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.
Shin
Youseung
Y
Department of Chemistry, University of Pittsburgh, Pennsylvania 15261, USA.
Fournier
Jean-Hugues
JH
Balachandran
Raghavan
R
Madiraju
Charitha
C
Raccor
Brianne S
BS
Zhu
Guangyu
G
Edler
Michael C
MC
Hamel
Ernest
E
Day
Billy W
BW
Curran
Dennis P
DP
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