Epothilones are 16-membered macrolides, originally isolated from myxobacterium in soil. It exerts an anti-tumor effect, like paclitaxel (taxol®), by stabilization of microtubule from tubulin polymerization. Many epothilones showed to be more potent than taxol in stabilization of microtubule in the absence of GTP at both 4° and 37°C. Several epothilones are currently under different phases of clinical trials as anti-tumor agents and have shown promising therapeutic effects. One of them, 12,13-desoxy-epothilone B (dEpoB) (Chou et al PNAS, 98:8113, 2001) developed by MSKCC is entering phase II of its clinical trials. We recently created a new class of epothilones, represented by 26-trifluoro-9,10-dehydro-12,13-deoxyepothilone B (F3-deH-dEpoB, or in brief, Fludelone) via a new route of total synthesis and molecular editing. Complete tumor disappearance of human mammary carcinoma xenografts MX-1 was achieved by Fludelone, deH-dEpoB, deH-EpoB and F3-deH-21-OH-dEpoB following Q2D or Q3D x 5 or more times of 6 hr-iv infusion via tail vein of nude mice. Fludelone was also curative against human colon carcinoma HCT-116 xenograft, human leukemia CCRF-CEM xenografts, including taxol-resistant tumor CCRF-CEM/taxol. Remarkably, MX-1 tumors as large as 1gm (3.4% of body weight) have been successfully ablated following 25mg/kg, Q3Dx8, 6h-iv infusion in 5 out of 5 nude mice. Furthermore, the body weight of Fludelone treated mice recovered to the pre-treatment state within one week after stopping treatment. Following Q3Dx9 treatment, none of the treated mice have relapsed for over one month following stopping treatment. Fludelone has a curative dose range of three fold for different therapeutic regimens. This is perhaps the widest safety margin reported to date for a prospective cancer chemotherapeutic agent. Extensive studies have concluded that three factors that work jointly that are attributable to the remarkable anti-tumor effect of Fludelone are: i. Removal of the epoxyl group at C12-13 position improves anti-tumor selectivity so it won’t overly hurt normal organs or tissues. ii. Dehydroxylation at C9-10 position markedly increases anti-tumor efficacy, and iii. Trifluorination at C26 position not only protects the molecule from metabolic destruction but also improves the penetration of the molecule into cancer cells.
[Proc Amer Assoc Cancer Res, Volume 45, 2004]