title: Inactivation of O(6)-alkylguanine-DNA alkyltransferase by folate esters of O(6)-benzyl-2'-deoxyguanosine and of O(6)-[4-(hydroxymethyl)benzyl]guanine.
abstract: 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 gamma-folate ester of O6-[4-(hydroxymethyl)benzyl]guanine was similar to that of the parent base. The gamma-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-(gamma-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.
authors: Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Post Office Box B, Building 538, Frederick, Maryland 21702, USA.
authors: Sahar
authors: S
authors: Javanmard
authors: Natalia A
authors: NA
authors: Loktionova
authors: Qingming
authors: Q
authors: Fang
authors: Gary T
authors: GT
authors: Pauly
authors: Anthony E
authors: AE
authors: Pegg
authors: Robert C
authors: RC
authors: Moschel
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004952:Esters; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002352:Carrier Proteins; D004952:Esters; D058973:Folate Receptors, GPI-Anchored; C095481:O(6)-(4-hydroxymethylbenzyl)guanine; D011956:Receptors, Cell Surface; C088636:O(6)-benzyl-2'-deoxyguanosine; D006147:Guanine; D005492:Folic Acid; D019853:O(6)-Methylguanine-DNA Methyltransferase; D003849:Deoxyguanosine; D002330:Carmustine