Guanine O6 to carrier ligand hydrogen bonding is a central feature of many hypotheses advanced to explain the anticancer activity of cis-type anticancer drugs, cis-PtA(2)X(2) (A(2) = diamine or two amines). Early structural evidence suggested that cis-Pt(NH(3))(2)(d(GpG)) (the cross-link model for the key cisplatin-DNA adduct) and other cis-PtA(2)(d(GpG)) adducts exist exclusively or mainly as the HH1 conformer with head-to-head (HH) bases. The dynamic motion of the d(GpG) in these adducts is too rapid to permit definitive characterization of both the conformation and the H-bonding. Hence, we use retro models having A(2) ligands designed to slow the motion. Here, we employ Me(2)ppz (N,N'-dimethylpiperazine), which lacks NH groups. Me(2)ppz is unique in having sp(3) N-methyl groups directly in the coordination plane, allowing the coexistence of multiple conformers but hindering dynamic motion in Me(2)ppzPt(d(GpG)) and Me(2)ppzPt(GpG) retro models. Dynamic processes are decreased enough in Me(2)ppzPt(d(GpG)) to permit HPLC separation of three abundant forms. After HPLC separation, the three re-equilibrate, proving that the three forms must be conformers and that Me(2)ppz has little influence on conformer distribution. This marks the first reported characterization of three abundant conformers for one cis-PtA(2)(d(GpG)) adduct. From NMR evidence, the Me(2)ppzPt(d(GpG)) HH1 conformer has uncanted bases. Another conformer, one of two recently discovered conformer types, has head-to-tail (HT) bases with Delta chirality. For this Delta HT1 form, several lines of evidence establish that the dinucleotide moieties have essentially identical structures in d(GpG) (and GpG) adducts of Me(2)ppzPt and other cis-PtA(2) complexes. For example, the shifts of the highly structure-sensitive G H8 NMR signals are almost identical for the Delta HT1 form of all adducts. In previous models, the stabilization of the Delta HT1 form could be attributed to G O6 H-bonding to A(2) NH groups. Such H-bonds are not possible for Me(2)ppz. The unambiguous conclusions are that G O6 H-bonding is weak and that neither canting nor H-bonding is essential in HH forms. These two features are present in almost all other small models but are essentially absent in the cross-link base pair (bp) step in duplexes. We conclude from our work that the forces favoring canting and H-bonding are weak, and we hypothesize that steric effects within the Lippard bp step adjacent to this cross-link bp step easily overcome these forces.

We employ retro models, cis-PtA2G2 (A2 = a diamine, G = guanine derivative), to assess the cross-linked head-to-head (HH) form of the cisplatin-DNA d(GpG) adduct widely postulated to be responsible for the anticancer activity. Retro models are designed to have minimal dynamic motion to overcome problems recognized in models derived from cisplatin [A2 = (NH3)2]; the latter models are difficult to understand due to rapid rotation of G bases about the Pt-N7 bond in solution and the dominance of the head-to-tail (HT) form in the solid. Observation of an HH form is unusual for cis-PtA2G2 models. Recently, we found the first HH forms for a cis-PtA2G2 model with A2 lacking NH groups in a study of new Me2ppzPtG2 models. (Me2ppz, N,N'-dimethylpiperazine, has inplane bulk which reduces dynamic motion by clashing with the G O6 as the base rotates into the coordination plane from the ground state position approximately perpendicular to this plane G = 5'-GMP and 3'-GMP.) The finding of an HH form (albeit in a mixture with HT forms) with both G H8 signals unusually downfield encouraged us to study additional Me2ppzPtG2 analogues in order to explain the unusual spectral features and to identify factors that influence the relative stability of HT and HH forms. Molecular modeling techniques suggest HH structures with the H8's close to the deshielding region of the z axis of the magnetically anisotropic Pt atom, explaining the atypical shift pattern. When G = 1-Me-5'-GMP, we obtained NMR evidence that the HH rotamer has a high abundance (34%) and that the three rotamers have nearly equal abundance. These findings and the observation that the relative HT distributions varied little or not at all as a function of pH when G = Guo, 1-MeGuo, or 1-Me-5'-GMP are consistent with two of our earlier proposals concerning phosphate groups in HT forms of cis-PtA2(GMP)2 complexes. We proposed that a G phosphate group can form hydrogen bonds with the cis G N1H ("second-sphere" communication) and (for 5'-phosphate) A2 NH groups. The new results with 1-Me-5'-GMP led us to propose a new role for a 5'-phosphate group; it can also favor the HH form by counteracting the natural preference for the G bases to adopt an HT orientation. Finally, the HH form was also sufficiently abundant to allow observation of a distinct 195Pt NMR signal (downfield of the resonance observed for the HT forms) for several complexes. This is the first report of an HH 195Pt NMR signal for cis-PtA2G2 complexes.

