Biological activity of the tryprostatins and their diastereomers on human carcinoma cell lines.
Tryprostatin A 1 and B 2 are indole alkaloid-based fungal products that act in the G2/M phase of the cell cycle. Tryprostatin A and B as well as their two enantiomers and four diastereomers have been synthesized via a common strategy. As a measure of cytotoxicity, these eight stereoisomers were assayed for their growth inhibitory properties in human breast, prostate, and lung cancer cell lines. The ability of the tryprostatins and the tryprostatin stereoisomers to induce topoisomerase II-mediated DNA relaxation or to inhibit tubulin polymerization was also examined. Although none of the stereoisomers were significantly active in topoisomerase II- or tubulin-based assays, ds2-try B 11 was found to exhibit a cytotoxicity profile more potent than etoposide 3 in the human cancer cell lines examined. In addition, ds2-try B 11 is comprised of an L-tryptophan derivative coupled to a D-proline moiety, the latter stereochemistry of which may enhance the activity of 11 and potential analogues in vivo.
Zhao
Shuo
S
Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, USA.
Smith
Kirsten S
KS
Deveau
Amy Morin
AM
Dieckhaus
Christine M
CM
Johnson
Michael A
MA
Macdonald
Timothy L
TL
Cook
James M
JM
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001704:Biopolymers; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001704:Biopolymers; D026121:Indole Alkaloids; D010879:Piperazines; D014404:Tubulin; C097858:tryprostatin A; C097859:tryprostatin B; D004247:DNA; D004250:DNA Topoisomerases, Type II