Vinblastine 20′ Amides: Synthetic Analogues That Maintain or Improve Potency and Simultaneously Overcome Pgp-Derived Efflux and Resistance
| Autor: | Dale L. Boger, Shouliang Yang, R. Matthew Cross, Daniel W. Carney, Aleksandar Radakovic, Daniel M. Brody, Vyom Shukla, John C. Lukesh, Katharine K. Duncan, Manuela M. Brütsch, Huijun Dong |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Antineoplastic Agents
ATP-binding cassette transporter Vinblastine 010402 general chemistry 01 natural sciences Article Matched pair Tubulin binding Structure-Activity Relationship Tubulin Cell Line Tumor Neoplasms Drug Discovery medicine Animals Humans Potency Structure–activity relationship ATP Binding Cassette Transporter Subfamily B Member 1 010405 organic chemistry Chemistry Amides Drug Resistance Multiple Tubulin Modulators 0104 chemical sciences Biochemistry Drug Resistance Neoplasm Cell culture Molecular Medicine Efflux medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 60:7591-7604 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A series of 180 vinblastine 20' amides were prepared in three steps from commercially available starting materials, systematically exploring a typically inaccessible site in the molecule enlisting a powerful functionalization strategy. Clear structure-activity relationships and a structural model were developed in the studies which provided many such 20' amides that exhibit substantial and some even remarkable enhancements in potency, many that exhibit further improvements in activity against a Pgp overexpressing resistant cancer cell line, and an important subset of the vinblastine analogues that display little or no differential in activity against a matched pair of vinblastine sensitive and resistant (Pgp overexpressing) cell lines. The improvements in potency directly correlated with target tubulin binding affinity, and the reduction in differential functional activity against the sensitive and Pgp overexpressing resistant cell lines was found to correlate directly with an impact on Pgp-derived efflux. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|