The naturally occurring diterpenoid taxol is a potent anticancer agent which shows activity in several tumor systems and has also shown excellent clinical activity against ovarian cancer and several other cancers. It is however in very short supply, currently being isolated from the bark of the western yew, Taxus brevifolia, in low overall yield. Improved methods of obtaining taxol are thus urgently needed to ensure that supplies are adequate to meet the demand for this exciting new drug. The overall goal of the proposed work is to improve the taxol supply by chemical means. In the first, short-term, part of the proposal, these improvements will be accomplished by developing ways to convert cephalomannine, a related and co-occurring compound, to taxol. In addition, methods will be developed to produce baccatin Ill in optimum yield from various Taxus species; baccatin Ill can be converted to taxol by chemistry developed by the co-principal investigator. The second, long-term, part of the proposal deals with methods to improve the taxol supply and improve taxol's medicinal value by developing more active or more accessible analogs. To this end, taxol analogs will be prepared and tested for bioactivity in the tubulin assembly assay and in other assays. The analogs to be prepared include those which differ by substitution at the C-2 or at the N-3' position of taxol, and also analogs that differ in the nature of the taxane ring system as a whole. The analog synthesis program will be guided by mechanistic hypotheses developed from previous work in the investigators' laboratories.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA055131-03
Application #
3199581
Study Section
Special Emphasis Panel (SRC (42))
Project Start
1991-08-01
Project End
1995-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Virginia Polytechnic Institute and State University
Department
Type
Schools of Arts and Sciences
DUNS #
003137015
City
Blacksburg
State
VA
Country
United States
Zip Code
24061
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Han, Y; Malak, H; Chaudhary, A G et al. (1998) Distances between the paclitaxel, colchicine, and exchangeable GTP binding sites on tubulin. Biochemistry 37:6636-44
Watson, J M; Kingston, D G; Chordia, M D et al. (1998) Identification of the structural region of taxol that may be responsible for cytokine gene induction and cytotoxicity in human ovarian cancer cells. Cancer Chemother Pharmacol 41:391-7
Chordia, M D; Kingston, D G; Hamel, E et al. (1997) Synthesis and biological activity of A-nor-paclitaxel analogues. Bioorg Med Chem 5:941-7
Han, Y; Chaudhary, A G; Chordia, M D et al. (1996) Interaction of a fluorescent derivative of paclitaxel (Taxol) with microtubules and tubulin-colchicine. Biochemistry 35:14173-83
Pengsuparp, T; Kingston, D G; Neidigh, K A et al. (1996) Evaluation of the cytotoxic mechanism mediated by baccatin III, the synthetic precursor of taxol. Chem Biol Interact 101:103-14
Grover, S; Rimoldi, J M; Molinero, A A et al. (1995) Differential effects of paclitaxel (Taxol) analogs modified at positions C-2, C-7, and C-3' on tubulin polymerization and polymer stabilization: identification of a hyperactive paclitaxel derivative. Biochemistry 34:3927-34
Chen, R; Kingston, D G (1994) Isolation and structure elucidation of new taxoids from Taxus brevifolia. J Nat Prod 57:1017-21
Samaranayake, G; Neidigh, K A; Kingston, D G (1993) Modified taxols, 8. Deacylation and reacylation of baccatin III. J Nat Prod 56:884-98
Liang, J; Kingston, D G (1993) Two new taxane diterpenoids from Taxus mairei. J Nat Prod 56:594-9