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, -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.
Deveau
Amy M
AM
Department of Chemistry and Physics, University of New England, Biddeford, ME 04005, USA. adeveau@une.edu
Costa
Nancy E
NE
Joshi
Elizabeth M
EM
Macdonald
Timothy L
TL
D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D054659:Diketopiperazines / Q000737:chemistry*; D019281:Dimerization; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002243:Carbolines; D054659:Diketopiperazines