Fluorinated antitumor agents

In the course of our study on the rational design, synthesis and SAR of new antitumor taxoids, we became interested in incorporating fluorine(s) into paclitaxel and taxoids in order to investigate the effects of fluorine on cytotoxicity, blocking of known metabolic pathways, and its use as a probe for identifying bioactive conformation(s) of taxane antitumor agents. 

For recent fluorinated nucleosides reviews, see (a) Meng, W-D. and Qing F-L. (2006) Fluori-nated nucleosides as antiviral and antitumor agents. Current Topics in Medicinal Chemistry, 6, 1499-1528 (b) Qing, F-L. and Qiu, X-L. (2007) Synthesis of gem-difluoromethylated sugar nucleosides. In Current Fluoroorganic Chemistry, ACS Symposium Series 949, pp. 305-322 and references cited therein. 

Keywords Anthraq clines - Fluoroanthraq clines Fluorinated antitumor agents... 

The practice of introducing fluorine atoms into molecules of biological interest, such as steroids, carbohydrates, antitumor agents, and other biologi-... 

The hydroxyl group in C-9 is very important for the antitumor activity of anthracyclines, and many derivatives have been synthesized confirming this. The only compound with an interesting activity was amrubicin (SM-5887), a 9-aminoanthracychne that in clinical trials showed almost the same antitumor activity and less cystic irritability as compared to DOXO and EPI [31,32]. When this hydroxyl group was substituted with a fluorine atom, the correspondent derivative showed lower activity as an antitumor agent than the reference compoimds (personal impubhshed data). Therefore, only chemical references are present in the literature on these derivatives. 

Reviews. - The topics, how functional NMR imaging and spectroscopy have been used in predicting response to anticancer therapy in rectal cancers and to assess the biliary excretion of chemotherapeutics, was explored as a review. With analytical fluorine NMR one may study noninvasively in vivo metabolites and pharmacokinetics of antibiotics, antitumor agents, and chemical warfare agents. An example was given of the use of NMR spectroscopy for imaging in humans as a short review. " ... 

Rebeccamycin is an antitumor or antibiotic agent isolated from bacteria " and contains a maleimide indolocarbazole framework. The Trp units in this molecule are chlorinated at the C-7 position and a flavin-dependent halogenase was identified as the enzyme that carries out this chlorination (Scheme 10). " There are many other halogenating enzymes known in the literature and these enzymes are responsible for the syntheses of metabolites containing bromine, chlorine, and fluorine. ... 

The antitumor chemotherapy agent clofarabine (104) sports halogen on the purine as well as on the sugar. The major portion of the synthesis involves preparation of the requisite fluorine-substituted furanose (101). The sequence begins with the conversion of the only free hydroxyl in allofuranose bis(acetonide) (95) to its tosylate (96). This group is then displaced by fluorine in its reaction with potassium fluoride to afford... 

In a previous paper [1], we reviewed the isolation of quassinoids, alkaloids, and fatty acids from Simaroubaceous plants during the period 1972-1988 and discussed their biological activities, such as antitumor, antimalarial, and anti-inflammatory agents as well as insect antifeedants, amoebicides, and herbicides. This review will add new quassinoids isolated from Simaroubaceous plants from 1988 onwards and their biological activities, for example, antitumor, anti-tumor-promotor (= inhibitor against TPA-induced EBV-EA activation), anti-HIV, anti-tuberculosis, and insect antifeedant activities. Furthermore, the stability of quassinoids, lower activities of degradation products, and the synthesis of fluorinated quassinoids are also described. 

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