The cisplatin anticancer drug preferentially attacks the GG sequence of DNA duplexes. Virtually all DNAs containing the key G*G* lesion (G* = N7 platinated G) have large distortions in the cross-link (G*G*) base pair (bp) step and also in the adjacent Lippard (XG*) bp step, making the adducts very different from B-form DNA in the XG*G* region. The XG*G* strand in duplexes also differs in several ways from single-strand (ss) models with G*G* and XG*G* sequences. In the duplex, the X residue has an N sugar, the 5'-G* and 3'-G* bases have slight "R" canting (3'-G* H8 atom toward the 5'-G* base), and there is no or weak H-bonding by the NH3 ligands. In most XG*G* ss models, X has an S sugar, the 5'-G* base normally cants strongly toward the 3'-G* base (L canting), and the NH3 forms an H-bond. Well-defined ss models exist in the solid state, but dynamic motion obscures the properties of the ss models in solution. In this work, we employ retro models (better defined, less dynamic ss models) to understand the differences between duplex and ss models. The retro models in this study lack carrier ligand NH's, thus eliminating H-bonding. To correlate previous ss solid-state models with our solution work, we constructed hybrid molecules by overlaying parts of known structures. The combined model and experimental information indicates that the X N-pucker is not favorable in L-canted ss models, that X residue steric effects (not H-bonding) favor L canting in ss models, that X N-pucker is needed for favorable WC hydrogen bonding and stacking interactions in duplexes, and that X N-pucker minimizes X base clashes with bases in the complementary strand in duplexes. The R canting minimizing clashes between the X and G* residues of the Lippard bp step (independent of X pucker) and the repositioning of the X residue base caused by the change from S-pucker to N-pucker together lead to the unusual features of the Lippard bp step in the duplex.

Metalation of 2,6-diphenylpyridine (1) by potassium tetrachloroplatinate in acetic acid gives a monocyclometalated chloride-bridged dimer 4. This dimer is split with CO to give a kinetic product 9t with the incoming CO trans to the orthometalated carbon. The kinetic product of cleavage is shown to be 16 kJ mol -1 higher in energy than the thermodynamic product 9c, which has the CO trans to the pyridine nitrogen. The isomerization of 9t to 9c is shown not to take place via an associative mechanism and, with analogue 11, is effectively suppressed when excess chloride is added, implying that it takes place via a chloride dissociation. The monocyclometalated 9 undergoes a second cyclometalation to give the C∧N∧C dicyclometalated complex 15 in high yield. This second cyclometalation is brought about by the simple expedient of adding water to the monocyclometalated precursor. The addition of water is rationalized on the basis of needing to ionize the HCl byproduct of the reaction. Using a substituted pyridine (5) analogous chemistry is observed. Single-crystal X-ray structures of one of the intermediates (6) and one of the final products (15) have been solved. Density functional theory calculations are used to rationalize the isomerizations of the monocyclometalated intermediates and the need to ionize HCl in the second cyclometalation.

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A novel glycolipid of mass 1935 and a phospholipid of mass 1522 are the main residual lipids (along with traces of PGP-Me, S-TGD-1, and PG) specifically associated with "delipidated" bacteriorhodopsin fractions BR I and BR II, prepared by Triton X-100 treatment of purple membrane (PM), from a genetically engineered strain (L33) of Halobacterium salinarum, and chromatography on phenyl-Sepharose CL-4B. The novel glycolipid and phospholipid are components of the PM matrix not previously described. The TLC isolated and purified novel glycolipid and phospholipid were shown, by chemical degradation, mass spectrometry, and NMR analyses, to have the structure, respectively, of a phosphosulfoglycolipid, 3-HSO(3)-Galp-beta1,6Manp-alpha1,2Glcp-alpha1,1-[sn-2, 3-di-O-phytanylglycerol]-6-[phospho-sn-2,3-di-O-phytanylglycero l], and of a glycerol diether analogue of bisphosphatidylglycerol (cardiolipin), sn-2,3-di-O-phytanyl-1-phosphoglycerol-3-phospho-sn-2, 3-di-O-phytanylglycerol.

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