Concise Synthesis and Biological Assessment of (+)‐Neopeltolide and a 16‐Member Stereoisomer Library of 8,9‐Dehydroneopeltolide: Identification of Pharmacophoric Elements

Abstract

We describe herein a concise synthesis of (+)-neopeltolide, a marine macrolide natural product that elicits a highly potent antiproliferative activity against several human cancer cell lines. Our synthesis exploited the powerful bond-forming ability and high functional group compatibility of olefin metathesis and esterification reactions to minimize manipulations of oxygen functionalities and to maximize synthetic convergency. Our findings include a chemoselective olefin cross-metathesis reaction directed by H-bonding, and a ring-closing metathesis conducted under non-high dilution conditions. Moreover, we developed a 16-member stereoisomer library of 8,9-dehydroneopeltolide to systematically explore the stereostructure-activity relationships. Assessment of the antiproliferative activity of the stereoisomers against A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma, HT-1080 human fibrosarcoma, and P388 murine leukemia cell lines has revealed marked differences in potency between the stereoisomers. This study provides comprehensive insights into the structure-activity relationship of this important antiproliferative agent, leading to the identification of the pharmacophoric structural elements and the development of truncated analogues with nanomolar potency.

Programmed Cell Death Induced by (−)-8,9-Dehydroneopeltolide in Human Promyelocytic Leukemia HL-60 Cells under Energy Stress Conditions

“…In this study, we investigated the effect of (−)-8,9-DNP [ 9 , 11 ], a potent synthetic analogue of (+)-neopeltolide, on HL-60 human promyelocytic leukemia cells. We found that 8,9-DNP decreased cell viability preferentially under the conditions in which glycolytic ATP generation was inhibited by 2-deoxy-D-glucose or by withdrawal of D-glucose from culture medium ( Figure 2 ).…”

“…We have previously reported the total synthesis of 1 and its synthetic analogues to elucidate the structure-activity relationships in detail [ 6 , 7 , 8 , 9 , 10 ]. During our synthetic campaign, we identified the pharmacophoric elements of 1 and discovered several highly potent and synthetically accessible analogues, as exemplified by (−)-8,9-dehydroneopeltolide (8,9-DNP, 2 ) [ 9 , 11 ]. Here we report that 8,9-DNP induced caspase-dependent apoptotic cell death in HL-60 human promyelocytic leukemia cells under energy stress conditions.…”

Application of catalytic Z-selective olefin metathesis in natural product synthesis

“…19 Its potent antiproliferative activity against various human cancer cell lines has attracted the attention of the synthesis community over the past years. [20][21][22][23] Recently, Hoveyda and coworkers reported the shortest synthesis to date with 28 steps employing four different Z-selective OM reactions (Scheme 8). 24…”

The Asymmetric Hetero‐Diels–Alder Reaction in the Syntheses of Biologically Relevant Compounds

“…97:3; Scheme 3). Additional macrocyclization, reduction, and esterification afforded the potent antiproliferative and cytotoxic agent [16,17] (+)-neopeltolide (20) in 14 % yield over five steps.…”