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

Abstract

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, -CH(3), 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 GI(50) 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.

• Authors: Amy M Deveau, Nancy E Costa, Elizabeth M Joshi, Timothy L Macdonald
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 18 Issue 12 Pg. 3522-5 (Jun 15 2008) ISSN: 1464-3405 [Electronic] England
• PMID: 18502124 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carbolines
• Diketopiperazines

Topics

• Carbolines (chemical synthesis, chemistry, pharmacology)
• Carcinoma (drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Crystallography, X-Ray
• Diketopiperazines (chemistry)
• Dimerization
• Drug Screening Assays, Antitumor
• Humans
• Models, Molecular
• Molecular Structure
• Stereoisomerism
• Structure-Activity Relationship