| Autor: |
Ojima, I., Slater, J. C., Kuduk, S. D., Takeuchi, C. S., Gimi, R. H., Sun, C.-M., Park, Y. H., Pera, P., Veith, J. M., Bernacki, R. J. |
| Zdroj: |
Journal of Medicinal Chemistry; January 31, 1997, Vol. 40 Issue: 3 p267-278, 12p |
| Abstrakt: |
A series of new taxoids derived from 14β-hydroxy-10-deacetylbaccatin III was synthesized by means of the β-lactam synthon method. Most of the new taxoids thus synthesized possess excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-29), and breast (MCF-7) cancer cell lines, and several of these taxoids show subnanomolar IC50 values which are severalfold to 1 order of magnitude better than those of paclitaxel and docetaxel. Modifications at the 3- and 3-N-positions exert marked effects on the activity. For the substituents at C-3, the cytotoxicity decreases in the order 2-furyl ~ 2-methyl-1-propenyl ≥ 2-methylpropyl > (E)-1-propenyl ≥ n-propyl > phenyl ≫ 2,2-dimethylpropyl. For the 3-N substituents, the activity decreases in the order t-BuOCO > Ph > n-hexanoyl. A significant increase in the cytotoxicity against the doxorubicin-resistant human breast cancer cell line MCF7-R that expresses the multidrug resistance (MDR) phenotype is observed by the proper modification of the substituent at C-10. The observed remarkable effects of the substituents at C-10 on the activity against MCF7-R can be ascribed to the effective inhibition of the binding of these new taxoids to P-glycoprotein that is responsible for MDR. |
| Databáze: |
Supplemental Index |
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