Synthesis and structure–activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein

Abstract

Tryprostatin A is a potent inhibitor of breast cancer resistance protein, consequently a series of structure-activity studies on the cell cycle inhibitory effects of tryprostatin A analogues as potential antitumor antimitotic agents have been carried out. These analogues were assayed for their growth inhibition properties and their ability to perturb the cell cycle in tsFT210 cells. SAR studies resulted in the identification of the essential structural features required for cytotoxic activity. The absolute configuration L-Tyr-L-pro in the diketopiperazine ring along with the presence of the 6-methoxy substituent on the indole moiety of 1 was shown to be essential for dual inhibition of topoisomerase II and tubulin polymerization. Biological evaluation also indicated the presence of the 2-isoprenyl moiety on the indole scaffold of 1 was essential for potent inhibition of cell proliferation. Substitution of the indole N a -H in 1 with various alkyl or aryl groups, incorporation of various L-amino acids into the diketopiperazine ring in place of L-proline, and substitution of the 6-methoxy group in 1 with other functionality provided active analogues. The nature of the substituents present on the indole N a -H or the indole C-2 position influenced the mechanism of action of these analogues. nalogues 68 (IC 50 = 10 μM) and 67 (IC 50 = 19 μM) were 7-fold and 3.5-fold more potent, respectively than 1 (IC 50 = 68 μM) in the inhibition of the growth of tsFT210 cells. Diastereomer-2 of tryprostatin B 8 was a potent inhibitor of the growth of three human carcinoma cell lines: H520 (IC 50 = 11.9 μM), MCF7 (IC 50 = 17.0 μM) and PC3 (IC 50 = 11.1 μM) and was equipotent with etoposide, a clinically used anticancer agent. Isothiocyanate analogue 71 and 6-azido analogue 72 were as potent as 1 in the tsFT210 cell proliferation and may be useful tools in labeling BCRP.

Site-directed Mutagenesis Switching a Dimethylallyl Tryptophan Synthase to a Specific Tyrosine C3-Prenylating Enzyme

“…In comparison with their nonprenylated precursors, these compounds show distinct and in general more potent biological and pharmacological activities (2,3,38,39). Prenylated tyrosine and derivatives build a small group within the prenylated aromatic natural products (40,41).…”

A Point Mutation inftmDBlocks the Fumitremorgin Biosynthetic Pathway inAspergillus fumigatusStrain Af293

“…6) Various biological activities of FTMs and synthetic derivatives of them, including cytotoxicity, cell cycle inhibition, and neurotoxicity, have been reported. 7,8) In fact, FTM-C is a very potent, specific inhibitor of breast cancer resistant protein, an ABC transporter related to multidrug resistance in cancer cells. 9,10) The putative FTM biosynthetic gene cluster was found by genome sequencing of the human pathogen A. fumigatus.…”

Introduction of New Tools for Chemical Biology Research on Microbial Metabolites

“…14,15) We cloned the gene cluster of fumitremorgins of Aspergillus fumigatus and isolated various derivative of the fumitremorgin family (Fig. 2).…”