Improved Total Synthesis and Structure-Activity Relationship of Arenastatin A, a Potent Cytotoxic Spongean Depsipeptide.

Abstract

An efficient asymmetric synthesis of a cyclic depsipeptide arenastatis A (1) is described. 1, isolated from the marine sponge Dysidea arenaria, exhibited extremely potent cytotoxicity with IC50 of pg/ml for KB cells, and in this context the structure-activity relationship among several stereoisomers of 1 and allied compounds has also been examined.

Flexible Routes to the 5‐Hydroxy Acid Fragment of the Cryptophycins

“…Depending on this, different strategies for dealing with the stereochemical issue have been developed. Thus, the anti stereochemistry can be set by epoxide opening, [11Ϫ13] by a syn aldol reaction followed by reduction of the carboxylate to a methyl group, [14,15] by crotylboration of an aldehyde, [16,17] by nucleophilic addition to a 2-methyl aldehyde, [18] by Frater alkylation of a 3-hydroxy ester, [17] or by a [2,3]-Wittig rearrangement. [19] If a diol precursor such as II is targeted, aldol strategies [20] or nucleophilic additions to the aldehyde derived from man-delate are possible.…”

Total Synthesis of Cryptophycin A and Analogs

“…Although numerous syntheses of both the arenastatins and cryptophycins have been published, 1,6,20 " 23 the epoxidation step has always 24 been done using m-CPBA or dimethyldioxirane. This is of significance because the two diastereomers formed, at best in a 2:1 ratio of ß:oc epoxides, cannot generally be separated by column chromatography.…”

“…A close structural relative of the cryptophycins, Arenastatin A (3), was isolated from the Okinawan marine sponge Dysidea arenaria. 6 Arenastatin A differs from Cryptophycin A in that it lacks both the chlorine on the aryl ring at CIO and the methyl group at C6. 6 Microtubules are dynamic components and are essential to cellular life.…”

“…6 Arenastatin A differs from Cryptophycin A in that it lacks both the chlorine on the aryl ring at CIO and the methyl group at C6. 6 Microtubules are dynamic components and are essential to cellular life. They are involved with many cell processes such as cell growth, division, locomotion, and intracellular transport.…”

Synthesis of Cryptophycin Affinity Labels and Tubulin Labeling

“…Formal and total syntheses of the cryptophycins have been published by several groups. [8][9][10][11][12][13][14] Also, a multitude of SAR studies of these molecules have been reported. 2 ' 3 " ,16 or Arenastatin A Although relatively little is known about the interactions of cryptophycins with tubulin, it is believed that the cryptophycins may interact in a manner different from those of other tubulin-binding antimitotic agents.…”