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Dna alkylation properties of enhanced functional analogs of cc 1065 incorporating the 1 2 9 9a tetrahydrocyclopropa 1 2 c benz 1 2 e indol 4 one cbi alkylation subunit

Dna alkylation properties of enhanced functional analogs of cc 1065 incorporating the 1 2 9 9a tetrahydrocyclopropa 1 2 c benz 1 2 e indol 4 one cbi alkylation subunit

Journal of the American Chemical Society 114(14): 5487-5496

Full details of a study of the DNA alkylation properties of analogs of (+)-CC-1065 possessing the 1,2,9,9a-tetrahydrocyclopropa[1,2-C]-benz[1,2-e]indol-4-one (CBI) alkylation subunit are described. Both enantiomers of N-BOC-CBI, a simple derivative of the alkylation subunit, exhibit an identical profile of DNA alkylation that is not distinguishable from that of (+)-N-BOC-CPI, the authentic alkylation subunit of (+)-CC-1065. In addition, the intensity of DNA alkylation as judged by the concentration of agent required for SV40 DNA fragment alkylation was determined to follow the following order: (+)-N-BOC-CBI > (-)-N-BOC-CBI (ca. 5-10x) and (+)-N-BOC-CBI > (+)-N-BOC-CPI (ca. 3-6x). A total of 40-45% of the adenines in the double-stranded DNA examined were found to be alkylated over a 10-fold agent concentration range. With three exceptions, the alkylation was found to occur at adenine flanked by a single 5' A or T base with a preference for 5'-d(A.ALPHA.)-3' > 5'-d(T.ALPHA.)-3'. In contrast, (+)-CBI-CDPI2 was found alkylate DNA in a more selective fashion, and a total of 20-25% of the adenines were alkylated over a 10000-1000-fold agent concentration range. The DNA alkylation was found to proceed with greater intensity (ca. 10000x) and with a readily distinguishable profile of selectivity in which the adenine N-3 alkylation site roved to be flanked by two 5' A or T bases: 5'-d(AA.ALPHA.)-3' 7G 5'-d(TT.ALPHA.)-3'> 5'-d(TA.ALPHA.)-3 .gtoreq. 5'-d(AT.ALPHA.)-3'. With (+)-CBI-CDPI2 there proved to be a strong preference for the fourth 5' base to be A or T, 5'-d(A/TXX.ALPHA.)-3' > 5'-d(G/CXX.ALPHA.)-3', a weaker preference for the fifth 5' base to be A or T, 5'-d(A/TXXX.ALPHA.)-3' > 5'-d(G/CXXX.ALPHA.)-3', and a weak preference for the 3' base preceeding the alkylation site to be a purine base, 5'-d(NNXX.ALPHA.Pu)-3' .gtoreq. 5'-(NNXX.ALPHA.Py)-3' where X = A or T . Potentially contributing to their enhanced cytotoxic potency, the CBI-based agents were found to alkylate DNA with a greater intensity and a faster relative rate than the corresponding CPI-based agent (e.g. k((+)-CBI-indole2)/k((+)-CPI-indole2) = 14). A discussion of the potential origin of the alkylation selectivity and the origin of the distinctions in the CBI and CPI-based agents is provided.

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Accession: 007223779

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DOI: 10.1021/ja00040a001

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