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Inactivation of O-6-Alkylguanine-DNA alkyltransferase by folate esters of O-6-Benzyl-2'-deoxyguanosine and of O-6- 4-(Hydroxymethyl)benzyl guanine

  1. Author:
    Javanmard, S.
    Loktionova, N. A.
    Fang, Q.
    Pauly, G. T.
    Pegg, A. E.
    Moschel, R. C.

  2. Author Address

    Natl Canc Inst, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. Penn State Univ, Coll Med, Dept Pharmacol, Hershey, PA 17033 USA.;Pegg, AE, Natl Canc Inst, Comparat Carcinogenesis Lab, Post Off Box B,Bldg 538, Frederick, MD 21702 USA.;aepl@psu.edu
    1. Year: 2007
    2. Date: Oct
  2. Journal: Journal of Medicinal Chemistry
    1. 50
    2. 21
    3. Pages: 5193-5201
  4. Type of Article: Article
  5. ISSN: 0022-2623
  1. Abstract:

    O-6-Alkylguanine-DNA alkyltransferase (alkyltransferase) provides an important source of resistance to some cancer chemotherapeutic alkylating agents. Folate ester derivatives of O-6-benzyl-2'-deoxyguanosine and of O-6- [4-(hydroxymethyl)benzyl] guanine were synthesized and tested for their ability to inactivate human alkyltransferase. Inactivation of alkyltransferase by the gamma-folate ester of O-6-[4-(hydroxymethyl)benzyl]guanine was similar to that of the parent base. The gamma-folate esters of O-6-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 O-6-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 O-6-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.

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  2. DOI: 10.1021/jm0705859
  3. View record in Web of Science®
  4. WOS: 000250110700017

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