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

Synthesis, Characterisation, and Preliminary In Vitro Studies of Vanadium(IV) Complexes with a Schiff Base and Thiosemicarbazones as Mixed Ligands

[VO(sal‐L‐tryp)(H2O)] (1, sal‐L‐tryp = N‐salicylidene‐L‐tryptophanate) was used as a precursor to produce the new complexes [VO(sal‐L‐tryp)(MeATSC)]·1.5C2H5OH [2, MeATSC = 9‐Anthraldehyde‐N(4)‐methylthiosemicarbazone], [VO(sal‐L‐tryp)(N‐ethhymethohcarbthio)]·H2O [3, N‐ethhymethohcarbthio = (E)‐N‐ethyl‐2‐(4‐hydroxy‐3‐methoxybenzylidene)hydrazinecarbothioamide] and [VO(sal‐L‐tryp)(acetylethTSC)]·C2H5OH {4, acetylethTSC = (E)‐N‐ethyl‐2‐[1‐(thiazol‐2‐yl)ethylidene]hydrazinecarbothioamide} by reaction with the respective thiosemicarbazone. The chemical and structural properties of these ligands and complexes were characterised by elemental analysis, ESI‐MS, FTIR, UV/Vis, ESR and 1H and 13C NMR spectroscopy and X‐ray crystallography. Dimethyl sulfoxide (DMSO) and [D6]DMSO solutions of 1–4 were oxidised in air to produce vanadium(V) species, which were verified by ESI‐MS and 51V NMR spectroscopy. The anticancer properties of 2–4 were examined with three colon cancer cell lines, HTC‐116, Caco‐2 and HT‐29, and noncancerous colonic myofibroblasts, CCD18‐Co. Compounds 2–3 exhibited less inhibitory effects in the CCD‐18Co cells, which indicates a possible cytotoxic selectivity towards colon cancer cells. In general, compounds that exhibit antiproliferative activity to cancer cells but do not affect noncancerous cells may have a potential in chemotherapy

PET Imaging of Extracellular pH in Tumors with \u3csup\u3e64\u3c/sup\u3eCu- and \u3csup\u3e18\u3c/sup\u3eF-Labeled pHLIP Peptides: A Structure–Activity Optimization Study

pH (low) insertion peptides (pHLIP peptides) target acidic extracellular environments in vivo due to pH-dependent cellular membrane insertion. Two variants (Var3 and Var7) and wild-type (WT) pHLIP peptides have shown promise for in vivo imaging of breast cancer. Two positron emitting radionuclides (64Cu and 18F) were used to label the NOTA- and NO2A-derivatized Var3, Var7, and WT peptides for in vivo biodistribution studies in 4T1 orthotopic tumor-bearing BALB/c mice. All of the constructs were radiolabeled with 64Cu or [18F]-AlF in good yield. The in vivo biodistribution of the 12 constructs in 4T1 orthotopic allografted female BALB/c mice indicated that NO2A-cysVar3, radiolabeled with either 18F (4T1 uptake; 8.9 ± 1.7%ID/g at 4 h p.i.) or 64Cu (4T1 uptake; 8.2 ± 0.9%ID/g at 4 h p.i. and 19.2 ± 1.8% ID/g at 24 h p.i.), shows the most promise for clinical translation. Additional studies to investigate other tumor models (melanoma, prostate, and brain tumor models) indicated the universality of tumor targeting of these tracers. From this study, future clinical translation will focus on 18F- or 64Cu-labeled NO2A-cysVar3

Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms

Background: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co‐occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. Methods and Results: We performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA‐, AAA‐, and TAA‐associated SNPs and tested these scores for association to case‐control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium–score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single‐nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10−5) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10−3). Conclusions: Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Models for B12-conjugated radiopharmaceuticals. Cobaloxime binding to new fac-[Re(CO)3(Me2bipyridine)(amidine)]BF4 complexes having an exposed pyridyl nitrogen

New mononuclear amidine complexes, fac-[Re(CO)3(Me2bipy)(HNC(CH3)(pyppz))]BF4 [(4,4\u27-Me2bipy (1), 5,5\u27-Me2bipy (2), and 6,6\u27-Me2bipy (3)] (bipy = 2,2\u27-bipyridine), were synthesized by treating the parent fac-[Re(I)(CO)3(Me2bipy)(CH3CN)]BF4 complex with the C2-symmetrical amine 1-(4-pyridyl)piperazine (pyppzH). The axial amidine ligand has an exposed, highly basic pyridyl nitrogen. The reaction of complexes 1-3 with a B12 model, (py)Co(DH)2Cl (DH = monoanion of dimethylglyoxime), in CH2Cl2 yielded the respective dinuclear complexes, namely, fac-[Re(CO)3(Me2bipy)(μ-(HNC(CH3)(pyppz)))Co(DH)2Cl]BF4 [(4,4\u27-Me2bipy (4), 5,5\u27-Me2bipy (5), and 6,6\u27-Me2bipy (6)]. (1)H NMR spectroscopic analysis of all compounds and single-crystal X-ray crystallographic data for 2, 3, 5, and 6 established that the amidine had only the E configuration in both the solid and solution states and that the pyridyl group is bound to Co in 4-6. Comparison of the NMR spectra of 1-3 with spectra of 4-6 reveals an unusually large wrong-way upfield shift for the pyridyl H2/6 signal for 4-6. The wrong-way H2/6 shift of (4-Xpy)Co(DH)2Cl (4-Xpy = 4-substituted pyridine) complexes increased with increasing basicity of the 4-Xpy derivative, a finding attributed to the influence of the magnetic anisotropy of the cobalt center on the shifts of the (1)H NMR signals of the pyridyl protons closest to Co. Our method of employing a coordinate bond for conjugating the fac-[Re(I)(CO)3] core to a vitamin B12 model could be extended to natural B12 derivatives. Because B12 compounds are known to accumulate in cancer cells, such an approach is a very attractive method for the development of (99m)Tc and (186/188)Re radiopharmaceuticals for targeted tumor imaging and therapy

Synthesis and Characterization of Pt(II) Complexes with Pyridyl Ligands: Elongated Octahedral Ion Pairs and Other Factors Influencing ¹H NMR Spectra

Our goal is to develop convenient methods for obtaining <i>trans</i>-[Pt^II(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 <i>cis</i>-[Pt^II(DMSO)₂Cl₂] (DMSO = dimethyl sulfoxide) with 4-Xpy in acetonitrile allowed isolation of a new series of simple <i>trans</i>-[Pt^II(4-Xpy)₂Cl₂] complexes. A side product with very downfield H2/6 signals led to our synthesis of a series of new [Pt^II(4-Xpy)₄]­Cl₂ salts. For both series in CDCl₃, the size of the H2/6 Δδ [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 [Pt^II(4-Xpy)₄]­Cl₂ salts in CDCl₃ (a solvent with low polarity) and the very downfield shift of the [Pt^II(4-Xpy)₄]­Cl₂ H2/6 signals for the solutions provide evidence for the presence of strong {[Pt^II(4-Xpy)₄]²⁺,2Cl^–} ion pairs that are stabilized by multiple CH···Cl contacts. This conclusion gains considerable support from [Pt^II(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 [Pt^II(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

Models for B₁₂-Conjugated Radiopharmaceuticals. Cobaloxime Binding to New <i>fac</i>-[Re(CO)₃(Me₂Bipyridine)(amidine)]BF₄ Complexes Having an Exposed Pyridyl Nitrogen

