Taxoids benzoyl

The coupling of baccatins 76 and 77 with IV-benzoyl-P-lactam 11 and the V-f-Boc-P-lactam 12 followed by deprotection using Zn in AcOH afforded taxoids 78-81 in fair to good yields. These taxoids possess strong to modest cytotoxicity against our standard five human cancer cell lines (Table 12). The microtubule disassembly inhibitory activity of these new taxoids was also evaluated. Taxoid 78 (SB-T-1011) exhibits activity same to or better than that of paclitaxel. Results are listed in Table 12. The attachment of the AT-acylphenylisoserine residue at the C-14 position (taxoids 80 and 81) instead of the original C-13 position results in ca. 10-fold decrease in cytotoxicity, but 80 still retains 10 nM level (IC50) cytotoxicity. 

A few reactions of the taxol side chain are of interest. The taxoid cephalomannine (8.7.1) co-occurs with taxol, and there is thus a potential for increasing the supply of taxol by using cephalomannine as a substrate. A simple conversion of cephalomannine to taxol was achieved by benzoylation and ozonolysis to the ketoamide 8.7.2, followed by treatment with -phenylenediamine under acidic conditions. The o-phenylenediamine induces a cleavage of the ketoamide to the amine, and intramolecular O—>N acyl transfer gives rise to taxol in good overall yield (336). 

Kirkiae T, Ojima I, Kirikae F, Ma Z, Kuduk SD, Slater JC, Takeuchi CS, Bonaud P-Y, Nakano M (1996) Stmctural Requirements of Taxoids for Nitric Oxide and Tumor Necrosis Factor Production by Murine Macrophages. Biochem Biophys Res Commun 227 227 Kirikae T, Ojima I, Ma Z, Kirikae F, Hirai Y, Nakano M (1998) Stmctural Significance of the Benzoyl Group at the C-3 -N Position of Paclitaxel for Nitric... 

The putative acyl transferases were cloned, and the functional assessment of these clones was conducted by heterologous expression in E. coli and assay of the derived soluble recombinant enzyme preparations for the relevant acyl transferase activities. By this means, cDNAs encoding the taxadien-5a-ol-0-acetyl transferase, the taxoid-2a-0-benzoyl transferase, the taxoid-lop-O-acetyl transferase, and the two transferases involved in C-13 side chain assembly were obtained. 

Metabolism study of new fluorine-containing taxoids. Enzyme inhibition studies have shown that the cytochrome P-450 (CYP) family of enzymes is playing a key role in the biotransformation of paclitaxel and docetaxel. It has been found that the CYP 2C enzyme subfamily is responsible for the 6a-hydroxylation of paclitaxel, while the CYP 3 A subfamily plays a key role in the hydroxylation of the Boc group of docetaxel as well as that of the 3 -phenyl and 2-benzoyl groups of paclitaxel (Figure 1) (11,25)... 

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