Ultra-potent vinca alkaloids: added molecular complexity further disrupts the tublin dimer-dimer interface
Synthetically-derived and previously inaccessible modifications of 20′-hydroxy-vinca derivative compounds such as vinblastine, vincristine or vindesine are disclosed that are a stunning 100-fold more active than the natural product (IC 50 's 50-75 pM vs 7 nM, HCT116), and are now accessible as a result of advances in the total synthesis of the natural product. Illustrative new ultra-potent vinblastines bind tubulin with much higher affinity and likely further disrupt the tubulin head-to-tail α/β dimer-dimer interaction by virtue of the strategic placement of an added conformationally well-defined, rigid and extended C20′-urea along the adjacent protein-protein interface. Added molecular complexity was used to markedly enhance target binding and functional biological activity, and represents a general approach to improving the properties of other natural products targeting a protein-protein interaction. A pharmaceutical composition containing an ultra-potent 20′-hydroxy-vinca derivative compound and a method of treating cancerous cells with such a compound are also disclosed.
1. A 20′-hydroxy-vinca derivative of structural Formula A or a pharmaceutically acceptable
A
R 1
R 2
R 3
Vinblastine
Vincristine
Vindesine
salt thereof, wherein R is a substituent of the formula
in which N is nitrogen and one of W, X, Y and Z can also be nitrogen (N), and when not nitrogen, W, X, Y and Z are CH or one of W, X, Y, Z is CR 4 , and R 4 is hydrido or an electron donating substituent, and
R b is F or H.
2. The 20′-hydroxy-vinca derivative or salt according to claim 1 , wherein one of W, X, Y and Z is nitrogen.
3. The 20′-hydroxy-vinca derivative or salt according to claim 2 , wherein W is nitrogen.
4. The 20′-hydroxy-vinca derivative or salt according to claim 2 , wherein X is nitrogen.
5. The 20′-hydroxy-vinca derivative or salt according to claim 2 , wherein Y is nitrogen.
6. The 20′-hydroxy-vinca derivative or salt according to claim 2 , wherein Z is nitrogen.
7. The 20′-hydroxy-vinca derivative or salt according to claim 1 , wherein R has a structural formula of one or more of
8. The 20′-hydroxy-vinca derivative or salt according to claim 7 , wherein R 4 is hydrido or is selected from the group consisting of a C 1 -C 4 hydrocarbyl, amino, mono-C 1 -C 4 hydrocarbylamino, di-C 1 -C 4 hydrocarbylamino and C 1 -C 4 hydrocarbyloxy group.
9. The 20′-hydroxy-vinca derivative or salt according to claim 1 , wherein R b is H.
10. The 20′-hydroxy-vinca derivative or salt according to claim 1 that is a derivative of vinblastine.
11. A 20′-substituted vinblastine of structural Formula B, or a pharmaceutically acceptable salt thereof
wherein R is a substituent of the formula
in which N is nitrogen and one of W, X, Y and Z can be nitrogen (N), and when not nitrogen, W, X, Y and Z are CH or one of W, X, Y, Z is CR 4 , where R 4 is hydrido or is selected from the group consisting of one or more of a C 1 -C 4 hydrocarbyl, amino, mono-C 1 -C 4 hydrocarbylamino, di-C 1 -C 4 hydrocarbylamino and C 1 -C 4 hydrocarbyloxy group.
12. The 20′-substituted vinblastine or salt according to claim 11 , wherein R 4 is amino.
13. The 20′-substituted vinblastine or salt according to claim 11 , wherein R has a structural formula of one or more of
14. A pharmaceutical composition that comprises a cancerous cell proliferation-inhibiting amount of a 20′-hydroxy-vinca derivative compound of claim 1 or a pharmaceutically acceptable salt thereof dissolved or dispersed in a physiologically acceptable carrier.
15. The pharmaceutical composition according to claim 14 , wherein a) one of W, X, Y and Z is nitrogen, b) R 4 is amino, and c) R b is H.
16. A method of inhibiting the growth of cancerous cells that comprises contacting said cancerous cells with a cancerous cell proliferation-inhibiting amount of a 20′-hydroxy-vinca derivative compound of claim 1 or a pharmaceutically acceptable salt thereof.
17. The method according to claim 16 , wherein said cancerous cells are contacted a plurality of times.
18. The method according to claim 16 , wherein said cancerous cells are contacted in vitro.
19. The method according to claim 16 , wherein said contacted cancerous cells are leukemia cells.
20. The method according to claim 16 , wherein said contacted cancerous cells are carcinoma cells.
21. The method according to claim 20 , wherein said contacted carcinoma cells are resistant to vinblastine.