Synthesis and Structure−Activity Correlation of Natural-Product Inspired Cyclodepsipeptides Stabilizing F-Actin

Abstract

The fundamental role played by actin in the regulation of eukaryotic cell maintenance and motility renders it a primary target for small-molecule intervention. In this arena, a class of potent cytotoxic cyclodepsipeptide natural products has emerged over the last quarter-century to stimulate the fields of biology and chemistry with their unique actin-stabilizing properties and complex peptide-polyketide hybrid structures. Despite considerable research effort, a structural basis for the activity of these secondary metabolites remains elusive, not least for the lack of high-resolution structural data and a reliable synthetic route to diverse compound libraries. In response to this, an efficient solid-phase approach has been developed and successfully applied to the total synthesis of jasplakinolide and chondramide C and diverse analogues. The key macrocylization step was realized using ruthenium-catalyzed ring-closing metathesis (RCM) that in the course of a library synthesis produced discernible trends in metathesis reactivity and E/Z-selectivity. After optimization, the RCM step could be operated under mild conditions, a result that promises to facilitate the synthesis of more extensive analogue libraries for structure-function studies. The growth inhibitory effects of the synthesized compounds were quantified and structure-activity correlations established which appear to be in good alignment with relevant biological data from natural products. In this way a number of potent unnatural and simplified analogues have been found. Furthermore, potentially important stereochemical and structural components of a common pharmacophore have been identified and rationalized using molecular modeling. These data will guide in-depth mode-of-action studies, especially into the relationship between the cytotoxicity of these compounds and their actin-perturbing properties, and should inform the future design of simplified and functionalized actin stabilizers as well.

A Quantitative Chemical Proteomics Approach to Profile the Specific Cellular Targets of Andrographolide, a Promising Anticancer Agent That Suppresses Tumor Metastasis

“…Actin, one of the most abundant cytoskeleton proteins, participates in cancer metastasis by regulating cell motility (46). The anti-metastatic effects of a variety of actin-binding agents have been extensively studied because of their therapeutic potential (47)(48)(49)(50). In particular, we found NF-B and ␤-actin were the top two target proteins with the highest differential ratios among all the targets involved in the metastatic pathway.…”

Migrastatics—Anti-metastatic and Anti-invasion Drugs: Promises and Challenges

“…These compounds are cyclodepsipeptides and have the ability to potently stabilize actin fibers in a manner comparable with phalloidin; however, in contrast to phalloidin, they are freely cell permeable, rendering them exciting targets for drug development (reviewed in [49]). Geodiamolide H was shown to inhibit invasiveness of human breast cancer Hs578T cells when tested in vitro at concentrations of 60–120 nM [50].…”

Versatile Homoallylic Boronates by Chemo‐, SN2′‐, Diastereo‐ and Enantioselective Catalytic Sequence of Cu−H Addition to Vinyl‐B(pin)/Allylic Substitution

“…after purification (Scheme 5). This is a valuable fragment that has been used in a total synthesis of a biologically active analog of natural product chondramide C. [19] Previously, however, preparation of enantiomerically pure 10 entailed the use of Brown’s chiral auxiliary, [20] necessitating somewhat forcing conditions along with the use of stoichiometric amounts of an exceptionally strong base ( n BuLi/KO t Bu to give n BuK); there is also the need for an equivalent of an organoboron reagent. Another functionalization procedure entails conversion of the homoallylic boronate formed by the reaction of allylic phosphate 1c to the corresponding 2-furyl product [Eq.…”