PUBLICATION
A simplified synthesis of novel dictyostatin analogs with in vitro activity against epothilone B resistant cells and antiangiogenic activity in zebrafish embryos
- Authors
- Vollmer, L.L., Jimenez, M., Camarco, D.P., Zhu, W., Daghestani, H.N., Balachandran, R., Reese, C.E., Lazo, J.S., Hukriede, N.A., Curran, D.P., Day, B.W., and Vogt, A.
- ID
- ZDB-PUB-110517-5
- Date
- 2011
- Source
- Molecular cancer therapeutics 10(6): 994-1006 (Journal)
- Registered Authors
- Hukriede, Neil
- Keywords
- none
- MeSH Terms
-
- 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
- PubMed
- 21490306 Full text @ Mol. Cancer Ther.
Citation
Vollmer, L.L., Jimenez, M., Camarco, D.P., Zhu, W., Daghestani, H.N., Balachandran, R., Reese, C.E., Lazo, J.S., Hukriede, N.A., Curran, D.P., Day, B.W., and Vogt, A. (2011) A simplified synthesis of novel dictyostatin analogs with in vitro activity against epothilone B resistant cells and antiangiogenic activity in zebrafish embryos. Molecular cancer therapeutics. 10(6):994-1006.
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 could be altered without loss of activity. The most potent synthetic dictyostatin analog described to date, 6-epi-dictyostatin, has in vivo antitumor activity against human breast cancer xenografts superior to paclitaxel. Despite their encouraging preclinical activities, the complex chemical structure of the dictyostatins presents a major obstacle in their development into novel antineoplastic therapies. We recently reported a streamlined synthesis of 16-desmethyl-25,26 dihydrodictyostatins and found several agents that compared with 6-epi-dictyostatin retained nanomolar activity in cellular microtubule bundling assays but showed cross-resistance to paclitaxel in cells with mutations in beta-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 C-6 epimer were able to displace [3H]paclitaxel and [14C]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. The data identify 25,26-dihydrodictyostatin and 6-epi-25,26-dihydrodictyostatin as candidates for scale-up synthesis and further preclinical development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping