TY  - JOUR
ID  - pittir18094
UR  - http://d-scholarship-dev.library.pitt.edu/18094/
IS  - 3
A1  - Raccor, BS
A1  - Vogt, A
A1  - Sikorski, RP
A1  - Madiraju, C
A1  - Balachandran, R
A1  - Montgomery, K
A1  - Shin, Y
A1  - Fukui, Y
A1  - Jung, WH
A1  - Curran, DP
A1  - Day, BW
Y1  - 2008/03/01/
N2  - Compounds that bind to microtubules (MTs) and alter their dynamics are highly sought as a result of the clinical success of paclitaxel and docetaxel. The naturally occurring compound (-)-dictyostatin binds to MTs, causes cell cycle arrest in G2/M at nanomolar concentrations, and retains antiproliferative activity in paclitaxel-resistant cell lines, making dictyostatin an attractive candidate for development as an antineoplastic agent. In this study, we examined a series of dictyostatin analogs to probe biological and biochemical structure-activity relationships. We used a high-content multiparameter fluorescence-based cellular assay for MT morphology, chromatin condensation, mitotic arrest, and cellular toxicity to identify regions of dictyostatin that were essential for biological activity. Four analogs (6-epi-dictyostatin, 7-epi-dictyostatin, 16-normethyldictyostatin, and 15Z,16-normethyldictyostatin) retained low nanomolar activity in the cell-based assay and were chosen for analyses with isolated tubulin. All four compounds were potent inducers of MT assembly. Equilibrium binding constant (K i) determinations using [14C]epothilone B, which has a 3-fold higher affinity for the taxoid binding site than paclitaxel, indicated that 6-epi-dictyostatin and 7-epi-dictyostatin displaced [14C] epothilone B with Ki values of 480 and 930 nM, respectively. 16-Normethyl-dictyostatin and 15Z,16-normethyldictyostatin had reduced affinity (Ki values of 4.55 and 4.47 ?M, respectively), consistent with previous reports showing that C16-normethyldictyostatin loses potency in paclitaxel-resistant cell lines that have a Phe270-to-Val mutation in the taxoid binding site of ?-tubulin. Finally, we developed a set of quantitative structure-activity relationship equations correlating structures with antiproliferative activity. The equations accurately predicted biological activity and will help in the design of future analogs. Copyright © 2008 The American Society for Pharmacology and Experimental Therapeutics.
JF  - Molecular Pharmacology
VL  - 73
SN  - 0026-895X
TI  - Cell-based and biochemical structure-activity analyses of analogs of the microtubule stabilizer dictyostatin
SP  - 718 
AV  - public
EP  -  726
ER  -