Synthesis and Biological Evaluation of the Sulfur-containing Analogue of N-Methano-carba-Thymidine

ELHALEM, ELEONORA; RODRIGUEZ, JUAN BAUTISTA

Paris, Francia

Congreso; Tenth Tetrahedron Symposium “Challenges in Organic and Bioorganic Chemistry”; 2009

Elsevier

Nucleosides have demonstrated to be an abundant source of lead drugs in the search for antiviral and antitumor agents. The isosteric replacement of the furanose ring by a cyclopentyl moiety affords a new class of metabolically stable nucleosides analogues known as carbocyclic nucleosides. The absence of the oxygen atom at the furanose ring enhances potential structural variations at different positions not possible with conventional nucleosides. The carbanucleoside analogue N-methanocarbathymidine 1 (R = CH2) has been found to exhibit potent antiherpetic activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) (Figure 1).1 The antiviral efficacy of this carbocyclic nucleoside is even greater than that shown by acyclovir, a well-known antiherpetic agent.1 It had been considered that the isosteric replacement of the cyclopropyl moiety of 1 by an epoxy group to give 2 would be benefit for molecular recognition due to the smaller size of the epoxy group. However, it was not possible to obtain the theoretical pyrimidine derivative 2 as a consequence of intermolecular enol base attack onto the epoxy group to form a tricyclic system.2 Due to the incompatibility of an epoxy group adjacent to a pyrimidine base, it was thought that the isosteric replacement of the cyclopropyl moiety by a thiirane group to form 3 would be more appropriate.3 We have demonstrated that it is possible to synthesize simple models of pyrimidine carbanucleosides built on a 6-thiabycyclo[3.1.0]hexane system as pseudosugar unit. The synthetic approach to access to the target molecule 3 is illustrated in the Scheme. Biological evaluation of 3 indicated that the title compound exhibited similar antiherpetic potency than acyclovir, taken as positive control