The complex diterpenoid Taxol (paclitaxel) is an exciting anti-cancer drug that is currently in clinical use against ovarian and breast cancer. It acts by an unusual mechanism of promoting microtubule assembly, and we are studying this by the synthesis of specifically labeled analogs, with the aim of identifying the nature of the binding of taxol to microtubules. We are also looking at structure-activity relationships in the taxol area, with the aim of designing potent and readily accessible taxol analogs. One of our synthetic targets is a taxol analog with a novel bridged structure, while other targets include both ring-contracted and ring-enlarged versions of taxol. This project blends synthesis, biological studies, and molecular modeling in an integrated effort to improve on one of the most important new anti-cancer natural products of the past 30 years. Recent publications on Taxol are shown below. For a diagram showing structure-activity relationships of Taxol click here.
Recent Taxol® Chemistry Publications from the Kingston Group (1996-2000).
C. M. Lin, Y. Q. Jiang, A. G. Chaudhary, J. M. Rimoldi, D. G. I. Kingston, and E. Hamel. "A Convenient Tubulin-based Quantitative Assay for Paclitaxel (Taxol) Derivatives More Active Than the Parent Compound".Cancer Chemother. Pharmacol., 1996, 34, 136-140.
M. D. Chordia and D. G. I. Kingston, "Synthesis and Biological Evaluation of 2-epi-Paclitaxel", J. Org. Chem., 1996, 61, 799-801.
J. M. Rimoldi, A. A. Molinero, M. D. Chordia, M. M. Gharpure, and D. G. I. Kingston, "An Improved Method for the Separation of Paclitaxel and Cephalomannine", J. Nat. Prod., 1996, 59, 167-168.
D. G. I. Kingston, "Sorties and Surprises: Unexpected Reactions of Taxol", Rev. Latinoamer. Quim., 1996, 24, 69-75.
Y. Han, A. G. Chaudhary, M. D. Chordia, D. L. Sackett, B. Perez-Ramirez, D. G. I. Kingston, and S. Bane, "Interaction of a Fluorescent Derivative of Paclitaxel (Taxol®) with Microtubules and Tubulin-Colchicine", Biochemistry, 1996, 35, 14173-14183.
T. Pengsuparp, D. G. I. Kingston, K. A. Neidigh, G. A. Cordell, and J. M. Pezzuto, "Evaluation of the Cytotoxic Mechanism Mediated by Baccatin III, the Synthetic Precursor of Taxol", Chem.-Biol. Interact., 1996, 101, 103-114.
M. V. Blagosklonny, P. Giannakakou, W. S. El-Deiry, D. G. I. Kingston, P. I. Higgs, L. Neckers, and T. Fojo, "Raf-1/bcl-2 Phosphorylation: A Step from Microtubule Damage to Cell Death" Cancer Res.1997, 37, 130-135.
M. D. Chordia, D. G. I. Kingston, E. Hamel and C. M. Lin "Synthesis and Biological Activity of A-nor-Paclitaxel Analogs" Bioorg. Med. Chem., 1997, 5, 941-947.
X. Liang, D. G. I. Kingston, B. H. Long, C. A. Fairchild, and K. A. Johnston "Paclitaxel Analogs Modified in Ring C: Synthesis and Biological Evaluation" Tetrahedron, 1997, 53, 3441-3456.
R. Nicholov, M. D. Chordia, D. G. I. Kingston, F. DiCosmo, "Molecular Mobility of Nitroxyl Labelled Taxol Analogues During Tubulin Assembly". FEBS Lett., 1997, 405, 73-76.
A. A. L. Gunatilaka, M. D. Chordia and D. G. I. Kingston, "An Efficient Conversion of Cephalomannine to Paclitaxel and 3'N-Aroyl-3'N-debenzoylpaclitaxel Analogs" J. Org. Chem., 1997, 62, 3775-3778.
M. D. Chordia and D. G. I. Kingston, "Synthesis and Biological Evaluation of Amide-Linked A-Norpaclitaxels", Tetrahedron , 1997, 53, 5699-5710.
