DNA binding studies of antitumor antibiotics and antitumor anthracene derivatives: Computer simulations and spectrophotometric titrations.

Persistent Link:
http://hdl.handle.net/10150/185221
Title:
DNA binding studies of antitumor antibiotics and antitumor anthracene derivatives: Computer simulations and spectrophotometric titrations.
Author:
Hill, Gordon Craig.
Issue Date:
1990
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Quinocarcin binds to d(ATGCAT)₂ with a preferred direction of 3' and the R configuration at C4 of the drug. A mode of action involving ring opening of the oxazolidine ring to form an iminium ion which can then alkylate the N2 of guanine has been reinforced by the current computer modeling study. The absolute configuration for quinocarcin should be reversed based on the fact that the optical isomer of the structure arbitrarily assigned in the literature forms a much better binding complex to DNA. Anthramycin binds to the 2-amino group of guanine but its mechanism of action proceeds through a neutral imine. The 3' direction is again favored but for this molecule, the preferred configuration is S. This computer modeling study provided a basis for a 2D NMR study which confirmed that anthramycin forms a 3'S adduct when it binds to d(ATGCAT)₂. Bisantrene and R9 are synthetic anthracene derivatives with antitumor activity. Use of UV spectroscopy provided insight into the ability of these compounds to intercalate between the base pairs of double helical DNA. Standard Scatchard plot analysis proved useless in determining the binding parameters. A McGhee-von Hippel equation was able to describe a portion of the data but a smoothing spline function was able to describe the data completely. Naphthyridinomycin studies indicate that it too prefers a covalent adduct in which the direction is 3' and the configuration is R at C7. When the noncovalent drug binds to d(ATGCAT)₂ it may bind with either the C3a face or the C7 face closest to N2 of guanine. Iminium ion mechanisms have been proposed for the binding of naphthyridinomycin to N2 of guanine in the minor groove of DNA and the computer modeling presents evidence to support such mechanisms. Saframycin A binds much better to d(GATGCATC)₂ as a hydroquinone species but the quinone can still bind in the same site. The 3' direction is clearly preferred with the R configuration at C7. The hydrogen bonding network of the hydroquinone is conserved in the noncovalent, iminium ion, and covalent 3'R models after 32 ps of dynamics. Iminium ion mechanisms have been proposed for the binding of saframycin A to N2 of guanine in the minor groove of DNA and the computer modeling presents evidence to support such mechanisms.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Chemistry
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmaceutical Sciences; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Remers, William A.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleDNA binding studies of antitumor antibiotics and antitumor anthracene derivatives: Computer simulations and spectrophotometric titrations.en_US
dc.creatorHill, Gordon Craig.en_US
dc.contributor.authorHill, Gordon Craig.en_US
dc.date.issued1990en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractQuinocarcin binds to d(ATGCAT)₂ with a preferred direction of 3' and the R configuration at C4 of the drug. A mode of action involving ring opening of the oxazolidine ring to form an iminium ion which can then alkylate the N2 of guanine has been reinforced by the current computer modeling study. The absolute configuration for quinocarcin should be reversed based on the fact that the optical isomer of the structure arbitrarily assigned in the literature forms a much better binding complex to DNA. Anthramycin binds to the 2-amino group of guanine but its mechanism of action proceeds through a neutral imine. The 3' direction is again favored but for this molecule, the preferred configuration is S. This computer modeling study provided a basis for a 2D NMR study which confirmed that anthramycin forms a 3'S adduct when it binds to d(ATGCAT)₂. Bisantrene and R9 are synthetic anthracene derivatives with antitumor activity. Use of UV spectroscopy provided insight into the ability of these compounds to intercalate between the base pairs of double helical DNA. Standard Scatchard plot analysis proved useless in determining the binding parameters. A McGhee-von Hippel equation was able to describe a portion of the data but a smoothing spline function was able to describe the data completely. Naphthyridinomycin studies indicate that it too prefers a covalent adduct in which the direction is 3' and the configuration is R at C7. When the noncovalent drug binds to d(ATGCAT)₂ it may bind with either the C3a face or the C7 face closest to N2 of guanine. Iminium ion mechanisms have been proposed for the binding of naphthyridinomycin to N2 of guanine in the minor groove of DNA and the computer modeling presents evidence to support such mechanisms. Saframycin A binds much better to d(GATGCATC)₂ as a hydroquinone species but the quinone can still bind in the same site. The 3' direction is clearly preferred with the R configuration at C7. The hydrogen bonding network of the hydroquinone is conserved in the noncovalent, iminium ion, and covalent 3'R models after 32 ps of dynamics. Iminium ion mechanisms have been proposed for the binding of saframycin A to N2 of guanine in the minor groove of DNA and the computer modeling presents evidence to support such mechanisms.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectChemistryen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmaceutical Sciencesen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorRemers, William A.en_US
dc.contributor.committeememberMartin, Arnolden_US
dc.contributor.committeememberBates, Robert B.en_US
dc.contributor.committeememberMash, Eugene A.en_US
dc.contributor.committeememberTimmermann, Barbaraen_US
dc.contributor.committeememberKollman, Peteren_US
dc.identifier.proquest9108421en_US
dc.identifier.oclc709911501en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.