A Very Rare Example of a Structurally Characterized 3′-GMP Metal Complex. NMR and Synthetic Assessment of Adducts Formed by Guanine Derivatives with [Pt(L\u3csup\u3etri\u3c/sup\u3e)Cl]Cl Complexes with an N,N′,N″ Tridentate Ligand (L\u3csup\u3etri\u3c/sup\u3e) Terminated by Imidazole Rings

© 2017 American Chemical Society. [Pt(N(R)-1,1′-Me2dma)Cl]Cl complexes with tridentate ligands (bis(1-methyl-2-methylimidazolyl)amine, R = H; N-(methyl)bis(1-methyl-2-methylimidazolyl)amine, R = Me) were prepared in order to investigate Pt(N(R)-1,1′-Me2dma)G adducts (G = monodentate N9-substituted guanine or hypoxanthine derivative). Solution NMR spectroscopy is the primary tool for studying metal complexes of nucleosides and nucleotides because such adducts rarely crystallize. However, [Pt(N(H)-1,1′-Me2dma)(3′-GMPH)]NO3·5H2O (5) was crystallized, allowing, to our knowledge, the first crystallographic molecular structure determination for a 3′-GMP platinum complex. The structure is one of only a very few structures of a 3′-GMP complex with any metal. Complex 5 has the syn rotamer conformation, with 3′-GMP bound by N7. All Pt(N(R)-1,1′-Me2dma)G adducts exhibit two new downfield-shifted G H8 signals, consistent with G bound to platinum by N7 and a syn/anti rotamer mixture. Anticancer-active monofunctional platinum(II) complexes have bulky carrier ligands that cause DNA adducts to be distorted. Hence, understanding carrier-ligand steric effects is key in designing new platinum drugs. Ligand bulk can be correlated with the degree of impeded rotation of the G nucleobase about the Pt-N7 bond, as assessed by the observation of rotamers. The signals of syn and anti rotamers are connected by EXSY cross-peaks in 2D ROESY spectra of Pt(N(H)-1,1′-Me2dma)G adducts but not in spectra of Pt(N(H)dpa)G adducts (N(H)dpa = bis(2-picolyl)amine), indicating that rotamer interchange is more facile and carrier-ligand bulk is lower in Pt(N(H)-1,1′-Me2dma)G than in Pt(N(H)dpa)G adducts. The lower steric hindrance is a direct consequence of the greater distance of the G nucleobase from the H4/4′ protons in the N(R)-1,1′-Me2dma carrier ligand in comparison to that from the H6/6′ protons in the N(H)dpa carrier ligand. Although in 5 the nucleotide is 3′-GMP (not the usual 5′-GMP) and the N(H)-1,1′-Me2dma carrier ligand is very different from those typically present in structurally characterized Pt(II) G complexes, the rocking and canting angles in 5 adhere to long-recognized trends

Linear Bidentate Ligands (L) with Two Terminal Pyridyl N-Donor Groups Forming Pt(II)LCl\u3csub\u3e2\u3c/sub\u3e Complexes with Rare Eight-Membered Chelate Rings

