Synthesis of diketopiperazine-based carboline homodimers and in vitro growth inhibition of human carcinomas

Starting from d- or l-tryptophan, we have synthesized and characterized six compounds 2.29–2.31a and b that belong to a class of nitrogen heterocycles: the carboline-based homodimers. Each individual homodimer features a 1,3-trans relationship on each side of the central diketopiperazine core, but differs in absolute stereochemistry and also in substitution on the 4′ and 4″ oxygens (–Bn, –CH3, or –H). The in vitro cytotoxicity of the six compounds was evaluated by measuring the growth inhibition in NCI–H520 and PC-3 human carcinoma cells. Phenol 2.30a inhibited cancer cell growth approximately three times better than its enantiomer 2.30b and possessed a GI50 comparable to the clinically used agent etoposide in both cell lines. We have concluded that both the stereochemistry imparted by l-tryptophan and the presence of hydroxy substituents at the 4′ and 4″ positions are necessary to generate cytotoxic properties in the homodimer class. We are now employing 2.30a as a new lead compound in our efforts to discover improved indole-based cancer chemotherapeutics.

Carboline homodimers like 2.30a were synthesized starting from D- or l-Trp–OCH3 and shown to inhibit the in vitro growth of PC-3 and NCI–H520 human cancers.Figure optionsDownload as PowerPoint slide