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

Coronary Microcirculatory vasoconstriction during ischemia in patients with unstable angina

OBJECTIVE To verify the behavior of coronary microvascular tone during spontaneous ischemia in patients with unstable angina (UA). BACKGROUND In UA, the pathogenetic role of vasoconstriction is classically confined at the stenotic coronary segment. However, microcirculatory vasoconstriction has been also suggested by previous experimental and clinical studies. METHODS The study included 10 patients with UA (recent worsening of anginal threshold and appearance of angina at rest) and single-vessel CAD. Blood flow velocity was monitored by a Doppler catheter in the diseased artery. Transstenotic pressure gradient was monitored by aortic and distal coronary pressure monitoring. Stenosis resistance was calculated as the ratio between pressure gradient and blood flow, microvascular resistance as the ratio between distal pressure and blood flow. Measurements were obtained at baseline, following intracoronary adenosine (2 mg) and during transient ischemia. Aortic and distal coronary pressures were also measured during balloon coronary occlusion. RESULTS Adenosine did not affect stenosis resistance, while it decreased (p , 0.05) microvascular resistance to 52 6 22% of baseline. Angina and ischemic ST segment shift were associated with transient angiographic coronary occlusion in 7 of 10 patients; however, in no case was ischemia associated with interruption of flow. Despite markedly different flow values, distal coronary pressure was similar during adenosine and during spontaneous ischemia (48 6 15 vs. 46 6 20 mm Hg, respectively, NS). During ischemia, a marked increase in the resistance of both coronary stenosis and coronary microcirculation was observed (to 1,233% 6 1,298% and 671% 6 652% of baseline, respectively, p , 0.05). Distal coronary pressure was markedly reduced during balloon coronary occlusion (14 6 7 mm Hg, p , 0.05 vs. both adenosine and ischemia), suggesting the absence of significant collateral circulation. CONCLUSIONS In patients with UA, transient myocardial ischemia is associated with vasoconstriction of both stenotic arterial segment and downstream microcirculation

Coronary occlusion: cause or consequence of acute myocardial infarction?

A 45-year-old man with unstable angina developed persistent ECG changes of myocardial ischemia during coronary angiography. Occlusion of the left anterior descending branch (LAD) was documented 20 minutes after these changes. Intracoronary nitrate, Ca antagonist, urokinase, removal by percutaneous transluminal coronary angioplasty (PTCA) of atherosclerotic obstructions, and emergency bypass surgery failed to restore myocardial perfusion. Only short periods of reflow were obtained by urokinase and PTCA. The repeated coronary injections demonstrated a progressive disappearance of the left anterior descending artery (LAD) starting from the distal portion and progressing retrogradely up to the origin of the vessel. The patient developed a transmural anterolateral myocardial infarction and 12 months later underwent cardiac transplantation for untractable failure. His heart was examined and the infarct confirmed. Analysis of this case suggests that coronary occlusion in acute myocardial infarction can be an event secondary to increased intramyocardial resistance rather than the cause of reduced coronary blood flow in subepicardial coronary arteries

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)

Why the term MINOCA does not provide conceptual clarity for actionable decision-making in patients with myocardial infarction with no obstructive coronary artery disease

When acute myocardial injury is found in a clinical setting suggestive of myocardial ischemia, the event is labeled as acute myocardial infarction (MI), and the absence of ≥50% coronary stenosis at angiography or greater leads to the working diagnosis of myocardial infarction with non-obstructed coronary arteries (MINOCA). Determining the mechanism of MINOCA and excluding other possible causes for cardiac troponin elevation has notable implications for tailoring secondary prevention measures aimed at improving the overall prognosis of acute MI. The aim of this review is to increase the awareness that establishing the underlying cause of a MINOCA is possible in the vast majority of cases, and that the proper classification of any MI should be pursued. The initial diagnosis of MINOCA can be confirmed or ruled out based on the results of subsequent investigations. Indeed, a comprehensive clinical evaluation at the time of presentation, followed by a dedicated diagnostic work-up, might lead to the identification of the pathophysiologic abnormality leading to MI in almost all cases initially labeled as MINOCA. When a specific cause of acute MI is identified, cardiologists are urged to transition from the "all-inclusive" term "MINOCA" to the proper classification of any MI, as evidence now exists that MINOCA does not provide conceptual clarity for actionable decision-making in MI with angiographically normal coronary arteries

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