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Analysis of structure activity relationships for LPS-mimetic activities of taxane analogs in murine macrophages

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

John F. Kadow

Discovery Chemistry Department, Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Wallingford, Connecticut, USA

Craig R. Fairchild

Oncology Drug Discovery, Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Princeton, New Jersey, USA

Kathy A. Johnston

Oncology Drug Discovery, Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Princeton, New Jersey, USA

Stefanie N. Vogel

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA, vogel{at}bob.usuf2.usuhs.mil

The anti-tumor agent, paclitaxel (active ingredient of Taxol^®), is best recognized for its ability to bind to microtubules and to block cell division. However, it has more recently been demonstrated to mimic the varied effects of bacterial lipopolysaccharide (LPS) in murine macrophages, actions that appear to be dissociable from its well-characterized ß-tubulin binding capacity. Secretion of tumor necrosis factor alpha (TNF) and induction of TNF gene expression were assessed in macrophages treated with paclitaxel analogs. Two structural modifications resulted in elevated TNF mRNA and protein secretion: (i) the presence of a cyclopropane carboxylate ester at C-4 rather than an acetate; or (ii) deoxygenation of the C-7 position. Certain modifications essentially eliminated activity: derivatization of the side chain 2' hydroxy group to form an ethyl carbonate, the presence of a benzoate at C-4 rather than an acetate, or de-acetylization to leave a free hydroxy group at the C-10 position. Substitution of the phenyl group at the 3' carbon position of the side chain with a 2-furyl group or the presence of a 2- or 3-pyridine carboxylate moiety at C-2 rather than a benzoate also resulted in a significant reduction in TNF. These structure—activity relationships can be distinguished from those that affect the cytotoxic effects of paclitaxel which are attributable to its microtubule binding activity.

Journal of Endotoxin Research, Vol. 5, No. 5-6, 261-267 (1999)
DOI: 10.1177/09680519990050050201


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