Synthesis and Studies of N, N‐(Dimethylamino) Methylene Prodrugs of Gemcitabine, Ara‐A and Ara‐G

Abstract

There is a need for developing prodrugs of nucleoside analogs to overcome limitations of permeability and bioavailability. One approach to nucleoside modification is by replacing the exocyclic amino groups on the nucleoside bases of adenosine, guanosine and cytidine with N, N‐(dialkylamino) methylene side chains to form their analogous amidine prodrug derivatives to improve their lipophilicity. In this study, the N, N‐(dimethylamino) methylene prodrugs of gemcitabine, 9‐β‐D‐arabinofuranosyladenine (Ara‐A), and 9‐β‐D‐arabinofuranosyl guanine (Ara‐G) were synthesized and their log P and hydrolysis rate constants were compared to 2′‐deoxycytidine and Ara‐C. Partition coefficients between 1‐octanol and the phosphate buffer saline (PBS) for all compounds were measured using the shake‐flask procedure. The lipophilicity of the prodrugs ranged from 1 to 1.5 fold more than the parent unmodified nucleoside. The hydrolytic pseudo‐first order rate constants were determined spectrophotometrically in PBS at 37 deg C. The hydrolytic studies indicated conversion of the prodrugs to the parent drugs was spontaneous with corresponding half‐lives of the prodrug ranging from 3 to more than 14 h. The dimethylamino‐methylene pro‐drug derivatives of Ara–G and Ara‐A were found to be more stable than the corresponding cytosine analogs. The Ara‐G prodrug derivative was the most stable derivative in terms of hydrolysis to its parent nucleoside. Cytotoxicity studies in an MCF‐7 cell line showed limited cytotoxic activity. These studies provide a basis to modulate the lipophilicity and hydrolytic stabilities of such nucleosides by varying the N,N‐dialkyl substitution to give derivatives with greater lipophilicity and stability.Support or Funding InformationSupported by the Graduate Studies Department of MCPHS University and Saudi Arabian Cultural Mission