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

Structural Characterization of the Rhenium(V) Oxo Complex of Mercaptoacetyltriglyclne in its Dianionic Form

Dianionic [MO(MAG3)]2−(MAG3 = penta-anionic form of mercaptoacetyltriglycine, M = 186Re, 99mTc) complexes have important applications in nuclear medicine. In vivo the complexes have a deprotonated carboxyl group that is important to their biodistribution. The solid-state structures of 99Tc and Re complexes with mercaptoacetyltriglycine reported previously are monoanions with protonated carboxyl groups. In the present work, we report the preparation and X-ray crystal structure of Na2[ReO(MAG3)]·5H2O (1), which contains the physiologically relevant dianion. The dianion is a distorted square pyramid with the nitrogen and sulphur donor atoms forming the base and the oxo ligand at the apex. The terminal carboxyl group is deprotonated, uncoordinated and has a syn orientation with respect to the oxo ligand. The syn conformation of the dianion in 1 differs in conformation from the anti-monoanion in [Bu4N][ReO(MAG3H)] but is similar to the syn-monoanion in [Ph4P][99TcO(MAG3 H)]

Synthesis of the Sulphonate and Phosphonate Derivatives of Mercaptoacetyltriglycine. X-Ray Crystal Structure of Na2[ReO(Mercaptoacetylglycylglycylaminomethanesulphonate)]·3H2O

Mercaptoacetyltriglycine forms complexes with 186/188Re and 99mTc radionuclides that are useful in nuclear medicine because they are substrates of the renal anion transport system. However, the renal clearance of [MO(MAG3)]2-(MAG3 = penta-anionic form of mercaptoacetyltriglycine, M = Re, Tc) complexes are less than ideal. Organic sulphonates are also transported by the renal anion transport system and phosphonates are similar to sulphonates in size and shape. In an effort to develop new ligands that form Re and Tc complexes and have improved renal clearances compared to [MO(MAG3)]2- complexes, the sulphonate and phosphonate derivatives of mercaptoacetyltriglycine were synthesized. The dianion [ReO(MAG2-AMS)]2- (MAG2-AMS = penta-anionic form of mercaptoacetylglycylglycylaminomethanesulphonic acid) was prepared for characterization by exchange reaction of ReOCl3(Me2S)(OPPh3) and isolated as the disodium salt. The structure of Na2[ReO(MAG2-AMS)]·3H2O (6) was determined by X-ray diffraction. The coordination geometry is pseudo square pyramidal, with the nitrogen and sulfur donor atoms forming a square base and the oxo ligand at the apex. The deprotonated sulphonate group has a syn conformation with respect to the oxo ligand. The renal clearances of [99mTcO(MAG2-AMS)]2- and [99mTcO(MAG2-AMP)]3- were similar in rats and suggest that the difference in total charge between the SO3- and PO32- groups is not important to renal clearance. However, their renal clearances were 40-50% less than that of [99mTcO(MAG3)]2- suggesting that the size and shape of the large tetrahedral SO3- and PO32- groups of [99mTcO(MAG2-AMS)]2- and [99mTcO(MAG2-AMP)]3- inhibit recognition by the renal transport system compared to the small planar CO2- group of [99mTcO(MAG3)]2-

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)

Prevention of poxvirus infection by tetrapyrroles

BACKGROUND: Prevention of poxvirus infection is a topic of great current interest. We report inhibition of vaccinia virus in cell culture by porphyrins and phthalocyanines. Most previous work on the inhibition of viruses with tetrapyrroles has involved photodynamic mechanisms. The current study, however, investigates light-independent inhibition activity. METHODS: The Western Reserve (WR) and International Health Department-J (IHD-J) strains of vaccinia virus were used. Virucidal and antiviral activities as well as the cytotoxicity of test compounds were determined. RESULTS: Examples of active compounds include zinc protoporphyrin, copper hematoporphyrin, meso(2,6-dihydroxyphenyl)porphyrin, the sulfonated tetra-1-naphthyl and tetra-1-anthracenylporphyrins, selected sulfonated derivatives of halogenated tetraphenyl porphyrins and the copper chelate of tetrasulfonated phthalocyanine. EC(50 )values for the most active compounds are as low as 0.05 µg/mL (40 nM). One of the most active compounds was the neutral meso(2,6-dihydroxyphenyl)porphyrin, indicating that the compounds do not have to be negatively charged to be active. CONCLUSIONS: Porphyrins and phthalocyanines have been found to be potent inhibitors of infection by vaccinia virus in cell culture. These tetrapyrroles were found to be active against two different virus strains, and against both enveloped and non-enveloped forms of the virus, indicating that these compounds may be broadly effective in their ability to inhibit poxvirus infection

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