Platinum Complexes With Tridentate Ligands as Models for Active Monofunctional Anticancer Drugs

<p>Pt(II) complexes bind preferentially at N7 of G residues of DNA, causing DNA structural distortions associated with anticancer activity. Some distortions induced by difunctional cisplatin are also found for monofunctional Pt(II) complexes with carrier ligands having bulk projecting toward the guanine base. This ligand bulk can be correlated with impeded rotation about the Pt–N7(guanine) bond. The objective of this study is to understand the influences of in-plane bulk of Pt(Ltri)G adducts (Ltri = tridentate carrier ligand, G = guanine derivative bound to a metal, but not tethered to another nucleobase). NMR spectroscopy provided conclusive evidence that Pt(Ltri)G (Ltri = di-(2-picolyl)amine (N(H)dpa), N-(6-methyl-2-picolyl)-N-(2-picolyl)amine (N(H)6-Medpa), di-(6-methyl-2-picolyl)amine (N(H)6,6′-Me2dpa), N-(6-methyl-2-picolyl)-N-(2-picolyl)amine (N(H)6,6′-Me2dpa), N(Me)-di-(6-methyl-2-picolyl)amine (N(Me)6,6′-Me2dpa), N(propionoic acid)-di-(6-methyl-2-picolyl)amine (N(prop)6,6′-Me2dpa), and tri-(6-methyl-2-picolyl)amine (6,6′,6′′-Me3tpa)) adducts exist as interconverting mixtures of syn and anti rotamers from the observation of two sharp, comparably intense guanine H8 NMR signals. Rotational interchange is impeded by Ltri, and the key interactions involved steric repulsions between the pyridyl and guanine rings. When G is added to [Pt(N(H)6,6′-Me2dpa)Cl]Cl, the expected Pt(N(H)6,6′-Me2dpa)G mono adduct forms having syn and anti conformers, but also the Pt(N(H)6,6′-Me2dpa)G2 bis adducts consisting of ΛHT and ΔHT conformers (HT = head-to-tail). When G is added to Pt(N(R)6,6′-Me2dpa)G adducts, the transformation of the bis adducts Pt(N(R)6,6′-Me2dpa)G2 are dramatically lessened, particularly when the bulk of the R group is increased. The stability of the Pt(N(R)6,6′-Me2dpa)G mono adducts are explained by the increased bulk of the N-substituent, making the bidentate coordination mode of the carrier ligand unfavorable.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

Chemistry

Year dc:date.available

2015

Author dc:creator

• Andrepont, Chase Koby

• monofunctional agents
• NMR
• platinum(II) complexes

Statement dc:rights

• withheld
• Secure the entire work for patent and/or proprietary purposes for a period of one year. Student has submitted appropriate documentation which states: During this period the copyright owner also agrees not to exercise her/his ownership rights, including public use in works, without prior authorization from LSU. At the end of the one year period, either we or LSU may request an automatic extension for one additional year. At the end of the one year secure period (or its extension, if such is requested), the work will be released for access worldwide.

Identifier

etd-05282015-073316
https://repository.lsu.edu/gradschool_dissertations/1443

OAI identifier oai:identifier

oai:repository.lsu.edu:gradschool_dissertations-2442