抗癌活性天然产物Cryptophycins的研究进展

总结了具有强抗癌活性的天然产物cryptophycins及其结构类似物的研究进展, 内容包括cryptophycin的合成、 活性-结构关系规律以及结构类似物的研究情况.     

Design, synthesis, and evaluation of azepine-based cryptophycin mimetics

Cryptophycins, depsipeptides isolated from terrestrial blue-green algae, show potent activity against a variety of tumor cell lines. Given the potential of the cryptophycins for cancer therapy, we developed a new class of non-peptide peptidomimetic, designed to replace the 16-membered macrolide ring with a 7-membered azepine ring for attachment of the cryptophycin side chains with the required spatial orientation to mimic the conformation of the relevant region of the natural product. Monte Carlo conformational analysis revealed excellent overlay of the local minimum structural model 6 and X-ray structure of (+)-cryptophycin-3 (5). Starting from this structural model, we designed and synthesized compounds (+)-25, (+)-30, and (+)-34 as potential mimics of cryptophycins. Compounds (+)-25, (+)-30, and (+)-34 were tested for in vitro cytotoxicity against six human cancer cell lines. Although only modest activities were observed, these results suggested that a new series of bioactive cryptophycin analogues might be available by structural modification of the central ring system of the cryptophycins.     

Probing the Hydrodynamic Behavior of Drug-Induced Tubulin Rings by Fluorescence Correlation Spectroscopy

We describe fluorescence correlation spectroscopy measurements of tubulin polymers composed of tubulin and either of two cytotoxic peptides – dolastatin 10 and cryptophycin 1. These peptides inhibit tubulin polymerization into microtubules, a major component of cellular networks, and instead induce the formation of predominantly single-walled tubulin rings. We determine ratios of the hydrodynamic diameter of dolastatin-tubulin or cryptophycin-tubulin polymers to that of tubulin dimers, which are compared with corresponding ratios calculated for two simple models: 1) a circular ring made with N contiguous spherical beads and 2) a circular ring constructed with N non-spherical monomers, each monomer being represented by 21-minibeads. We find that the computed ratios from the 21-minibead representation agree well with the measured ones when N = 28 and N = 16 for dolastatin-tubulin and cryptophycin-tubulin ring polymers, respectively. That is, the rings are made with 14 and 8 tubulin dimers, confirming the numbers derived by other techniques. The present results further support the applicability of theories that have been developed for calculating hydrodynamic properties of supramolecular biological structures.     

Ring Polymers of Tubulin Induced by Binding of Natural Antimitotic Peptides

A number of natural products with potent antimitotic activity are peptides and depsipeptides that bind to tubulin, provoke depolymerization of microtubules, and induce formation of single layer rings of tubulin dimers. These peptides are all hydrophobic and small relative to tubulin (3-5 amino acid residues), yet induce rings polymers with properties that can differ significantly in size and self-association. In addition, these compounds exhibit potent cytotoxicity that varies by several hundred fold from one compound to another. Cryptophycin induces unusually homogeneous rings, composed of eight tubulin dimers, that are stable to dilution at least to nanomolar tubulin concentrations.