Sequence selectivity of azinomycin B in DNA alkylation and cross-linking: a QM/MM study.

Abstract

Azinomycin B--a well-known antitumor drug--forms cross-links with DNA through alkylation of purine bases and blocks tumor cell growth. This reaction has been modeled using the ONIOM (B3LYP/6-31+g(d):UFF) method to understand the mechanism and sequence selectivity. ONIOM results have been checked for reliability by comparing them with full quantum mechanics calculations for selected paths. Calculations reveal that, among the purine bases, guanine is more reactive and is alkylated by aziridine ring through the C10 position, followed by alkylation of the epoxide ring through the C21 position of Azinomycin B. While the mono alkylation is controlled kinetically, bis-alkylation is controlled thermodynamically. Solvent effects were included using polarized-continuum-model calculations and no significant change from gas phase results was observed.

• Authors: Dhurairajan Senthilnathan, Anbarasan Kalaiselvan, Ponnambalam Venuvanalingam
• Journal: Journal of molecular modeling (J Mol Model) Vol. 19 Issue 1 Pg. 383-90 (Jan 2013) ISSN: 0948-5023 [Electronic] Germany
• PMID: 22930355 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cross-Linking Reagents
• Intercellular Signaling Peptides and Proteins
• Naphthalenes
• Peptides
• azinomycin B
• Guanine
• DNA
• Adenine

Topics

• Adenine (chemistry)
• Alkylation
• Base Sequence
• Cross-Linking Reagents (chemistry)
• DNA (chemistry, genetics)
• Guanine (chemistry)
• Intercellular Signaling Peptides and Proteins
• Models, Molecular
• Naphthalenes (chemistry, pharmacology)
• Peptides (chemistry, pharmacology)
• Quantum Theory
• Static Electricity
• Thermodynamics