Expanding the Landscape of Phosphorous-Based Open Shell Species: Stable Mono-, Di-, and Trianionic Radicals Based on a Contorted Triphosphaalkene.

The stepwise reduction of the highly contorted truxene-based triphosphaalkene 1 using KC8 led to the isolation of mono-, di-and tri-anionic species. The solid-state molecular structures of mono- and diradical anionic species were elucidated by single crystal X-ray diffractions, revealing elongated P-C bonds and a pronounced "indene" aromatization compared to the parent system. All three radical species displayed distinct Electron Paramagnetic Resonance (EPR) spectra, providing compelling evidence for the open-shell electronic configuration of both the diradical and triradical species-an observation unprecedented in any previously reported phosphorous-based anionic polyradicals. Mulliken spin density calculations revealed a dominant localization of radical spin on a single phosphorous atom in the monoanion. In the dianion, spin localization is observed on two phosphorous atoms (~34% each), with a minor contribution from the third phosphorous (0.13%), while the trianion demonstrates a uniform distribution of spin density (~30%) across each phosphorous atom.

Introducing Phosphorus into the Overcrowded Thiele's hydrocarbon Family: Unveiling Contorted Main Group Diradicaloids with Dynamic Redox Behavior.

Thiele's Hydrocarbons (THs) featuring a 9,10-anthrylene core with switchable geometric and electronic configurations offer exciting possibilities in advanced functional materials. Despite significant advances in main group-based diradicaloids in contemporary chemistry, main group THs containing an anthrylene cores have remained elusive, primarily due to the lack of straightforward synthetic strategies and the inherent high reactivity of these species. In this study, we utilize an anthracene-based phosphine synthon to demonstrate, for the first time, a facile and high-yielding synthetic strategy for robust P-functionalized overcrowded ethylenes (OCEs) within the TH family. These OCEs feature a non-symmetric environment, incorporating (thio)xanthyl and phosphaalkene termini. We systematically probe the electronic structures of these derivatives to illustrate the impact of the isolobal phosphaalkene motif on the quinoidal/diradicaloid character. Notably, the compounds exhibit dynamic redox behavior, leading to orthogonally twisted conformational changes upon oxidation, with a kinetically locked redox-couple.

Diosmium compounds containing bis(imidazole)-p-quinone bridging ligands.

The doubly deprotonated bridging ligand L12- derived from 2,6-bis(2-pyridyl)-1,5-dihydro-1',4'-benzoquinono[2',3'-d:5',6'-d']diimidazole H2L1 forms coordination compounds with two bis(2,2'-bipyridine)osmium(II) complex fragments in anti ([1](ClO4)2) and syn configurations ([2](ClO4)2) of {(µ-L1)[Os(bpy)2]2}(ClO4)2, as evident from crystal structure analyses. Exchange of the metal-coordinating 2-pyridyl functions in the bridge through non-coordinating 4-tolyl substituents (L12- → L22-) leads to [3](ClO4)2 which involves chelation of the [Os(bpy)2]2+ groups through imidazole-N and carbonyl-O atoms of the central p-quinone function. In addition to identification, the compounds were subjected to electrochemical (CV, DPV) and spectroelectrochemical (UV-vis-NIR, EPR) analyses of electron transfer, the results being supported by results from TD-DFT calculations. Essential differences between [1n+]/[2n+] and [3n+] systems were found regarding variable but mostly metal centred oxidation, the two processes separated much more for [3n+]. The first reduction is bpy ([1+], [2+]) or quinone ligand centred ([3+]). Electronic structures and electron transfer behaviour are thus highly sensitive to differences of configuration and coordination.

Nanostructured lipid carriers of isradipine for effective management of hypertension and isoproterenol induced myocardial infarction.

