Date of Award
Honors Thesis (Colby Access Only)
Colby College. Chemistry Dept.
Julie T. Millard
Paul G. Greenwood
In chemical terms an alkylating agent is a compound capable of replacing a proton in another molecule by an alkyl cation. In terms of cancer chemotherapy alkylating agents are a class of drugs that include some of the most useful clinical agents (Hartley, 1993). In the early endeavors to understand the biological effects of alkylating agents it was determined that difunctional or bifunctional agents exert more powerful cytotoxic action than monofunctional agents (Brookes and Lawley, 1961a). Alkylating agents have the ability to form interstrand and intrastrand cross-links in DNA, and this is believed to be how they exert their cytotoxic effect The formation of a cross-link is a two step process. First, one of the functional groups must bind to form a monoadduct, and then the second functional group must bind to form a cross-link. Not all of the monoadducts form cross-links and as such are genotoxic (Figure 1) (Hartley, 1993). Recent research has discovered that the sequence specificity of interstrand cross-linking for nitrogen mustards is determined by the conversion of the monoadduct to the cross-link, rather than having specificity in the initial formation ofthe monoadduct (Hopkins et al., 1991). The predominant site of alkylation of nucleic acids is the N7 position of guanine, which is the most nucleophilic site among the bases of DNA. It has since been determined that the extent of guanine N7 alkylation correlates positively with cytotoxicity (Sunters et al., 1992). Original work postulated that interstrand cross-links occur at a duplex 5'-GC sequence. It was reasoned that the alkylating agent must be at least 8 Ain length in order to span the distance between the N7 position of guanines on opposite strands (Brookes and Lawley, 1961a).
Alkylating agents, cross-links, DNA, monoadducts
Recommended CitationPimentel, Elisabeth Aimee, "DNA Bending Induced by Diepoxybutane" (1998). Honors Theses. Paper 421.
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