Doctor of Philosophy (PhD)
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.
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Maheshwari, Vidhi, "Retro Models of the Cisplatin-DNA Cross-link with Carrier Ligands Having sp2 N-donor Triazine Rings" (2008). LSU Doctoral Dissertations. 1989.
Luigi G. Marzilli