The objective of the present paper is to formulate nanostructured lipid carriers (NLCs) of a calcium channel blocker, isradipine, to enhance its oral bioavailability and prolong its antihypertensive effect apart from evaluating efficacy of the formulation in isoproterenol induced myocardial infarction in rats. Formulation was optimized using quality by design (QbD)-based approach. Three factors i.e., total lipid concentration (%), homogenization pressure (bar), and number of cycles were optimized through Box-Behnken design to estimate their effect on critical quality attributes (CQAs) viz., size (nm), % entrapment efficiency, and in vitro % drug release which were found to be 80.9 ± 1.7 nm, 83.51 ± 2.15%, and 83.3 ± 3.86% after 24 h, respectively. In vivo pharmacokinetic study indicated 4.207 and 1.907 times increase in the oral bioavailability of optimized nanostructured lipid carrier without and with cycloheximide (lymphatic transport inhibitor), respectively. Treatment with ISO (isoproterenol) significantly diverges the levels of antioxidant marker, TBARS (thiobarbituric acid), and ultrastructure of the cardiac tissue indicating significant myocardial damage. Pretreatment of nanostructured lipid carrier of isradipine (ISD-NLCs) significantly prevented the antioxidant status and ultrastructural changes in the heart. In conclusion, this study confirms that optimized NLCs can substantially improve oral bioavailability of isradipine and presents a promising strategy in the management of hypertension for longer duration of time apart from demonstrating its preclinical efficacy in cardioprotection.

Role of AMP-activated protein kinase on cardio-metabolic abnormalities in the development of diabetic cardiomyopathy: A molecular landscape.

Cardiovascular complications associated with diabetes mellitus remains a leading cause of morbidity and mortality across the world. Diabetic cardiomyopathy is a descriptive pathology that in absence of co-morbidities such as hypertension, dyslipidemia initially characterized by cardiac stiffness, myocardial fibrosis, ventricular hypertrophy, and remodeling. These abnormalities further contribute to diastolic dysfunctions followed by systolic dysfunctions and eventually results in clinical heart failure (HF). The clinical outcomes associated with HF are considerably worse in patients with diabetes. The complexity of the pathogenesis and clinical features of diabetic cardiomyopathy raises serious questions in developing a therapeutic strategy to manage cardio-metabolic abnormalities. Despite extensive research in the past decade the compelling approaches to manage and treat diabetic cardiomyopathy are limited. AMP-Activated Protein Kinase (AMPK), a serine-threonine kinase, often referred to as cellular "metabolic master switch". During the development and progression of diabetic cardiomyopathy, a plethora of evidence demonstrate the beneficial role of AMPK on cardio-metabolic abnormalities including altered substrate utilization, impaired cardiac insulin metabolic signaling, mitochondrial dysfunction and oxidative stress, myocardial inflammation, increased accumulation of advanced glycation end-products, impaired cardiac calcium handling, maladaptive activation of the renin-angiotensin-aldosterone system, endoplasmic reticulum stress, myocardial fibrosis, ventricular hypertrophy, cardiac apoptosis, and impaired autophagy. Therefore, in this review, we have summarized the findings from pre-clinical and clinical studies and provided a collective overview of the pathophysiological mechanism and the regulatory role of AMPK on cardio-metabolic abnormalities during the development of diabetic cardiomyopathy.

Fused N-Heterocyclic-Bridged Isomeric Diruthenium Complexes [(acac)2Ru(µ-DIPQD)Ru(acac)2]n, n = +2, + 1, 0, -1, -2.

