Inactivation of O6-Alkylguanine-DNA Alkyltransferase by Folate Esters of O6-Benzyl-2‘-deoxyguanosine and of O6-[4-(Hydroxymethyl)benzyl]guanine
journal contributionposted on 18.10.2007, 00:00 by Sahar Javanmard, Natalia A. Loktionova, Qingming Fang, Gary T. Pauly, Anthony E. Pegg, Robert C. Moschel
O6-Alkylguanine-DNA alkyltransferase (alkyltransferase) provides an important source of resistance to some cancer chemotherapeutic alkylating agents. Folate ester derivatives of O6-benzyl-2‘-deoxyguanosine and of O6-[4-(hydroxymethyl)benzyl]guanine were synthesized and tested for their ability to inactivate human alkyltransferase. Inactivation of alkyltransferase by the γ-folate ester of O6-[4-(hydroxymethyl)benzyl]guanine was similar to that of the parent base. The γ-folate esters of O6-benzyl-2‘-deoxyguanosine were more potent alkyltransferase inactivators than the parent nucleoside. The 3‘-ester was considerably more potent than the 5‘-ester and was more than an order of magnitude more active than O6-benzylguanine, which is currently in clinical trials to enhance therapy with alkylating agents. They were also able to sensitize human tumor cells to killing by 1,3-bis(2-chloroethyl)-1-nitrosourea, with O6-benzyl-3‘-O-(γ-folyl)-2‘-deoxyguanosine being most active. These compounds provide a new class of highly water-soluble alkyltransferase inactivators and form the basis to construct more tumor-specific and potent compounds targeting this DNA repair protein.