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Novel Stable Camptothecin Derivatives Replacing the E-Ring Lactone by a Ketone Function Are Potent Inhibitors of Topoisomerase I and Promising Antitumor Drugs

Institut National de la Santé et de la Recherche Médicale U837, Université de Lille 2, Facultéde Médecine, Institut de Médecine Prédictive et Recherche Thérapeutique, Centre Oscar Lambret and Institut de Recherches sur le Cancer de Lille, Lille, France (A.L., C.B.-M., R.M., S.D., M.-H.D.-C., C.B.); and Division of Cancer Drug Discovery, Institut de Recherches Servier, Croissy sur Seine, France (S.L., L.K.-B., P.H., G.L., J.A.H., A.P.)

The E-ring lactone is the Achilles' heel of camptothecin derivatives: although it is considered necessary for the inhibition of the enzyme topoisomerase I (topo1), the opening of the lactone into a carboxylate abolishes the generation of topo1-mediated DNA breaks. S38809 is a novel camptothecin analog with a stable 5-membered E-ring ketone; therefore, it lacks the lactone function. DNA relaxation and cleavage assays revealed that S38809 functions as a typical topo1 poison by stimulating DNA cleavage at TG sites. The activity was strongly dependent on the stereochemistry of the C-7 carbon atom that bears the hydroxy group. S38809 proved to be a potent cytotoxic agent, with a mean IC₅₀ of 5.4 nM versus 11.6 nM for topotecan and 3.3 nM for SN38 (the active metabolite of irinotecan) on a panel of 31 human tumor cell lines. The cytotoxicity of S38809 and its ability to stabilize cleavable complexes was considerably reduced in camptothecin-resistant cells that express a mutated topo1, confirming that topo1 is its primary target. Cell death induced by topo1 poisoning requires the conversion of DNA single-strand breaks into double-strand breaks that can be detected by the formation of phosphorylated histone H2AX. In HCT116 cells, topotecan, SN38, and S38809 induced histone H2AX phosphorylation in S phase of the cell cycle, with S38809 being as potent as SN38 and 5-fold more potent than topotecan. In vivo, S38809 showed a marked antitumor activity against HCT116 xenografts. These findings open a new route for improving the pharmacological properties of camptothecin derivatives.

Address correspondence to: Dr. Amélie Lansiaux, INSERM U-837 and Centre Oscar Lambret, ICRL, 59045 Lille, France. E-mail: amelie.lansiaux{at}lille.inserm.fr