π-Conjugated bridged isomeric diruthenium(II) complexes [(acac)2RuII(µ-DIPQD)RuII(acac)2], 1 (trans) and 2 (cis) (acac- = acetylacetonate, (8E,16E)-N8,N16-diphenylindeno[1,2-b]indeno[2',1':5,6]pyrazino[2,3-g]quinoxaline-8,16-diimine (trans-DIPQD), and (12E,16E)-N12,N16-diphenylindeno[1,2-b]indeno[1',2':5,6]pyrazino[2,3-g]quinoxaline-12,16-diimine (cis-DIPQD) were separated and structurally characterized. The structures of the rac (ΔΔ/ΛΛ) forms of 1 and 2 exhibit two units of {Ru(acac)2}, linked to adjacent pyrazine and imine nitrogen donors of the bridge (DIPQD) in trans and cis modes, with metal-metal separations of 9.050 and 6.330 Å, respectively. The packing diagrams of 1 and 2 revealed an intermolecular π···π stacking interaction (3.202-3.398 Å) involving the face-to-face arrangement of the aromatic rings of DIPQD in adjacent molecules and varying solid-state packing modes, slipped stacking in the former versus brick-layer stacking in the latter. The electronic forms associated with multiple reversible one-electron redox steps of 1 and 2 were addressed by DFT (MO composition, Mulliken spin density distribution), supported by EPR of intermediate paramagnetic states and by UV-vis-NIR spectroelectrochemistry in all redox states. The results reveal similar electronic forms along the redox series irrespective of their isomeric identities in 1 and 2, viz., primarily metal-based oxidations ([(acac)2RuII(µ-DIPQD)RuIII(acac)2]+, 1+/2+, S = 1/2; [(acac)2RuIII(µ-DIPQD)RuIII(acac)2]2+, 12+/22+, S = 1) and bridge-based reductions ([(acac)2RuII(µ-DIPQD•-)RuII(acac)2]-, 1•-/2•-, S = 1/2; [(acac)2RuII(µ-DIPQD2-)RuII(acac)2]2-, 12-/22-, S = 1). TD-DFT analysis of the electronic transitions in the complexes suggests bridge-targeted mixed metal/ligand-based multiple charge transfer transitions over the visible to NIR region in all redox states, while a weak band involving the radical bridge appeared in the long-wavelength region (∼2000 nm) in 1•-/2•-.

Nerolidol attenuates cyclophosphamide-induced cardiac inflammation, apoptosis and fibrosis in Swiss Albino mice.

Incidence and prevalence of cancer is an alarming situation globally. For the treatment of cancer many anticancer drugs have been developed but, unfortunately, their potential cardiotoxic side effects raised serious concerns about their use among clinicians. Cyclophosphamide is a potent anticancer and immunosuppressant drug but its use is limited due to cardiotoxic side effect. Thus, there is a need for the development of certain drug which can reduce cardiotoxicity and can be used as an adjuvant therapy in cancer patients. In this direction we, therefore planned to evaluate nerolidol (NER) for its cardioprotective potential against cyclophosphamide-induced cardiotoxicity in Swiss Albino mice. Animals were divided into 6 groups. Vehicle control; Cyclophosphamide (CP 200); NER 400 per se; NER 200 + CP 200; NER 400 + CP 200; and fenofibrate (FF 80) + CP 200. Dosing was done for 14 days along with a single dose of CP 200 on the 7th day. On 15th day animals were sacrificed and various biochemical parameters pertaining to oxidative stress, nitrative stress, inflammation, apoptosis and fibrosis were estimated in the blood and heart tissues. Histopathological analysis (H & E and Masson's trichrome staining); ultrastructural analysis (transmission electron microscopy) and immunohistochemical analysis were also performed along with mRNA expression and molecular docking to establish the cardioprotective potential of nerolidol. Nerolidol acted as a potent cardioprotective molecule and attenuated CP-induced cardiotoxicity.

Host-Guest Feature of DPPP Bridged Arene-Ruthenium Clip Derived Molecular Rectangle.

