Structure Determination, Conformational Analysis, Chemical Stability Studies, and Antitumor Evaluation of the Cryptophycins. Isolation of 18 New Analogs from Nostoc sp. Strain GSV 224

Trimurtulu Golakoti, Junichi Ogino, Carl E. Heltzel, Trang Le Husebo, Craig M. Jensen, Linda K. Larsen, Gregory M.L. Patterson, Richard E. Moore, Susan L. Mooberry, Thomas H. Corbett, Frederick A. Valeriote

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Abstract

Using a modified isolation procedure devoid of methanol, 18 new cyclic cryptophycins have been isolated from Nostoc sp. GSV 224 as minor constituents in addition to cryptophycins-1 (A), -2 (B), -3 (C), and -4 (D). Acyclic cryptophycins are not found, indicating that the previously reported cryptophycins-5 (E methyl ester), -6 (F methyl ester), and -7 (G) are artifacts produced as a consequence of using methanol in the isolation scheme. Seventeen of the new cyclic analogs differ in structure in either one of the two hydroxy acid units, viz. unit A [(5S,6S,7R,8R)-7,8-epoxy-5-hydroxy-6-methyl-8-phenyl-2(E)-octenoic acid for cryptophycin-1 or (5S,6S)-5-hydroxy-6-methyl-8-phenyl-2(E),7(E)-octadienoic acid for cryptophycin-3] and unit D [(2S)2-hydroxy-4-methylvaleric acid], or one of the two amino acid units, viz. unit B [(2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propionic acid] and unit C [(2R)-3-amino-2-methylpropionic acid], found in the cyclic ABCD peptolide. In unit A of cryptophycins-26, -28, -30, and -40, the methyl group on C-6 is missing or the Δ2-double bond is hydrated. In unit B of cryptophycins-16, -17, -23, -31, -43, and -45, the aromatic ring is phenolic and/or possesses two or zero chlorines. In unit C of cryptophycins-21 and -29, the methyl group on C-2 is missing. In unit D of cryptophycins-18, -19, -49, -50, and -54, a different alkyl group (propyl, isopropyl, or sec-butyl) is attached to C-2. Only one of the new analogs, cryptophycin-24, differs in structure for two units by lacking chlorine in unit B and the methyl group in unit C. Revised structures are presented for cryptophycins-5, -6, and -7 and are correlated with cryptophycin-3, the relative stereochemistry of which has been further rigorously established by X-ray crystallography. NOE studies show that the preferred conformations of most cryptophycins in solution differ from the conformation of cryptophycin-3 in the crystal state. Although cryptophycin-1 is relatively stable at pH 7, both in ionic and nonionic media, the ester bond linking units C and D is fairly labile to solvolysis and mild base hydrolysis. Structure—activity relationship studies indicate that the intact macrolide ring, the epoxide group, the chloro and O-methyl groups in unit B, and the methyl group in unit C are needed for the in vivo activity of cryptophycin-1.

Original languageEnglish (US)
Pages (from-to)12030-12049
Number of pages20
JournalJournal of the American Chemical Society
Volume117
Issue number49
DOIs
StatePublished - Jan 1 1995

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ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Golakoti, T., Ogino, J., Heltzel, C. E., Husebo, T. L., Jensen, C. M., Larsen, L. K., Patterson, G. M. L., Moore, R. E., Mooberry, S. L., Corbett, T. H., & Valeriote, F. A. (1995). Structure Determination, Conformational Analysis, Chemical Stability Studies, and Antitumor Evaluation of the Cryptophycins. Isolation of 18 New Analogs from Nostoc sp. Strain GSV 224. Journal of the American Chemical Society, 117(49), 12030-12049. https://doi.org/10.1021/ja00154a002