Effects of the bifunctional alkylating agents mitomycin C and nitrogen mustards on the structure of DNA.
Item
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Title
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Effects of the bifunctional alkylating agents mitomycin C and nitrogen mustards on the structure of DNA.
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Identifier
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AAI8915581
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identifier
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8915581
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Creator
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Chawla, Anil Kumar.
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Contributor
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Adviser: Maria Tomasz
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Date
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1988
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Language
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English
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Publisher
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City University of New York.
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Subject
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Chemistry, Biochemistry
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Abstract
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Mitomycin C (MC) can alkylate DNA monofunctionally or bifunctionally depending upon the activation of one or both masked functions of this drug. One can select monofunctional or bifunctional activation of MC using appropriate conditions of reducing agents. The mechanism which governs such activation was determined by analysis of adducts distribution as shown by high-performance liquid chromatography (HPLC) of enzymatically digested complexes of M. luteus DNA and poly(dG-dC). Effects of MC adducts on DNA conformation and dynamics were determined to assess the altered conformational behavior of selectively modified DNA and poly(dG-dC). We showed by means of circular dichroism (CD) and HPLC that all types of Z-DNAs are substrates for monofunctional alkylation by MC and remain in the Z-form. Upon bifunctional activation of MC, Z-form of poly(dG-dC)/Co{dollar}\sp{lcub}3+{rcub}{dollar} reverts to B-form and crosslinked adduct is formed. No such Z {dollar}\to{dollar} B shift is possible in poly(dG-m{dollar}\sp5{dollar}dC) thus in this case MC binding is terminated at monofunctional stage. Experimental results showed a good correlation with computer assisted energy minimized molecular models. These results indicate that Z-DNA can not be crosslinked by MC.;Effects of alkylation products of nitrogen mustards were also determined on B {dollar}\to{dollar} Z transitions of poly(dG-dC). Bis (2-chloroethyl)methylamine (HN2) was used as a bifunctional and N,N-dimethyl 2-chloroethylamine (HN1) as a monofunctional alkylating agent. Extent of modification of the guanine was determined by HPLC of perchloric acid digested samples. Results showed a good correlation between the loss of intensity of 187 nm band of vacuum CD and the extent of modification of guanine in all complexes. B {dollar}\to{dollar} Z inhibition was observed by all complexes and it may be due to the interruption of cooperative B {dollar}\to{dollar} Z transition process as samples were denatured at the alkylated base pairs.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