The development of DPPP2- (H2DPPP = 2,5-dihydro-3,6-di-2-pyridylpyrrolo(3,4-c)pyrrole-1,4-dione) bridged (NN∩NN) diruthenium complexes [(Cym)(X)RuII(µ-dppp)RuII(X)(Cym)] (Cym = para-cymene and X = OTf- (1), SCN- (2), N3- (3), NO2-(4)) are considered as the probable molecular clips for the construction of metallarectangle. Crystal structures of 2-4 established anticonfiguration with respect to monodentate SCN-, N3- and NO2- groups, respectively. Though molecular clips 2-4 failed to provide the desired metallarectangle in combination with the 4,4'-bipyridine spacer, 1 with the labile OTf groups facilitated to achieve the metallarectangle 5. The crystal structure of 5 revealed that two twisted 4,4'-bipyridine spacers bridged between the two units of dimeric 1 in symmetric fashion, which in effect led to the newer class of molecular rectangle 5 with a hydrophobic cavity size of the cationic host of 8.32 × 11.11 Å2. Furthermore, the host-guest interaction potential of 5 with special reference to the guest molecule, pyrene, was explored. The crystal structure of the resultant molecule 6 ascertained the partial encapsulation of two pyrene molecules inside the hydrophobic cavity of 5, due to the twisted 4,4'-bipyridine spacer units between the two ruthenium clips. It also attributed a noncovalent CH-π interaction involving protons of pyrene and the π-electron cloud of 4,4'-bipyridine as well as a weak interaction between pyrene protons and the pendant C═O group of DPPP. Encapsulation of the guest molecule (pyrene) inside the cavity of the metallarectangle was also monitored by following the quenching of florescent intensity of pyrene on addition of 5.

Effects of nimodipine, vinpocetine and their combination on isoproterenol-induced myocardial infarction in rats.

BACKGROUND: Myocardial infarction (MI) remains a major cause of morbidity and mortality worldwide. Nimodipine is a calcium (Ca2+) channel blocker as well as a PDE1 inhibitor and primarily used in subarachnoid haemorrhage (SAH) due to its blood-brain barrier crossing property. Nimodipine and vinpocetine inhibit the degradation of phosphodiester bond which increases cGMP and cAMP levels causing vasodilation. MATERIAL AND METHODS: We have divided rats randomly into Group I - Vehicle control; Group II - Toxic control (ISO 85 mg/kg, i.p.); Group III, IV and V - Nimodipine (5, 10 and 15 mg/kg, i.p. respectively) with ISO; Group VI- Nimodipine (15 mg/kg) alone; Group VII - Nimodipine + Vinpocetine (10 mg/kg + 10 mg/kg) with ISO; Group VIII - Nimodipine + Vinpocetine (10 mg/kg + 10 mg/kg) alone; Group IX- Diltiazem (25 mg/kg, p.o) with ISO; Group X- Diltiazem (25 mg/kg) alone and Group XI- Vinpocetine (10 mg/kg, p.o.) with ISO for 7 days. After 24 h of the last dose, haemodynamics were assessed then animals were sacrificed and biochemical, histopathological and ultrastructural changes were measured. RESULTS: Treatment with ISO significantly deviated the haemodynamic parameters (HR, SAP, DAP and MAP), biochemical parameters (CK-MB, LDH, SGOT, cGMP and Troponin-T) and antioxidant markers (TBARS, SOD, CAT, GSH, GPx, GST and GR). Haemotoxylin and eosin staining of the cardiac tissue and ultrastructural study also indicated significant myocardial damage. Pretreatment with nimodipine (10 and 15 mg/kg, i.p), vinpocetine (10 mg/kg, p.o) and their combination significantly restored the antioxidant status, haemodynamic profile, cellular architecture and ultrastructural changes in the heart. CONCLUSION: Nimodipine and vinpocetine both showed cardioprotection when given alone. However, their combination showed better restoration in terms of oxidative stress, cardiac membrane damage, haemodynamics, histopathology and ultrastructural changes.

Molecular mechanism involved in cyclophosphamide-induced cardiotoxicity: Old drug with a new vision.

