Synthesis and biological evaluation of (-)-16-normethyldictyostatin: a potent analogue of (-)-dictyostatin.
[structure: see text] (-)-16-Normethyldictyostatin has been made by total synthesis and is a potent antitumor agent in cells expressing wild-type tubulin and in one mutant cell line that is resistant to paclitaxel, but it is much less active than dictyostatin in another paclitaxel-resistant cell line where Val is substituted for Phe270. This provides strong evidence that the C16 methyl group of the dictyostatins is oriented toward Phe270 in the paclitaxel-binding site on beta-tubulin.
Department of Chemistry, University of Pittsburgh, Pennsylvania 15261, USA.
Youseung
Y
Shin
Jean-Hugues
JH
Fournier
Raghavan
R
Balachandran
Charitha
C
Madiraju
Brianne S
BS
Raccor
Guangyu
G
Zhu
Michael C
MC
Edler
Ernest
E
Hamel
Billy W
BW
Day
Dennis P
DP
Curran
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000033:anatomy & histology; D002417:Cattle; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D017239:Paclitaxel / Q000494:pharmacology; D010649:Phenylalanine / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000096:biosynthesis*; D014633:Valine / Q000235:genetics
C509570:16-normethyldictyostatin; D000970:Antineoplastic Agents; D018942:Macrolides; D014404:Tubulin; C470814:dictyostatin; D010649:Phenylalanine; D014633:Valine; D017239:Paclitaxel