title: Synthesis and evaluation of 1,2,8, 8a-Tetrahydrocyclopropa[c]pyrrolo[3,2-e]indol-4(5H)-one, the parent alkylation subunit of CC-1065 and the duocarmycins: impact of the alkylation subunit substituents and its implications for DNA alkylation catalysis.
abstract: The synthesis of 1,2,8,8a-tetrahydrocyclopropa[c]pyrrolo[3, 2-e]indol-4(5H)-one (CPI), the parent CC-1065 and duocarmycin SA alkylation subunit, is detailed. The parent CPI alkylation subunit lacks the C7 methyl substituent of the CC-1065 alkylation subunit and the C6 methoxycarbonyl group of duocarmycin SA, and their examination permitted the establishment of the impact of these natural product substituents. The studies revealed a CPI stability comparable to the CC-1065 alkylation subunit but which was 6x more reactive than the (+)-duocarmycin SA alkylation subunit, and it displayed the inherent reaction regioselectivity (4:1) of the natural products. The single-crystal X-ray structure of (+)-N-BOC-CPI depicts a near identical stereoelectronic alignment of the cyclopropane accounting for the identical reaction regioselectivity and a slightly diminished vinylogous amide conjugation relative to (+)-N-BOC-DSA suggesting that the stability distinctions stem in part from this difference in the vinylogous amide as well as alterations in the electronic nature of the fused pyrrole. Establishment of the DNA binding properties revealed that the CPI-based agents retain the identical DNA alkylation selectivities of the natural products. More importantly, the C6 methoxycarbonyl group of duocarmycin SA was found to increase the rate (12-13x) and efficiency (10x) of DNA alkylation despite its intrinsic lower reactivity while the CC-1065 C7 methyl group was found to slow the DNA alkylation rate (4x) and lower the alkylation efficiency (ca. 4x). The greater DNA alkylation rate and efficiency for duocarmycin SA and related analogues containing the C6 methoxycarbonyl is proposed to be derived from the extended length that the rigid C6 methoxycarbonyl provides and the resulting increase in the DNA binding-induced conformational change which serves to deconjugate the vinylogous amide and activate the alkylation subunit for nucleophilic attack. The diminished properties resulting from the CC-1065 C7 methyl group may be attributed to the steric impediment this substituent introduces to DNA minor groove binding and alkylation. Consistent with this behavior, the duocarmycin SA C6 methoxycarbonyl group increases biological potency while the CC-1065 C7 methyl group diminishes it.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Boger
authors.forename: A
authors.initials: A
authors.lastname: Santillán
authors.forename: M
authors.initials: M
authors.lastname: Searcey
authors.forename: S R
authors.initials: SR
authors.lastname: Brunette
authors.forename: S E
authors.initials: SE
authors.lastname: Wolkenberg
authors.forename: M P
authors.initials: MP
authors.lastname: Hedrick
authors.forename: Q
authors.initials: Q
authors.lastname: Jin
mesh_terms: D000477:Alkylating Agents / Q000737:chemistry*; D000478:Alkylation; D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D001483:Base Sequence; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D004279:DNA, Viral / Q000737:chemistry; D000080890:Duocarmycins; D007202:Indicators and Reagents; D045563:Indolequinones; D007211:Indoles; D007933:Leucomycins / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: C412580:1,2,8,8a-tetrahydrocyclopropa(c)pyrrolo(3,2-e)indol-4(5H)-one; D000477:Alkylating Agents; D000903:Antibiotics, Antineoplastic; D004279:DNA, Viral; D000080890:Duocarmycins; D007202:Indicators and Reagents; D045563:Indolequinones; D007211:Indoles; D007933:Leucomycins; D009838:Oligodeoxyribonucleotides; D011758:Pyrroles; D015363:Quinolones; C066098:duocarmycin SA; C018782:CC 1065; D004247:DNA