Cyclophosphamide (CP) is an important anticancer drug which belongs to the class of alkylating agent. Cyclophosphamide is mostly used in bone marrow transplantation, rheumatoid arthritis, lupus erythematosus, multiple sclerosis, neuroblastoma and other types of cancer. Dose-related cardiotoxicity is a limiting factor for its use. CP-induced cardiotoxicity ranges from 7 to 28% and mortality ranges from 11 to 43% at the therapeutic dose of 170-180 mg/kg, i.v. CP undergoes hepatic metabolism that results in the production of aldophosphamide. Aldophosphamide decomposes into phosphoramide mustard & acrolein. Phosphoramide is an active neoplastic agent, and acrolein is a toxic metabolite which acts on the myocardium and endothelial cells. This is the first review article that talks about cyclophosphamide-induced cardiotoxicity and the different signaling pathways involved in its pathogenicity. Based on the available literature, CP is accountable for cardiomyocytes energy pool alteration by affecting the heart fatty acid binding proteins (H-FABP). CP has been found associated with cardiomyocytes apoptosis, inflammation, endothelial dysfunction, calcium dysregulation, endoplasmic reticulum damage, and mitochondrial damage. Molecular mechanism of cardiotoxicity has been discussed in detail through crosstalk of Nrf2/ARE, Akt/GSK-3ß/NFAT/calcineurin, p53/p38MAPK, NF-kB/TLR-4, and Phospholamban/SERCA-2a signaling pathway. Based on the available literature we support the fact that metabolites of CP are responsible for cardiotoxicity due to depletion of antioxidants/ATP level, altered contractility, damaged endothelium and enhanced pro-inflammatory/pro-apoptotic activities resulting into cardiomyopathy, myocardial infarction, and heart failure. Dose adjustment, elimination/excretion of acrolein and maintenance of endogenous antioxidant pool could be the therapeutic approach to mitigate the toxicities.

Diruthenium Complexes of p-Benzoquinone-Imidazole Hybrid Ligands: Innocent or Noninnocent Behavior of the Quinone Moiety.

After double deprotonation, 2,6-diaryl-p-benzoquinonodiimidazoles (aryl=4-tolyl (I) or 2-pyridyl (II)) were shown to bridge two [Ru(bpy)2 ]2+ (bpy=2,2'-bipyridine) complex fragments through the imidazolate N and p-quinone O (I→12+ ) or through the imidazolate N and pyridyl N donor atoms (II→22+ ). Characterization by crystal structure analysis, 1 H/13 C NMR spectroscopy, cyclic and differential pulse voltammetry, and spectroelectrochemistry (UV/Vis/NIR, IR, EPR) in combination with TD-DFT calculations revealed surprisingly different electronic structures for redox systems 1n and 2n . Whereas 12+ is reduced to a radical complex with considerable semiquinone character, the reduction of 22+ with its exclusive N coordination exhibits little spin on the now redox-innocent quinone moiety, compared with the electron uptake by the pyridyl-imidazolate chelating site. The first of two close-lying oxidation processes occurs at the bridging heteroquinone ligand, whereas the second oxidation is partly (14+ ) or predominantly (24+ ) centered on the metal atoms.

Non-innocence and mixed valency in tri- and tetranuclear ruthenium complexes of a heteroquinone bridging ligand.

The redox-active ligand 5,7,12,14-tetraazapentacene-6,13-quinone = L forms structurally characterised compounds with three (1) or four (2) [Ru(acac)2] complex fragments in which each of the metals is N,O-chelated. The new tris- and tetrakis-bidentate chelate compounds exhibit ruthenium centres bridged at about 4 Å by quinone O atoms which are then situated across the pentacene π system at about 6-8 Å distance. Several electron transfer processes were observed by voltammetry (CV, DPV) and the intermediates identified by EPR and UV-Vis-NIR spectroelectrochemistry. TD-DFT calculations were applied to assign the proper oxidation states within the multistep redox systems {(µn-L)[Ru(acac)2]n}k, n = 3 or 4, revealing both metal and ligand based electron transfer.

