Mechanism of bioactivation and DNA crosslinking activity of new mitomycin analogs.
Item
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Title
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Mechanism of bioactivation and DNA crosslinking activity of new mitomycin analogs.
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Identifier
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AAI9431364
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identifier
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9431364
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Creator
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He, Qiao-Yun.
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Contributor
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Adviser: Maria Tomasz
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Date
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1994
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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, Organic | Chemistry, Pharmaceutical | Chemistry, Biochemistry
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Abstract
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Two new disulfide derivatives of mitomycin C (MC), namely, BMY-25067 and KW-2149, are known to be more active but less toxic (especially, less myelosuppressive) than MC. A related synthetic dimeric mitomycin disulfide M-18 also shows remarkable antitumor activities. In order to understand the basis of the superior anticancer properties of this group of MC disulfide derivatives, experiments were conducted to investigate their mode of action as compared to that of MC. MC's mode of action is intrinsically related to its ability to bind covalently to DNA. The covalent reactivity of MC with DNA requires enzymatic or chemical reduction. In the first portion of this work, the transformations of BMY-25067 subjected to enzymatic or chemical reduction or acid-catalyzed "activation" were elucidated. It is found that the chemical behavior of BMY-25067 upon these activations is shown to be similar to that of MC, but the distribution of the activation products is very different from that of the analogous products of MC. M-18 gave similar transformation products. The results from enzymatic reduction kinetic studies of BMY-25067, M-18 and MC indicated that the new disulfide analogs of MC are subject to the same bioreductive activation process as MC. They were found to differ from MC, however, in a very interesting way: BMY-25067, KW-2149 and M-18 are subject to reductive activation by the thiol, glutathione. Another important new property of BMY-25067 is its ready rearrangement to the symmetrical dimeric mitomycin disulfide M-18 by thiol-exchange. Two mechanisms are proposed to explain these findings.;The influence of the 7-substituent on the DNA-cross-linking activity of mitomycin analogs was studied in detail. It is clear from the present results that reductive activation is the key to DNA-cross-linking: Mitomycin A (MA) cross-links DNA under Na{dollar}\sb2{dollar}S{dollar}\sb2{dollar}O{dollar}\sb4{dollar}, NADPH-cytochrome c reductase and thiol reductive conditions, whereas a mitosene analog, WV-15, and MC do so only under Na{dollar}\sb2{dollar}S{dollar}\sb2{dollar}O{dollar}\sb4{dollar} reductive conditions. The corresponding E{dollar}\sp{lcub}\rm o{rcub}{dollar}'s (MA {dollar}>{dollar} MC = WV-15) correlate with the fact that MA is activated faster than MC and WV-15. These results are also correlated with cytotoxicity. The most significant finding is that all three disulfide analogs (BMY-25067, KW-2149 and M-18) cross-link DNA under activation by thiols, despite the fact that they have low-redox-potentials like MC. It is shown that a new activation mechanism is responsible for this property, namely reduction of the disulfide group by thiols. This unique property may be responsible for the higher bioactivity of these analogs compared to mitomycin C.;The non-covalent interactions of mitomycins with DNA have been examined. It is found that mitomycins do not bind to DNA non-covalently, but their "activated form" can do so. The electrostatic attraction between drug and DNA predominately affects the binding. The hydrogen bonds between 10-carbamate group of drugs and DNA may contribute moderately to the stability of the complex. The binding of the drug is non-specific with respect to DNA composition and sequence.
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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.
