Identifier

etd-07072008-234509

Degree

Doctor of Philosophy (PhD)

Department

Chemistry

Document Type

Dissertation

Abstract

Rapid rotation of guanine base derivatives about Pt–N7 bonds results in fluxional behavior of models of the key DNA intrastrand G–G cross-link leading to anticancer activity of Pt(II) drugs (G = deoxyguanosine). This behavior impedes the characterization of LPtG2 models (L = one bidentate or two cis-unidentate carrier ligands; G = guanine derivative). The objective of this study is to understand the types of conformers formed as L is systematically varied. This work, relevant to Pt(II) anticancer drugs, has evolved from published studies with sp3 N-ligands (e.g., 2,2'-bipiperidine), to C2 symmetrical or unsymmetrical sp2 N-ligands having pyridine and/or triazine rings. NMR spectroscopy provided conclusive evidence that LPtG2 (L = 5,5'-dimethyl-2,2'-bipyridine (5,5'-Me2bipy), 3-(4'-methylpyridin-2'-yl)-5,6-dimethyl-1,2,4-triazine) (MepyMe2t), and bis-3,3'-(5,6-dialkyl-1,2,4-triazine) (R4dt)) complexes exist as interconverting mixtures of head-to-tail (HT) and head-to-head (HH) conformers. The triazine rings have a N plus lone pair in the same position as the C6H of pyridine rings, and NMR spectral studies indicate that the LPtG2 adducts are more dynamic when L has a triazine ring. For the first time, the two possible HH conformers (HHa and HHb) were identified for (MepyMe2t)Pt(5'-GMP)2, an adduct having an unsymmetrical L. Although O6–O6 clashes involving the two cis G bases favor the HT over the HH arrangement, the HH conformer of (R4dt)Pt(5'-GMP)2 adducts has a high abundance (~50%), a finding attributed to a reduction in O6–O6 steric clashes permitted by the overall low steric effects of R4dt ligands. The (R4dt)Pt(d(G*pG*)) adduct (G* = N7 platinated G residue linked with a sugar-phosphodiester backbone), is the first adduct having a high abundance of a fourth form. The characteristics of this form suggest it is the elusive lambda HT conformer; in addition, this adduct had the normally observed HH1, HH2 and delta HT conformers. Studies with the (R4dt)Pt(d(G*pG*)) adducts provided the first clear evidence that the sugar-phosphodiester backbone between two adjacent G’s slows the rate of exchange between the conformers. For (R4dt)Pt(d(G*pG*)), a 3'-flanking T has no significant influence on the structure of the d(G*pG*) cross-link or the distribution of conformers, whereas the 5'-T residue led to the exclusive presence of the HH1 conformer.

Date

2008

Document Availability at the Time of Submission

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.

Committee Chair

Luigi G. Marzilli

Included in

Chemistry Commons

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