title: CBI-CDPBO1 and CBI-CDPBI1: CC-1065 analogs containing deep-seated modifications in the DNA binding subunit.
abstract: The synthesis and preliminary examination of CBI-CDPBO1 (2) and CBI-CDPBI1 (3), CBI analogs of CC-1065 (1) and the duocarmycins incorporating the 3-carbamoyl-1,2-dihydro-3H-pyrrolo[3,2-e]benzoxazole-7-carboxylate (CDPBO) and 3-carbamoyl-1,2-dihydro-3H-pyrrolo[3,2-e]benzimidazole-7-carboxylate (CDPBI) DNA binding subunits, are detailed. The agents contain deep-seated modifications in the DNA binding subunits of the natural products with incorporation of a nitrogen capable of functioning as a hydrogen bond acceptor (CDPBO, CDPBI) or hydrogen bond donor (CDPBI) on their inside concave face which is in intimate contact with the minor groove floor. The CDPBO subunit was prepared through use of a novel and effective MnO2-mediated oxidative coupling of 2-(benzyloxy)ethylamine with 5-hydroxyindole (4) to directly provide 2-[(benzyloxy)methyl]pyrrolo[3,2-e]benzoxazole (6, 48%) in a reaction cascade that initially proceeds with amine regioselective C4 nucleophilic addition to the in situ generated p-quinone monoimine 13. Subsequent conversion of 6 to 8 (debenzylation; MnO2-NaCN, CH3OH) and selective reduction of the fused pyrrole (Et3SiH-CF3CO2H) completed the synthesis of the 1,2-dihydro-3H-pyrrolo[3,2-e]benzoxazole-7-carboxylate ring system. The CDPBI subunit was prepared through selective C4 nitration of 22 followed by reduction of the nitro group and acid-catalyzed closure to the corresponding 2-[(benzyloxy)methyl]pyrrolo[3,2-e]benzimidazole 25. The final conversion of 25 to the 1,2-dihydro-3H-pyrrolo[3,2-e]benzimidazole-7-carboxylate ring system (CDPBI) followed the same protocols introduced for CDPBO. The DNA alkylation efficiencies of 2 and 3 were identical and both were substantially diminished relative to that of CBI-CDPI1 (40). Thus, the introduction of a single nitrogen atom in the DNA binding subunit of 40 has a pronounced and detrimental effect on the relative efficiency (100 x) of DNA alkylation. Consistent with these observations, the in vitro cytotoxic activity of (+)-2 and (+)-3 were comparable (IC50 = 200 pM, L1210) and 40 x less potent than (+)-40 (IC50 = 5 pM, L1210). In contrast to the large impact these small structural changes had on the efficiency of DNA alkylation, the selectivity of DNA alkylation by 2 and 3 was unperturbed and both agents were found to alkylate the same major sites as CBI-CDPI1 (40). The potential origin of these effects is discussed.
authors.affiliation: Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Boger
authors.forename: W
authors.initials: W
authors.lastname: Yun
authors.forename: H
authors.initials: H
authors.lastname: Cai
authors.forename: N
authors.initials: N
authors.lastname: Han
mesh_terms: D000478:Alkylation; D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry*; D001483:Base Sequence; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology; D001583:Benzoxazoles / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D004279:DNA, Viral / Q000737:chemistry*; D000080890:Duocarmycins; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D007933:Leucomycins / Q000737:chemistry*; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship
chemical_list: D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D001583:Benzoxazoles; D004279:DNA, Viral; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; C096656:N(2)-((3'-carbamoyl-1',2'-dihydro-3'H-pyrrolo(3',2'-e)benzoxazol-7'-yl)carbonyl)-1,2,9,9a-tetrahydrocyclopropa(c)benz(e)indol-4-one; C096655:N2-((3'-carbamoyl-1',2'-dihydro-3'H-pyrrolo(3',2'-e)benzimidazol-7'-yl)carbonyl)-1,2,9,9a-tetrahydrocyclopropa(c)benz(e)indol-4-one; C018782:CC 1065