Synthesis and biological evaluation of structurally highly modified analogues of the antimitotic natural product curacin A.
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.
Wipf
Peter
P
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. pwipf@pitt.edu
Reeves
Jonathan T
JT
Balachandran
Raghavan
R
Day
Billy W
BW
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001704:Biopolymers; D001798:Blood Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003521:Cyclopropanes / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry; D014407:Tumor Cells, Cultured
C454000:3,4,5-trimethoxybenzaldehyde O-(8-hydroxy-5-methyl-8-thiophen-2-ylacta-2,4-dienyl)oxime; D000970:Antineoplastic Agents; D001704:Biopolymers; D001798:Blood Proteins; D003521:Cyclopropanes; D010091:Oximes; D013844:Thiazoles; D013876:Thiophenes; D014404:Tubulin; C095843:curacin A