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A simplified synthesis of novel dictyostatin analogues with In Vitro activity against epothilone B-resistant cells and antiangiogenic activity in zebrafish embryos

Vollmer, LL and Jiménez, M and Camarco, DP and Zhu, W and Daghestani, HN and Balachandran, R and Reese, CE and Lazo, JS and Hukriede, NA and Curran, DP and Day, BW and Vogt, A (2011) A simplified synthesis of novel dictyostatin analogues with In Vitro activity against epothilone B-resistant cells and antiangiogenic activity in zebrafish embryos. Molecular Cancer Therapeutics, 10 (6). 994 - 1006. ISSN 1535-7163

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Abstract

The natural product (-)-dictyostatin is a microtubule-stabilizing agent that potently inhibits the growth of human cancer cells, including paclitaxel-resistant clones. Extensive structure-activity relationship studies have revealed several regions of the molecule that can be altered without loss of activity. The most potent synthetic dictyostatin analogue described to date, 6-epi-dictyostatin, has superior in vivo antitumor activity against human breast cancer xenografts compared with paclitaxel. In spite of their encouraging activities in preclinical studies, the complex chemical structure of the dictyostatins presents a major obstacle for their development into novel antineoplastic therapies. We recently reported a streamlined synthesis of 16-desmethyl-25,26-dihydrodictyostatins and found several agents that, when compared with 6-epi-dictyostatin, retained nanomolar activity in cellular microtubule-bundling assays but had lost activity against paclitaxel-resistant cells with mutations in β-tubulin. Extending these studies, we applied the new, highly convergent synthesis to generate 25,26-dihydrodictyostatin and 6-epi-25,26-dihydrodictyostatin. Both compounds were potent microtubule- perturbing agents that induced mitotic arrest and microtubule assembly in vitro and in intact cells. In vitro radioligand binding studies showed that 25,26-dihydrodictyostatin and its C6-epimer were capable of displacing [ H]paclitaxel and [ C]epothilone B from microtubules with potencies comparable to (-)-dictyostatin and discodermolide. Both compounds inhibited the growth of paclitaxel- and epothilone B-resistant cell lines at low nanomolar concentrations, synergized with paclitaxel in MDA-MB-231 human breast cancer cells, and had antiangiogenic activity in transgenic zebrafish larvae. These data identify 25,26-dihydrodictyostatin and 6-epi-25,26- dihydrodictyostatin as candidates for scale-up synthesis and further preclinical development. ©2011 AACR. 3 14


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Vollmer, LL
Jiménez, M
Camarco, DP
Zhu, W
Daghestani, HN
Balachandran, R
Reese, CE
Lazo, JS
Hukriede, NA
Curran, DPcurran@pitt.eduCURRAN
Day, BW
Vogt, A
Date: 1 June 2011
Date Type: Publication
Journal or Publication Title: Molecular Cancer Therapeutics
Volume: 10
Number: 6
Page Range: 994 - 1006
DOI or Unique Handle: 10.1158/1535-7163.mct-10-1048
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 1535-7163
MeSH Headings: Angiogenesis Inhibitors--chemical synthesis; Angiogenesis Inhibitors--chemistry; Angiogenesis Inhibitors--pharmacology; Animals; Antineoplastic Agents--chemical synthesis; Antineoplastic Agents--chemistry; Antineoplastic Agents--pharmacology; Cell Line, Tumor; Drug Screening Assays, Antitumor; Epothilones--pharmacology; HeLa Cells; Humans; Macrolides--chemical synthesis; Macrolides--chemistry; Macrolides--pharmacology; Microtubules--drug effects; Microtubules--metabolism; Mitosis--drug effects; Paclitaxel--pharmacology; Structure-Activity Relationship; Tubulin--metabolism; Zebrafish
Other ID: NLM NIHMS289440, NLM PMC3112307
PubMed Central ID: PMC3112307
PubMed ID: 21490306
Date Deposited: 16 Nov 2012 16:55
Last Modified: 30 Mar 2021 14:56
URI: http://d-scholarship.pitt.edu/id/eprint/16335

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