Synthesis and Structure–Activity Relationship Study of NBRI16716B, an Antitumor Natural Product

Abstract

The total synthesis of NBRI16716B (2), a naturally occurring modulator of tumor-stroma interactions, was successfully achieved. Using this synthetic route, a dehydroxy analogue (21) and a derivative lacking the 5-hydroxy-3-methylpentenoyl side chain (22) became accessible. A preliminary structure-activity relationship study to unveil the structural requirements for selective inhibition of tumor cells cocultured with stromal cells revealed that both of the hydroxamate structures of 2 are indispensable, whereas the 5-hydroxy-3-methylpentenoyl side chain is not essential.

Chemical Studies on Bioactive Natural Products Directed toward Development of Novel Antiinfective and Anticancer Medicines

“…45) A diketopiperazine-based natural product, NBRI16716 B (35), 46) and leucinostatin A (36) 47) were found to decelerate the growth of DU-145 prostate cancer cells co-cultured with the corresponding PrSC stromal cells. The latter, a long-known natural product with a nonapeptide structure and diverse biological activities, [48][49][50][51][52][53][54][55][56][57] reduced the expression of insulin-like growth factor I (IGF-I). However, at the outset of this research, the primary molecular targets of these three hit compounds were not known, which motivated my synthetic study aiming at the development of more potent analogues through SAR research and crafting molecular probes to bait counterpart proteins.…”