A New Laboratory Scale Synthesis for the Anticancer Drug 3′-C-Ethynylcytidine­

Abstract

A new synthetic route for the preparation of larger quan- tities of the anticancer nucleoside analogue 3 -C-ethynylcytidine is described. Starting from cytidine which was orthogonally protected in three steps, the ketonucleoside analogue as the key intermediate was obtained through oxidation of the unprotected 3 -hydroxy group. Stereoselective addition of the trimethylsilyl-protected acetylide residue at the 3 -carbonyl group followed by a complete deprotection afforded 3 -C-ethynylcytidine in an overall yield of 24% in seven steps. Ethynylated ribonucleoside analogues have shown their in vitro and in vivo antitumor potential against serveral different cell lines as well as tumor models. 1 These test re- sults suggested 1-(3-C-ethynyl- -D-ribopentafuran- osyl)cytosine (3 -C-ethynylcytidine, ECyd) as the most promising representative of this new drug class which en- tered Phase I 2 clinical trials in patients with solid tumors. Due to its antitumor potential 1 and unique mechanism of action, 3,4 we consider ECyd as a possible new key struc- ture for newly developed anticancer drugs with optimized antitumor potential obtained by derivatization of this par- ent nucleoside analogue. This motivates the need for a facile synthetic route to ECyd in preparative amounts with high yields. The preparation of sugar-modified nucleoside analogues can be achieved as visualized in Scheme 1 through two main synthetic routes. Synthetic route 1 chooses an appropriate sugar as starting material that is monofunctionalized through the introduc- tion of protection groups, followed by the desired modifi- cation affording the modified sugar ready for the N- glycosidation. Meanwhile the appropriate nucleobase is protected and after activation both starting materials are condensed by building the N-glycoside bond to the pro- tected, modified nucleoside analogue, which is deprotect- ed subsequently to the desired nucleoside analogue. This reaction route requires a minimum of five reaction steps. Synthetic route 2 starts with the naturally occurring nucle- oside in which during the first two reaction steps protect- ing groups are introduced into the nucleobase and subsequently into the sugar residue. The protected nucle- oside is modified in the desired way affording the fully protected modified nucleoside analogue, which is depro- tected yielding the desired product. This reaction route re- quires a minimum of four reaction steps. The advantages of synthetic route 1 lie in its increased flexibility: - The reaction route can be designed to afford the - as well as the -anomer. - Carbocyclic nucleoside analogues are available. - Sugar residues with strong modifications can be used. Moreover the reaction condi-