10′-fluorinated Vinca alkaloids provide enhanced biological activity against MDR cancer cells
AssigneeThe Scripps Research Institute
InventorDale L. Boger
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Abstract
A 10′-fluoro-vinca alkaloid compound or its pharmaceutically acceptable salt is disclosed, as are methods of its preparation and use. A disclosed 10′-fluoro-vinca alkaloid compound has better cytotoxic potency against leukemia and cancer cell lines, and is about 8-times more cytotoxic to a multiple drug resistant cancer cell line than is a parental 10′-unsubstituted vinca alkaloid.
Claims30
A 10′-fluoro-vinca alkaloid compound or its pharmaceutically acceptable salt that corresponds in structure to a compound shown in Tables A or B below:
- TABLE A
- R1
- R2
- R3
- 10′-Fluoro- vinblastine
- —CH3
- 10′-Fluoro- vincristine
- 10′-Fluoro- vindesine
- —CH3
- —OH
- 1-Desmethyl- 10′-fluoro- vinblastine
- —H
- TABLE B
- n
- R1
- R2
- R3
- 10′-Fluoro- vinorelbine
- 1
- —CH3
- 10′-Fluoro- anhydro- vinblastine
- 2
- —CH3
- 10′-Fluoro- anhydro- vincristine
- 2
- 10′-Fluoro- anhydro- vindesine
- 2
- —CH3
- —OH.
In a method of treating a mammal with cancer, lymphoma or leukemia that comprises administering a pharmaceutical composition containing an effective amount of a microtubule formation-inhibiting or mitosis-inhibiting amount of a vinca alkaloid, the improvement that comprises replacing said effective amount of a vinca alkaloid with an effective amount of a 10′-fluoro-vinca alkaloid compound that corresponds in structure to a compound shown in Tables A or B below:
- TABLE A
- R1
- R2
- R3
- 10′-Fluoro- vinblastine
- —CH3
- 10′-Fluoro- vincristine
- 10′-Fluoro- vindesine
- —CH3
- —OH
- 1-Desmethyl- 10′-fluoro- vinblastine
- —H
- TABLE B
- n
- R1
- R2
- R3
- 10′-Fluoro- vinorelbine
- 1
- —CH3
- 10′-Fluoro- anhydro- vinblastine
- 2
- —CH3
- 10′-Fluoro- anhydro- vincristine
- 2
- 10′-Fluoro- anhydro- vindesine
- 2
- —CH3
- —OH.
Dependencies are inferred from the claim text.