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Cell-based and biochemical structure-activity analyses of analogs of the microtubule stabilizer dictyostatin

Raccor, BS and Vogt, A and Sikorski, RP and Madiraju, C and Balachandran, R and Montgomery, K and Shin, Y and Fukui, Y and Jung, WH and Curran, DP and Day, BW (2008) Cell-based and biochemical structure-activity analyses of analogs of the microtubule stabilizer dictyostatin. Molecular Pharmacology, 73 (3). 718 - 726. ISSN 0026-895X

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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 μM, 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 β-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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Raccor, BS
Vogt, A
Sikorski, RP
Madiraju, C
Balachandran, R
Montgomery, K
Shin, Y
Fukui, Y
Jung, WH
Curran, DPcurran@pitt.eduCURRAN
Day, BW
Date: 1 March 2008
Date Type: Publication
Journal or Publication Title: Molecular Pharmacology
Volume: 73
Number: 3
Page Range: 718 - 726
DOI or Unique Handle: 10.1124/mol.107.042598
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0026-895X
MeSH Headings: Alkanes--metabolism; Alkanes--pharmacology; Alkanes--toxicity; Animals; Benzimidazoles--metabolism; Binding Sites; Brain Chemistry; Carbamates--metabolism; Carbamates--pharmacology; Carbamates--toxicity; Carcinoma--drug therapy; Carcinoma--pathology; Cattle; Cell Line, Tumor; Cell Nucleus--drug effects; Cell Nucleus--metabolism; Cell Proliferation--drug effects; Epothilones--antagonists & inhibitors; Epothilones--pharmacology; Epothilones--toxicity; Female; Fluorescein-5-isothiocyanate--metabolism; Fluorescent Antibody Technique, Indirect; Fluorescent Dyes--metabolism; G2 Phase--drug effects; HeLa Cells; Histones--metabolism; Humans; Kinetics; Lactones--metabolism; Lactones--pharmacology; Lactones--toxicity; Macrolides--chemical synthesis; Macrolides--chemistry; Macrolides--metabolism; Macrolides--pharmacology; Microtubules--drug effects; Molecular Structure; Ovarian Neoplasms--drug therapy; Ovarian Neoplasms--pathology; Paclitaxel--metabolism; Paclitaxel--pharmacology; Paclitaxel--toxicity; Phosphorylation--drug effects; Protein Binding; Pyrones--metabolism; Pyrones--pharmacology; Pyrones--toxicity; Quantitative Structure-Activity Relationship; Radioligand Assay; Tubulin--biosynthesis; Tubulin Modulators--metabolism; Tubulin Modulators--pharmacology; Tubulin Modulators--toxicity
PubMed ID: 18073274
Date Deposited: 03 May 2013 15:39
Last Modified: 22 Jun 2021 12:56


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