Copyright © 2018 American Chemical Society. NMR and X-ray diffraction studies were conducted on Pt(II)LCl2 complexes prepared with the new N-donor ligands N(SO2R)Mendpa (R = Me, Tol; n = 2, 4). These ligands differ from N(H)dpa (di-2-picolylamine) in having the central N within a tertiary sulfonamide group instead of a secondary amine group and having Me groups at the 6,6′-positions (n = 2) or 3,3′,5,5′-positions (n = 4) of the pyridyl rings. The N(SO2R)3,3′,5,5′-Me4dpa ligands are coordinated in a bidentate fashion in Pt(N(SO2R)3,3′,5,5′-Me4dpa)Cl2 complexes, forming a rare eight-membered chelate ring. The sulfonamide N atom did not bind to Pt(II), consistent with indications in the literature that tertiary sulfonamides are unlikely to anchor two meridionally coordinated five-membered chelate rings in solutions of coordinating solvents. The N(SO2R)6,6′-Me2dpa ligands coordinate in a monodentate fashion to form the binuclear complexes [trans-Pt(DMSO)Cl2]2(N(SO2R)6,6′-Me2dpa). The monodentate instead of bidentate N(SO2R)6,6′-Me2dpa coordination is attributed to 6,6′-Me steric bulk. These binuclear complexes are indefinitely stable in DMF-d7, but in DMSO-d6 the N(SO2R)6,6′-Me2dpa ligands dissociate completely. In DMSO-d6, the bidentate ligands in Pt(N(SO2R)3,3′,5,5′-Me4dpa)Cl2 complexes also dissociate, but incompletely; these complexes provide rare examples of association-dissociation equilibria of N,N bidentate ligands in Pt(II) chemistry. Like typical cis-PtLCl2 complexes, the Pt(N(SO2R)3,3′,5,5′-Me4dpa)Cl2 complexes undergo monosolvolysis in DMSO-d6 to form the [Pt(N(SO2R)3,3′,5,5′-Me4dpa)(DMSO-d6)Cl]+ cations. However, unlike typical cis-PtLCl2 complexes, the Pt(N(SO2R)3,3′,5,5′-Me4dpa)Cl2 complexes surprisingly do not react readily with the excellent N-donor bioligand guanosine. A comparison of the structural features of over 50 known relevant Pt(II) complexes having smaller chelate rings with those of the very few relevant Pt(II) complexes having eight-membered chelate rings indicates that the pyridyl rings in Pt(N(SO2R)3,3′,5,5′-Me4dpa)Cl2 complexes are well positioned to form strong Pt-N bonds. Therefore, the dissociation of the bidentate ligand and the poor biomolecule reactivity of the Pt(N(SO2R)3,3′,5,5′-Me4dpa)Cl2 complexes arise from steric consequences imposed by the -CH2-N(SO2R)-CH2- chain in the eight-membered chelate ring

Synthesis and Characterization of Pt(II) Complexes with Pyridyl Ligands: Elongated Octahedral Ion Pairs and Other Factors Influencing \u3csup\u3e1\u3c/sup\u3eH NMR Spectra

© 2017 American Chemical Society. Our goal is to develop convenient methods for obtaining trans-[PtII(4-Xpy)2Cl2] complexes applicable to 4-substituted pyridines (4-Xpy) with limited volatility and water solubility, properties typical of 4-Xpy, with X being a moiety targeting drug delivery. Treatment of cis-[PtII(DMSO)2Cl2] (DMSO = dimethyl sulfoxide) with 4-Xpy in acetonitrile allowed isolation of a new series of simple trans-[PtII(4-Xpy)2Cl2] complexes. A side product with very downfield H2/6 signals led to our synthesis of a series of new [PtII(4-Xpy)4]Cl2 salts. For both series in CDCl3, the size of the H2/6 δ[coordinated minus free 4-Xpy H2/6 shift] decreased as 4-Xpy donor ability increased from 4-CNpy to 4-Me2Npy. This finding can be attributed to the greater synergistic reduction in the inductive effect of the Pt(II) center with increased 4-Xpy donor ability. The high solubility of [PtII(4-Xpy)4]Cl2 salts in CDCl3 (a solvent with low polarity) and the very downfield shift of the [PtII(4-Xpy)4]Cl2 H2/6 signals for the solutions provide evidence for the presence of strong {[PtII(4-Xpy)4]2+,2Cl-} ion pairs that are stabilized by multiple CH···Cl contacts. This conclusion gains considerable support from [PtII(4-Xpy)4]Cl2 crystal structures revealing that a chloride anion occupies a pseudoaxial position with nonbonding (py)C-H···Cl contacts (2.4-3.0 Å). Evidence for (py)C-H···Y contacts was obtained in NMR studies of [PtII(4-Xpy)4]Y2 salts with Y counterions less capable of forming H-bonds than chloride ion. Our synthetic approaches and spectroscopic analysis are clearly applicable to other nonvolatile ligands

Metallation of Isatin (2,3-Indolinedione). X-Ray Structure and Solution Behavior of Bis(Isatinato)Mercury(II)

