl)-1H-indole (BPR0L075) (1) is a potent inhibitor of tubulin polymerization which exhibits both in vitro and in vivo activities against a broad spectrum of solid tumours. This compound was originally designed as a heterocyclic analogue of combretastatin A4 (CA-4), a natural stilbene derivative that disrupts the tumour vasculature and causes tumour regression [1,2]. We describe here the design and synthesis of two disubstituted analogues of 1 (i.e. 15 and 8), presenting the B-ring substitution pattern of CA-4, along with their biological evaluation as potential antivascular agents. New compound 15, bearing a hydroxyl group at the 7-position of the indole nucleus that mimics the hydroxyl group at the 3-position of the B-ring of CA-4, was identified as a potent inhibitor of tubulin polymerization and also as a cytotoxic agent at nanomolar levels. In addition, compound 15 displayed marked morphological activity (rounding up) at nanomolar concentrations on endothelial cells, which is indicative of potential antivascular activity. The SAR are discussed here.