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.
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
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping