Evaluation of the tubulin-bound paclitaxel conformation: synthesis, biology, and SAR studies of C-4 to C-3' bridged paclitaxel analogues.
The important anticancer drug paclitaxel binds to the beta-subunit of the alphabeta-tubulin dimer in the microtubule in a stoichiometric ratio, promoting microtubule polymerization and stability. The conformation of microtubule-bound drug has been the subject of intense study, and various suggestions have been proposed. In previous work we presented experimental and theoretical evidence that paclitaxel adopts a T-shaped conformation when it is bound to tubulin. In this study we report additional experimental data and calculations that delineate the allowable parameters for effective paclitaxel-tubulin interactions.
Ganesh
Thota
T
Department of Chemistry, M/C 0212, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA.
Yang
Chao
C
Norris
Andrew
A
Glass
Tom
T
Bane
Susan
S
Ravindra
Rudravajhala
R
Banerjee
Abhijit
A
Metaferia
Belhu
B
Thomas
Shala L
SL
Giannakakou
Paraskevi
P
Alcaraz
Ana A
AA
Lakdawala
Ami S
AS
Snyder
James P
JP
Kingston
David G I
DG
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D012996:Solutions; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry*
D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D047029:Lactams, Macrocyclic; D012996:Solutions; D014404:Tubulin; D017239:Paclitaxel