The first X-ray structure of an isatin (2,3-indolinedione, isaH) metal complex, bis(isatinato)memury(II) (C16H8N2O4Hg) (1), was determined. (1) was obtained from the reaction of isaH with mercury(II) acetate in methanol. Analogously, treatment of sodium saccharinate and mercury(II) acetate in methanol yielded Hg(saccharinato)2•0.5CH3OH (3). (1) crystallizes in the monoclinic system, space group P21/ a with a = 7.299(1) Å, b = 8.192(1) Å, c = 11.601(1) Å , β = 105.82(1)°, V = 667.4 Å3, Z = 2, Dcalc = 2.452 g cm−3, MoKα radiation(λ = 0.71073 Å), μ = 115.5 cm-1, F(000) = 460, 21(1) °C. The structure was refined on the basis of 2023 observed reflections to R= 0.044. The two deprotonated, non coplanar isa ligands are trans to each other in a head to tail orientation and bound to the Hg through the nitrogen in a linear N-Hg-N arrangement. The Hg atom is at the center of symmetry of the complex and displaced by 0.62 Å from the two planes of the isa ligands (τ Hg-N1-C2-O2= -16°). The Hg-N bond length is 2.015 Å. Noπ-aryl-memury(ll)-π-aryl stacking interaction was observed either in the solid state or in the solution state. The IR, electronic, and 1H and 13CNMR spectral data of (1) and (3) suggest binding of the memury to the heterocyclic nitrogen, in agreement with the crystal structure determination of (1)

Neglected bidentate sp2 N-donor carrier ligands with triazine nitrogen lone pairs: platinum complexes retromodeling cisplatin guanine nucleobase adducts

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 not linked by a phosphodiester group). We have examined the formation of LPtG2 adducts with G = 5\u27- and 3\u27-GMP and L = sp(2) N-donor bidentate carrier ligands [5,5\u27-dimethyl-2,2\u27-bipyridine (5,5\u27-Me2bipy), 3-(4\u27-methylpyridin-2\u27-yl)-5,6-dimethyl-1,2,4-triazine) (MepyMe2t), and bis-3,3\u27-(5,6-dialkyl-1,2,4-triazine) (R4dt)]. NMR spectroscopy provided conclusive evidence that these LPt(5\u27-GMP)2 complexes exist as interconverting mixtures of head-to-tail (HT) and head-to-head (HH) conformers. For a given G, the rates of G base rotation about the Pt-N7 bonds of LPtG2 models decrease in the order Me4dt \u3e Et4dt \u3e MepyMe2t \u3e 5,5\u27-Me2bipy. This order reveals that the pyridyl ring C6 atom + H atom grouping is large enough to impede the rotation, but the equivalently placed triazine ring N atom + N lone pair grouping is sterically less impeding. For the first time, the two possible HH conformers (HHa and HHb) in the case of an unsymmetrical L have been identified in our study of (MepyMe2t)Pt(5\u27-GMP)2. Although O6-O6 clashes involving the two cis G bases favor the HT over the HH arrangement for most LPtG2-type complexes, the HH conformer of (R4dt)Pt(5\u27-GMP)2 adducts has a high abundance (approximately 50%). We attribute this high abundance to a reduction in O6-O6 steric clashes permitted by the overall low steric effects of R4dt ligands. Under the reaction conditions used, 3\u27-GMP forms a higher abundance of the LPt(GMP)2 adduct than does 5\u27-GMP, a result attributable to more favorable second-sphere communication in the LPt(3\u27-GMP)2 adduct than in the LPt(5\u27-GMP)2 adduct

Investigation relevant to the conformation of the 17-membered Pt(d(GpG)) macrocyclic ring formed by Pt anticancer drugs with DNA: Pt complexes with a Goldilocks carrier ligand

