+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 007223779

Download citation: RISBibTeXText

DOI: 10.1021/ja00040a001


Related references

Functional analogies between actin tubulin and g proteins. Journal of Cellular Biochemistry Suppl. (14 Part C): 115, 1990

Synthesis and Properties of Sub-50-nm Europium Oxide Nanoparticles. Journal of Colloid and Interface Science 215(1): 179-182, 1999

Evaluation of functional GABA(B) receptors in dental pulp. Journal of Endodontics 27(10): 620-623, 2001

Synthesis and evaluation of 1'-[18F]fluorometoprolol as a potential tracer for the visualization of beta-adrenoceptors with PET. Nuclear Medicine and Biology 20(5): 637-642, 1993

An improved suicide vector for construction of chromosomal insertion mutations in bacteria. Gene (Amsterdam) 118(1): 145-146, 1992

Synthesis and evaluation of dopamine D3 receptor antagonist 11C-GR218231 as PET tracer for P-glycoprotein. Journal of Nuclear Medicine 46(8): 1384-1392, 2005

Synthesis and evaluation of dihydropyrroloquinoline compounds that selectively inhibit P-glycoprotein. Proceedings of the American Association for Cancer Research Annual Meeting 42: 953, 2001

Synthesis of n substituted derivatives of 1 o 1' alkenyl 2 acetyl sn glycero 3 phosphoethanolamine and their effects on platelet aggregation. Khimiko Farmatsevticheskii Zhurnal 24(9): 48-50, 1990

Synthesis and evaluation of dual site inhibitors of 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase. Bioorganic and Medicinal Chemistry Letters 21(17): 5092-5097, 2011

Synthesis and evaluation of dummy molecularly imprinted microspheres for the specific solid-phase extraction of six anthraquinones from slimming tea. Journal of Separation Science 38(8): 1263-1270, 2015

Synthesis and Photoreactivity of Aryl substituted 4,5-Dithienyl dithiol-2-ones. 2009

Synthesis and Preliminary Biological Study of Bisindolylmethanes Accessed by an Acid-Catalyzed Hydroarylation of Vinylindoles. Tetrahedron 68(26): 5203-5208, 2012

1,2,5-Trithiepin: A 10pi-Electron Heteroaromatic System. Journal of Organic Chemistry 62(8): 2432-2436, 1997

Synthesis and evaluation of AGN 193080 A potent agent for the reduction of intraocular pressure. Abstracts of Papers American Chemical Society 209(1-2): MEDI 193, 1995

Synthesis and evaluation of C3- and C4-substituted 2-aminobicyclo hexane-2,6-dicarboxylates at group II metabotropic glutamates receptors. Abstracts of Papers American Chemical Society 220(Part 1): MEDI 105, 2000