J. M. Watson, D. G. I. Kingston, M. D. Chordia, C. A. Rinehart, and J. S. Haskill, "Localization of the Structural Region of Taxol Responsible for Cytokine Gene Induction and Cytotoxicity in Human Ovarian Cancer Cells", Cancer Chemother. Pharm. 1998, 41, 391-397.
D. G. I. Kingston, "Studies on the Chemistry of Taxol®" Pure Appl. Chem., 1998, 70, 331-334.
Y. Han, H. Malak, A. G. Chaudhary, M. D. Chordia, D. G. I. Kingston, and S. Bane, "Distances Between the Paclitaxel, Colchicine, and Exchangeable GTP Binding Sites on Tubulin" Biochemistry 1998, 37, 6636-6644.
H. Yuan and D. G. I. Kingston, "Synthesis of 6a-Hydroxypaclitaxel, the Major Human Metabolite of Paclitaxel."Tetrahedron Lett., 1998, 39, 4967-4970.
D. G. I. Kingston, A. G. Chaudhary, M. D. Chordia, M. Gharpure, A. A. L. Gunatilaka, P. I. Higgs, J. M. Rimoldi, L. Samala, P. G. Jagtap, P. Giannakakou, Y. Q. Jiang, C. M. Lin, E. Hamel, B. H. Long, C. A. Fairchild, and K. A. Johnston,"Synthesis and Biological Evaluation of 2-Acyl Analogues of Paclitaxel (Taxol")" J. Med. Chem. 1998, 41, 3715-3726.
J. J. Pennington, A. G. Fett-Neto, S. A. Nicholson, D. G. I. Kingston, and F. DiCosmo "Acetyl-CoA:10Deacetylbaccatin-III-10-O-Acetyltransferase Activity in Leaves and Cell Suspension Cultures of Taxus cuspidata." Phytochemistry, 1998, 49, 2261-2266.
P. G. Jagtap and D. G. I. Kingston, "A Facile N-Debenzoylation of Paclitaxel: Conversion of Paclitaxel to Docetaxel." Tetrahedron Lett. 1999, 40, 189-192.
H. Yuan and D. G. I. Kingston "Synthesis and Biological Evaluation of C-1 and Ring Modified A-norpaclitaxels." Tetrahedron 1999, 55, 9089-9100.
H. Yuan, David G. I. Kingston, Chii M. Lin and Ernest Hamel "Synthesis and Biological Activity of a Novel C4-C6 Bridged Paclitaxel Analog." Tetrahedron 1999, 55, 9707-9716.
E. Baloglu and D. G. I. Kingston "The Taxane Diterpenoids" J. Nat. Prod. 1999, 62, 1448-1472.
Y.-K. Li, B. Poliks, L. Cegelski, M. Poliks, Z. Gryczynski, G. Piszczek, P. G. Jagtap, D. J. Studelska, D. G. I. Kingston, J. Schaefer, and S. Bane, "The Conformation of Microtubule-Bound Paclitaxel Determined by Fluorescence Spectroscopy and REDOR NMR." Biochemistry, 2000, 39, 281-291.
Y. Li, R. Edsall, Jr., P. G. Jagtap, D. G. I Kingston, and S. Bane "Equilibrium Studies of a Fluorescent Paclitaxel Derivative Binding to Microtubules." Biochemistry, 2000, 39, 616-623.
D. G. I. Kingston. Recent Advances in the Chemistry of Taxol. J. Nat. Prod, 2000, 63, 726-734.
L. He, P. G. Jagtap, D. G. I. Kingston, H.-J. Shen, G. A. Orr, and S. B.Horwitz. A Common Pharmacophore for Taxol and the Epothilones Based on the Biological Activity of a Taxane Molecule Lacking a C-13 Side Chain. Biochemistry 2000, 39, 3972-3978.
H. Yuan and D. G. I. Kingston "Synthesis and Biological Evaluation of C-6 and C-7 Modified Paclitaxels." Tetrahedron 2000, 56, 6407-6414.
M. D. Chordia, H. Yuan, P. G. Jagtap, J. F. Kadow, B. H. Long, C. R. Fairchild, K. A. Johnston, and D. G. I. Kingston "Synthesis and Bioactivity of 2,4-Diacyl Analogs of Paclitaxel." Biorg. Med. Chem. 2000, in press.