Platinum anticancer drug DNA intrastrand cross-link models, LPt(d(G*pG*)) (G* = N7-platinated G residue, L = R(4)dt = bis-3,3\u27-(5,6-dialkyl)-1,2,4-triazine), and R = Me or Et), undergo slow Pt-N7 bond rotation. NMR evidence indicated four conformers (HH1, HH2, ΔHT1, and ΛHT2); these have different combinations of guanine base orientation (head-to-head, HH, or head-to-tail, HT) and sugar-phosphodiester backbone propagation relative to the 5\u27-G* (the same, 1, or opposite, 2, to the direction in B DNA). In previous work on LPt(d(G*pG*)) adducts, Pt-N7 rotation was too rapid to resolve conformers (small L with bulk similar to that in active drugs) or L was too bulky, allowing formation of only two or three conformers; ΛHT2 was not observed under normal conditions. The (R(4)dt)Pt(d(G*pG*)) results support our initial hypothesis that R(4)dt ligands have Goldilocks bulk, sufficient to slow G* rotation but insufficient to prevent formation of the ΛHT2 conformer. Unlike the (R(4)dt)Pt(5\u27-GMP)(2) adducts, ROESY spectra of (R(4)dt)Pt(d(G*pG*)) adducts showed no EXSY peaks, a result providing clear evidence that the sugar-phosphodiester backbone slows conformer interchange. Indeed, the ΛHT2 conformer formed and converted to other conformers slowly. Bulkier L (Et(4)dt versus Me(4)dt) decreased the abundance of the ΛHT2 conformer, supporting our initial hypothesis that steric crowding disfavors this conformer. The (R(4)dt)Pt(d(G*pG*)) adducts have a low abundance of the ΔHT1 conformer, consistent with the proposal that the ΔHT1 conformer has an energetically unfavorable phosphodiester backbone conformation; its high abundance when L is bulky is attributed to a small d(G*pG*) spatial footprint for the ΔHT1 conformer. Despite the Goldilocks size of the R(4)dt ligands, the bases in the (R(4)dt)Pt(d(G*pG*)) adducts have a low degree of canting, suggesting that the ligand NH groups characteristic of active drugs may facilitate canting, an important aspect of DNA distortions induced by active drugs

Exploring the universality of unusual conformations of the 17-membered Pt(d(G*pG*)) macrochelate ring. Dependence of conformer formation on a change in bidentate carrier ligand from an sp3 to an sp2 nitrogen donor

Early studies on cis-PtA2(d(G*pG*)) (A2 = diamine or two amines, G = N7-platinated G) and cis-Pt(NH3)2(d(G*pG*)) models for the key cisplatin-DNA cross-link suggested that they exist exclusively or mainly as the HH1 conformer (HH1 = head-to-head G bases, with 1 denoting the normal direction of backbone propagation). These dynamic models are difficult to characterize. Employing carrier A2 ligands designed to slow dynamic interchange of conformers, we found two new conformers, DeltaHT (head-to-tail G* bases with a Delta chirality) and HH2 (with 2 denoting the backbone propagation direction opposite to normal). However, establishing that the non-HH1 conformations exist as an intrinsic feature of the 17-membered Pt(d(G*pG*)) ring requires exploring a range of different carrier ligands. Here we employ the planar aromatic sp(2) N-donor 5,5\u27-Me(2)bipy (5,5\u27-dimethyl-2,2\u27-bipyridine) ligand, having a shape very different from those of previously used nonplanar sp(3) N-donor bidentate carrier ligands, which often bear NH groups. The 5,5\u27-Me(2)bipy H6 and H6\u27 protons project toward the d(G*pG*) moiety and hinder the dynamic motion of 5,5\u27-Me(2)bipyPt(d(G*pG*)). We again found HH1, HH2, and DeltaHT conformers with typical properties, supporting the conclusions that the new DeltaHT and HH2 conformers exist universally in dynamic cis-PtA2(d(G*pG*)) adducts, including cis-Pt(NH3)2(d(G*pG*)), and that the carrier ligand typically has little influence on the overall structure of the Pt(d(G*pG*)) macrocyclic ring of a given conformer. The sizes of the G H8 to H6/H6\u27 NOE cross-peaks indicate little base canting in all 5,5\u27-Me(2)bipyPt(d(G*pG*)) conformers, suggesting that carrier-ligand NH groups favor the canting of one G base in the HH1 and HH2 conformers of typical cis-PtA2(d(G*pG*)) adducts

