Use of Fluorine in the Medicinal Chemistry and Chemical Biology of Bioactive Compounds–A Case Study on Fluorinated Taxane Anticancer Agents Iwao Ojima* [a] Introduction It has been shown that the introduction of fluorine to a bioac- tive molecule causes minimal steric alterations and, hence, can facilitate interactions of that biomolecule with enzyme active sites, receptor recognition sites, transport mechanisms, and other biological systems. [1,2] At the same time, however, the in- troduction of fluorine significantly alters the physico-chemical properties of the bioactive molecule because of its large elec- tronegativity. Thus, this type of modification can also induce modified biological responses. [1,2] Rational designs exploiting these special properties of fluo- rine have been successful in the development of new and ef- fective biochemical tools as well as medicinal and therapeutic agents. [2] Fluorinated congeners can also serve as excellent probes for the investigation of biochemical mechanisms. 19 F NMR spectroscopy can provide unique and powerful tools for mechanistic investigations in biology. [2] This minireview describes the exploitation of the unique nature of fluorine in the medicinal chemistry and chemical bi- ology of taxane anticancer agents as a showcase in this field of research. Taxane Anticancer Drugs Paclitaxel (Taxol ¾ ) and docetaxel (Taxotõre ¾ ) are two of the most important anticancer drugs, approved for clinical use in chemotherapy against various human tumors, for example, metastatic breast cancer, ad- vanced ovarian cancer, non- small-cell lung cancer, and Kapo- si's sarcoma. [3,4] These drugs are currently un- dergoing clinical trials worldwide for the treatment of other can- cers, such as head and neck, prostate, and cervical cancers. Ef- fective chemotherapy in combi- nation with other anticancer agents like cisplatin, carboplatin, or doxorubicin has also been developed. These ™taxane∫ anti- cancer drugs bind to the b-tubulin subunit, accelerate the poly- merization of tubulin, and stabilize the resultant microtubules, thereby inhibiting their depolymerization. This results in the arrest of the cell-division cycle, mainly at the G2/M stage, and leads to apoptosis through the cell-signaling cascade. [5,6] Al- though both paclitaxel and docetaxel possess potent antitumor activity, recent reports have shown that treatment with these drugs often encounters undesirable side effects as well as drug resistance. [3,4,7] Therefore, it is important to develop new taxane anticancer agents with fewer side effects, superior pharmaco- logical properties, and improved activity against various classes of tumors, especially against drug-resistant human cancer. Fluorotaxane Anticancer Agents In the course of our extensive studies on the design, synthesis, and structure±activity relationships (SAR) of taxane anticancer agents, we synthesized fluorine-containing taxanes by means of the b-lactam synthon method [8±10] (Scheme 1) to investigate the effects of fluorine incorporation on cytotoxicity and the blockage of known metabolic pathways. [11±13] The primary sites [a] Prof. I. Ojima Institute of Chemical Biology and Drug Discovery and Department of Chemistry, State University of New York Stony Brook, NY 11794-3400 (USA) Fax:(+ 1)631-632-7942 E-mail:iojima@notes.cc.sunysb.edu Scheme 1. Synthesis of fluorine-containing taxanes by means of the b-lactam synthon method. HMDS = hexamethyl- disilazide. 628 ¹ 2004 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim DOI: 10.1002/cbic.200300844 ChemBioChem 2004,5,628±635