Syntheses and Structure−Activity Relationships of Taxoids Derived from 14β-Hydroxy-10-deacetylbaccatin III

• Published in: Journal of medicinal chemistry 1997-01, Vol.40 (3), p.267-278
• Main Authors: Ojima, Iwao, Slater, John C, Kuduk, Scott D, Takeuchi, Craig S, Gimi, Rayomand H, Sun, Chung-Ming, Park, Young Hoon, Pera, Paula, Veith, Jean M, Bernacki, Ralph J
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - metabolism; Antineoplastic Agents, Phytogenic - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; General aspects; Humans; Magnetic Resonance Spectroscopy; Medical sciences; Molecular Conformation; Molecular Structure; Paclitaxel - analogs & derivatives; Paclitaxel - chemical synthesis; Paclitaxel - chemistry; Paclitaxel - metabolism; Paclitaxel - pharmacology; Pharmacology. Drug treatments; Structure-Activity Relationship; Taxoids; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960563e

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.