Vinca alkaloids fluorination

Vinflumine (Javlor ) is a second-generation Vinca alkaloid. It is more active than the nonfluorinated parent compound (vinorelbine) in several cancers (Figure 8.7). Vinflumine is currently in Phase III clinical trials as a chemotherapeutic agent against a variety of cancers (metastasic breast cancer, small cell lung cancer, and bladder cancer). This drug inhibits mitotic assembly, via inhibition of tubulin polymerization in microtubules, a major element of the cytoskeleton. Effects of fluorine substimtion on tubulin affinity or on metabolism are not responsible for the increased efficiency and decreased toxicity. The synthesis of vinflumine is reported in Chapter 4. ... 

VFL is a novel vinca alkaloid obtained by semisynthesis using super-acidic chemistry to introduce two fluorine atoms selectively at the 20 position of VRLB. The preclinical evaluations of the new derivative VFL have already suggested that certain in vitro assays, in addition to in vivo experiments, could be proposed to select more rationally newer generation Vincas. Moreover, recent studies have demonstrated that certain newly identifled properties, such as antiangiogenic activities, could enlarge the therapeutic usage of natural and semisynthetic vinca alkaloids. VFL is presently in phase III experimentation for treatment of bladder cancer and nonsmall-cell lung cancer (NSCLC) [72]. 

Kruczynski A, Barret JM, Erievant C, Colpaert F, Fahy J, Hill BT. Antimitotic and tubulin-interacting properties of vinflunine, a novel fluorinated Vinca alkaloid. Biochem. Pharmacol. 1998 55 635-648. 

Vinca dimer indole alkaloids (e.g., vinblastine) act as spindle poison. They bind tubulin, inhibiting polymerization into microtubules, major elements of the cytoske-Vinblastine itself and its analogue vinorelbine (Navelbine ) are marketed for cancer therapies (Figure 4.48). Because of the obvious difficulty in synthesizing such highly complex structures, there were no reports on the preparation of fluorinated derivatives until the remarkable work of Jacquesy s group on the synthesis in super-acidic media. 5 ... 

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