Synthesis of cis Adducts of Cyclopenta[cd]Pyrene with Deoxyguanosine and Deoxyadenosine

Abstract

Recent analysis of DNA adducts of cyclopenta[cd]pyrene (CPP) formed in vitro by reaction of CPP-3, 4-oxide, with calf thymus DNA, suggested ring opening of the enantiomeric 3,4-epoxide predominantly by cis addition. We describe herein the chemical synthesis of DNA adducts resulting from benzylic cis ring opening of CPP-3,4-oxide by the exocyclic amino group of 2′-deoxyguanosine (dG) and 2′-deoxyadenosine (dA). The methodology involves synthesis of cis-3,4-dihydro-3-amino-4-hydroxycyclopenta[cd]pyrene followed by its coupling with appropriately protected halo-purinedeoxyribose intermediates. The diastereomeric mixture of products resulted in the coupling reaction was separated by HPLC and characterized by 1H NMR and MS analysis. Co-chromatography of the synthetic standards with in vitro adducts confirmed the identity and the stereochemical preference of the CPP-DNA adducts.