New mononuclear amidine complexes, <i>fac</i>-[Re­(CO)₃(Me₂bipy)­(HNC­(CH₃)­(pyppz))]­BF₄ [(4,4′-Me₂bipy (<b>1</b>), 5,5′-Me₂bipy (<b>2</b>), and 6,6′-Me₂bipy (<b>3</b>)] (bipy = 2,2′-bipyridine), were synthesized by treating the parent <i>fac</i>-[Re^I(CO)₃(Me₂bipy)­(CH₃CN)]­BF₄ complex with the <i>C</i>₂-symmetrical amine 1-(4-pyridyl)­piperazine (pyppzH). The axial amidine ligand has an exposed, highly basic pyridyl nitrogen. The reaction of complexes <b>1</b>–<b>3</b> with a B₁₂ model, (py)­Co­(DH)₂Cl (DH = monoanion of dimethylglyoxime), in CH₂Cl₂ yielded the respective dinuclear complexes, namely, <i>fac</i>-[Re­(CO)₃(Me₂bipy)­(μ-(HNC­(CH₃)­(pyppz)))­Co­(DH)₂Cl]­BF₄ [(4,4′-Me₂bipy (<b>4</b>), 5,5′-Me₂bipy (<b>5</b>), and 6,6′-Me₂bipy (<b>6</b>)]. ¹H NMR spectroscopic analysis of all compounds and single-crystal X-ray crystallographic data for <b>2</b>, <b>3</b>, <b>5</b>, and <b>6</b> established that the amidine had only the <i>E</i> configuration in both the solid and solution states and that the pyridyl group is bound to Co in <b>4</b>–<b>6</b>. Comparison of the NMR spectra of <b>1</b>–<b>3</b> with spectra of <b>4</b>–<b>6</b> reveals an unusually large “wrong-way” upfield shift for the pyridyl H2/6 signal for <b>4</b>–<b>6</b>. The wrong-way H2/6 shift of (4-Xpy)­Co­(DH)₂Cl (4-Xpy = 4-substituted pyridine) complexes increased with increasing basicity of the 4-Xpy derivative, a finding attributed to the influence of the magnetic anisotropy of the cobalt center on the shifts of the ¹H NMR signals of the pyridyl protons closest to Co. Our method of employing a coordinate bond for conjugating the <i>fac</i>-[Re^I(CO)₃] core to a vitamin B₁₂ model could be extended to natural B₁₂ derivatives. Because B₁₂ compounds are known to accumulate in cancer cells, such an approach is a very attractive method for the development of ^99mTc and ^186/188Re radiopharmaceuticals for targeted tumor imaging and therapy

Models for B₁₂-Conjugated Radiopharmaceuticals. Cobaloxime Binding to New <i>fac</i>-[Re(CO)₃(Me₂Bipyridine)(amidine)]BF₄ Complexes Having an Exposed Pyridyl Nitrogen

New mononuclear amidine complexes, <i>fac</i>-[Re­(CO)₃(Me₂bipy)­(HNC­(CH₃)­(pyppz))]­BF₄ [(4,4′-Me₂bipy (<b>1</b>), 5,5′-Me₂bipy (<b>2</b>), and 6,6′-Me₂bipy (<b>3</b>)] (bipy = 2,2′-bipyridine), were synthesized by treating the parent <i>fac</i>-[Re^I(CO)₃(Me₂bipy)­(CH₃CN)]­BF₄ complex with the <i>C</i>₂-symmetrical amine 1-(4-pyridyl)­piperazine (pyppzH). The axial amidine ligand has an exposed, highly basic pyridyl nitrogen. The reaction of complexes <b>1</b>–<b>3</b> with a B₁₂ model, (py)­Co­(DH)₂Cl (DH = monoanion of dimethylglyoxime), in CH₂Cl₂ yielded the respective dinuclear complexes, namely, <i>fac</i>-[Re­(CO)₃(Me₂bipy)­(μ-(HNC­(CH₃)­(pyppz)))­Co­(DH)₂Cl]­BF₄ [(4,4′-Me₂bipy (<b>4</b>), 5,5′-Me₂bipy (<b>5</b>), and 6,6′-Me₂bipy (<b>6</b>)]. ¹H NMR spectroscopic analysis of all compounds and single-crystal X-ray crystallographic data for <b>2</b>, <b>3</b>, <b>5</b>, and <b>6</b> established that the amidine had only the <i>E</i> configuration in both the solid and solution states and that the pyridyl group is bound to Co in <b>4</b>–<b>6</b>. Comparison of the NMR spectra of <b>1</b>–<b>3</b> with spectra of <b>4</b>–<b>6</b> reveals an unusually large “wrong-way” upfield shift for the pyridyl H2/6 signal for <b>4</b>–<b>6</b>. The wrong-way H2/6 shift of (4-Xpy)­Co­(DH)₂Cl (4-Xpy = 4-substituted pyridine) complexes increased with increasing basicity of the 4-Xpy derivative, a finding attributed to the influence of the magnetic anisotropy of the cobalt center on the shifts of the ¹H NMR signals of the pyridyl protons closest to Co. Our method of employing a coordinate bond for conjugating the <i>fac</i>-[Re^I(CO)₃] core to a vitamin B₁₂ model could be extended to natural B₁₂ derivatives. Because B₁₂ compounds are known to accumulate in cancer cells, such an approach is a very attractive method for the development of ^99mTc and ^186/188Re radiopharmaceuticals for targeted tumor imaging and therapy