New porphyrins bearing positively charged peripheral groups linked by a sulfonamide group to meso-tetraphenylporphyrin: interactions with calf thymus DNA

New water-soluble cationic meso-tetraarylporphyrins (TArP, Ar = 4-C(6)H(4)) and some metal derivatives have been synthesized and characterized. One main goal was to assess if N-methylpyridinium (N-Mepy) groups must be directly attached to the porphyrin core for intercalative binding of porphyrins to DNA. The new porphyrins have the general formula, [T(R(2)R(1)NSO(2)Ar)P]X(4/8) (R(1) = CH(3) or H and R(2) = N-Mepy-n-CH(2) with n = 2, 3, or 4; or R(1) = R(2) = Et(3)NCH(2)CH(2)). Interactions of selected porphyrins and metalloporphyrins (Cu(II), Zn(II)) with calf thymus DNA were investigated by visible circular dichroism (CD), absorption, and fluorescence spectroscopies. The DNA-induced changes in the porphyrin Soret region (a positive induced CD feature and, at high DNA concentration, increases in the Soret band and fluorescence intensities) indicate that the new porphyrins interact with DNA in an outside, non-self-stacking binding mode. Several new metalloporphyrins did not increase DNA solution viscosity and thus do not intercalate, confirming the conclusion drawn from spectroscopic studies. Porphyrins known to intercalate typically bear two or more N-Mepy groups directly attached to the porphyrin ring, such as the prototypical meso-tetra(N-Mepy)porphyrin tetracation (TMpyP(4)). The distances between the nitrogens of the N-Mepy group are estimated to be approximately 11 A (cis) and 16 A (trans) for the relatively rigid TMpyP(4). For the new flexible porphyrin, [T(N-Mepy-4-CH(2)(CH(3))NSO(2)Ar)P]Cl(4), the distances between the nitrogens are estimated to be able to span the range from approximately 9 to approximately 25 A. Thus, the N-Mepy groups in the new porphyrins can adopt the same spacing as in known intercalators such as TMpyP(4). The absence of intercalation by the new porphyrins indicates that the propensity for the N-Mepy group to facilitate DNA intercalation of cationic porphyrins requires direct attachment of N-Mepy groups to the porphyrin core

Guanine nucleobase adducts formed by [Pt(di-(2-picolyl)amine)Cl]Cl: evidence that a tridentate ligand with only in-plane bulk can slow guanine base rotation

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. Pt(N(H)dpa)(G) adducts (N(H)dpa = di-(2-picolyl)amine, G = 5\u27-GMP, 5\u27-GDP, 5\u27-GTP, guanosine, 9-EtG, and 5\u27-IMP) were used to assess whether a tridentate carrier ligand having bulk concentrated in the coordination plane can impede guanine nucleobase rotation. Because the Pt(N(H)dpa) moiety contains a mirror plane but is unsymmetrical with respect to the coordination plane, Pt(N(H)dpa)(G) adducts can form anti or syn rotamers with the guanine O6 and the central N-H of N(H)dpa on the opposite or the same side of the coordination plane, respectively. The observation of two sharp, comparably intense guanine H8 NMR signals provided evidence that these Pt(N(H)dpa)(G) adducts exist as mixtures of syn and anti rotamers, that rotational interchange is impeded by N(H)dpa, and that the key interactions involves steric repulsions between the pyridyl and guanine rings. The relative proximity of the guanine H8 to the anisotropic pyridyl rings allowed us to conclude that the syn rotamer was usually more abundant. However, the anti rotamer was more abundant for the Pt(N(H)dpa)(5\u27-GTP) adduct, in which a hydrogen bond between the 5\u27-GTP γ-phosphate group and the N(H)dpa central N-H is geometrically possible. In all previous examples of the influence of hydrogen bond formation on rotamer abundance in Pt(II) guanine adducts, these hydrogen bonding interactions occurred between ligand groups in cis positions. Thus, the role of a trans ligand group in influencing rotamer abundance, as found here, is unusual