Synthesis and biological evaluation of structurally highly modified analogues of the antimitotic natural product curacin A.

Abstract

Structure-activity relationship analysis of synthetic analogues of curacin A revealed the lack of activity of traditional heterocyclic replacements of the thiazoline ring or cyclopropyl analogues of the core diene segment. The significance of the C(3)-C(4)-(Z)-alkene geometry was established, and a novel oxime analogue was designed that displays biological properties that are a close match of the natural product lead. The much less lipophilic, structurally simplified oxime 50 was only slightly weaker at inhibiting the growth of cultured human tumor cells than the natural product and was found to be more potent than curacin A at inhibiting the assembly of purified tubulin. Accordingly, the oxime moiety is likely to serve as a novel bioisostere of the (Z)-alkene group.

• Authors: Peter Wipf, Jonathan T Reeves, Raghavan Balachandran, Billy W Day
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 45 Issue 9 Pg. 1901-17 (Apr 25 2002) ISSN: 0022-2623 [Print] United States
• PMID: 11960501 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 3,4,5-trimethoxybenzaldehyde O-(8-hydroxy-5-methyl-8-thiophen-2-ylacta-2,4-dienyl)oxime
• Antineoplastic Agents
• Biopolymers
• Blood Proteins
• Cyclopropanes
• Oximes
• Thiazoles
• Thiophenes
• Tubulin
• curacin A

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Biopolymers
• Blood Proteins (metabolism)
• Cell Division (drug effects)
• Cyclopropanes (chemistry, pharmacology)
• Drug Screening Assays, Antitumor
• Humans
• Oximes (chemical synthesis, chemistry, pharmacology)
• Protein Binding
• Stereoisomerism
• Structure-Activity Relationship
• Thiazoles (chemistry, pharmacology)
• Thiophenes (chemical synthesis, chemistry, pharmacology)
• Tubulin (chemistry)
• Tumor Cells, Cultured