Ashok G. Chaudhary

Synthesis of taxol from baccatin III via an oxazoline intermediate

Abstract Taxol ( 1 ) can be prepared in good yield by coupling the oxazoline carboxylic acid 5 with 7-(triethylsilyl)baccatin III, followed by hydrolysis. The oxazolines 7 and 8 can also be prepared directly from taxol.

Synthesis of 10-deacetoxytaxol and 10-deoxytaxotere

10-Deacetoxytaxol (9) and 10-deoxytaxotere (10) have been prepared from 10-deacetylbaccatin III by attachment of the C-13 side-chain and deoxygenation. 10-Deacetoxytaxol is comparable to taxol in its cytotoxicity to P-388 cells, but 10-deoxytaxotere is significantly more cytotoxic than taxol.

A convenient tubulin-based quantitative assay for paclitaxel (Taxol) derivatives more effective in inducing assembly than the parent compound

Abstract A room temperature biochemical assay, based on centrifugal removal of tubulin polymer, was developed to permit ready detection of paclitaxel analogs more active than the parent compound and to permit reliable quantification of differences in activity relative to paclitaxel in terms of drug concentration. The assay was validated by comparing paclitaxel to two compounds (docetaxel and 2-debenzoyl-2-meta-azidobenzoylpaclitaxel) known to be more active under multiple reaction conditions. The assay was designed to yield a relatively high EC50 (23 μM) for paclitaxel. This was possible because paclitaxel only weakly induced tubulin assembly at room temperature in 0.4 M glutamate without exogenous GTP. Under these same reaction conditions 50% assembly occurred with 4.7  μM 2-debenzoyl-2-meta-azidobenzoylpaclitaxel and 11 μM docetaxel. These biochemical EC50 values were in agreement with the relative cytotoxicity of the three compounds for human Burkitt lymphoma CA46 cells (IC50 values for paclitaxel, docetaxel, and 2-debenzoyl-2-meta-azidobenzoylpaclitaxel were 40, 10, and 3 nM, respectively).

Identification of the structural region of taxol that may be responsible for cytokine gene induction and cytotoxicity in human ovarian cancer cells

Purpose: Interleukin-8 (IL-8) is a pleiotropic chemokine with both chemoattractant and angiogenic properties. In addition to its cytotoxic effects on ovarian cancer cells, taxol can transcriptionally activate genes such as IL-8 that may play a role in tumorigenesis. Utilizing IL-8 as a prototypic marker of tumor-derived modulators of growth, we undertook a systematic study of taxol and 11 structurally modified taxol analogs to identify the region of the taxane skeleton responsible for IL-8 gene induction. Methods: The human ovarian cancer cell line OVCA-420 was exposed to taxol or taxol analogs. IL-8 gene induction was assessed by Northern blot analysis after 6 h and cytotoxicity after 72 h. Results: Changes in the southern hemisphere (C-1 to C-4) of the taxane skeleton had greater effects on IL-8 induction than changes in the northern hemisphere (C-7 to C-11). Some of the taxol analogs modified at positions C-1 and/or C-2 with increased hydrophobicity induced IL-8 expression more than threefold over that induced by taxol or taxotere and more than 20-fold over control cells. Cells that failed to induce IL-8 gene expression in response to taxol were only marginally responsive to the analogs unless first primed with IL-1β. Modifications to the northern hemisphere did not alter taxols effect on IL-8 expression in human cells, but did influence TNFα expression in murine macrophage cells, suggesting species and/or gene specificity. We found a direct correlation between IL-8 induction and cytotoxicity, in that analogs that dramatically upregulated IL-8 expression proved to be the most cytotoxic, inhibiting cell survival by >90%. Conclusion: Taken together our results demonstrate that changes in the southern hemisphere of the taxane skeleton influence both the gene induction and cytotoxic potential of taxol in human ovarian cancer cells.

Synthesis and biological evaluation of 4-deacetoxypaclitaxel

Abstract 4-Deacetoxypaclitaxel ( 9 ) has been prepared in seven steps from paclitaxel (Taxol ® ). It is significantly less active than paclitaxel in tubulin-assembly and cytotoxicity bioassays.