The Synthesis of Cryptophycins

Abstract

Nature provides a huge reservoir of highly diverse chemical compounds with interesting biological properties. Secondary metabolites continue to represent promising candidates for therapeutic applications and drugs are very often based on natural products. Frequently, the total synthesis of such compounds is a real challenge, and this also drives the development of new synthetic methodology.This review article focuses on the biochemistry and chemistry of cryptophycins, a class of 16-membered macrocyclic depsipeptides. The first representative was isolated more than 15 years ago from cyanobacteria. With respect to structure, the class can be subdivided into two structural categories, containing either an epoxide or an alkene moiety. The bioactivity of cryptophycins is based on their ability to interact with tubulin. They display considerable tumourselective cytotoxicity both against multidrug-resistant tumour cell lines and solid tumours implanted in mice. Consequently, cryptophycin derivatives are considered as potential antitumour drugs.Despite the fact that the cryptophycins were discovered only recently, several different synthetic approaches have already been published. In addition to information on the synthesis of the subunits A-D, strategies for both their assembly and the macrocyclisation are compiled in this review.

Total synthesis and biological evaluation of fluorinated cryptophycins

“…The IC 50 values of the fluorinated cryptophycins 22 and 31 were compared to cryptophycin-52 in Table 1 [17]. While the cytotoxicity of the unit A-modified analogue 22 against the tumor cell line KB-3-1 was only by about a factor of 4 decreased compared to cryptophycin-52, the pentafluorophenylalanine-containing derivative 31 was much less active.…”

“…Finally, unit D is leucic acid, the hydroxy analogue of leucine. Numerous synthetic analogues have been obtained in the frame of structure–activity-relationship studies (SAR-studies), as reviewed in [17–18]. …”

“…In unit B the chlorine and the methoxy substituents at the D-tyrosine residue were crucial for high antimitotic activity [17–18]. Moore et al patented the synthesis of fluorinated analogues of cryptophycin-1 and cryptophycin-52 [20].…”

2-Phenyl-tetrahydropyrimidine-4(1H)-ones – cyclic benzaldehyde aminals as precursors for functionalised β2-amino acids

“…Examples are cryptophycin-1 (a highly cytotoxic depsipeptide produced by cyanobacteria Nostoc sp. GSV224 and ATCC53789) [11–14] as well as a class of lipopeptides isolated from various fungi, comprising topostatin (a topoisomerase I and II inhibitor) [15], YM-170320 (an inhibitor of ergosterol biosynthesis) [16], and fusaristatins A and B [17]. …”