Isomeric Diruthenium Complexes of a Heterocyclic and Quinonoid Bridging Ligand: Valence and Spin Alternatives for the Metal/Ligand/Metal Arrangement.

5,7,12,14-Tetraazapentacene-6,13-quinone (L) reacts with 2 equiv of [Ru(acac)2(CH3CN)2] to form two linkage isomeric bis(chelate) compounds, [{RuII(acac)2}2(µ-L)], blue 1, with 5,6;12,13 coordination and violet 2 with 5,6;13,14 coordination. The linkage isomers could be separated, structurally characterized in crystals as rac diastereomers (ΔΔ/ΛΛ), and studied by voltammetry (CV, DPV), EPR, and UV-vis-NIR spectroelectrochemistry (meso-1, rac-2). DFT and TD-DFT calculations support the structural and spectroscopic results and suggest a slight energy preference (ΔE = 263 cm-1) for the rac-isomer 1 as compared to 2. Starting from the RuII-(µ-L0)-RuII configurations of 1 and 2 with low-lying metal-to-ligand charge transfer (MLCT) absorptions, the compounds undergo two reversible one-electron oxidation steps with open-shell intermediates 1+ (Kc = 4 × 104) and 2+ (Kc = 6 × 105). Both monocations display metal-centered spin according to EPR, but the DFT-calculated spin densities suggest a RuIII(µ-L•-)RuIII three-spin situation with opposite spin density at the bridging ligand for the meso form of 1+, estimated to lie 1887 cm-1 lower in energy than rac-1+, which is calculated with a Class II mixed-valent situation RuIII-(µ-L0)-RuII. A three-spin arrangement RuIII-(µ-L•-)-RuIII with negative spin density at one metal site is suggested by DFT for rac-2+ which is more stable by ΔE = 890 cm-1 than rac-1+. Reduction of 1 or 2 (Kc = 107-108) occurs mainly at the central bridging ligand with notable contributions (30%) from the metals in 1- and 2-. The mixed-valent RuIII(µ-L)RuII versus radical-bridged RuIII(µ-L•-)RuIII alternative is discussed comprehensively in comparison with related valence-ambiguous cases.

1,5-Diamido-9,10-anthraquinone, a Centrosymmetric Redox-Active Bridge with Two Coupled ß-Ketiminato Chelate Functions: Symmetric and Asymmetric Diruthenium Complexes.

The dinuclear complexes {(µ-H2L)[Ru(bpy)2]2}(ClO4)2 ([3](ClO4)2), {(µ-H2L)[Ru(pap)2]2}(ClO4)2 ([4](ClO4)2), and the asymmetric [(bpy)2Ru(µ-H2L)Ru(pap)2](ClO4)2 ([5](ClO4)2) were synthesized via the mononuclear species [Ru(H3L)(bpy)2]ClO4 ([1]ClO4) and [Ru(H3L)(pap)2]ClO4 ([2]ClO4), where H4L is the centrosymmetric 1,5-diamino-9,10-anthraquinone, bpy is 2,2'-bipyridine, and pap is 2-phenylazopyridine. Electrochemistry of the structurally characterized [1]ClO4, [2]ClO4, [3](ClO4)2, [4](ClO4)2, and [5](ClO4)2 reveals multistep oxidation and reduction processes, which were analyzed by electron paramagnetic resonance (EPR) of paramagnetic intermediates and by UV-vis-NIR spectro-electrochemistry. With support by time-dependent density functional theory (DFT) calculations the redox processes could be assigned. Significant results include the dimetal/bridging ligand mixed spin distribution in 3(3+) versus largely bridge-centered spin in 4(3+)-a result of the presence of Ru(II)-stabilizig pap coligands. In addition to the metal/ligand alternative for electron transfer and spin location, the dinuclear systems allow for the observation of ligand/ligand and metal/metal site differentiation within the multistep redox series. DFT-supported EPR and NIR absorption spectroscopy of the latter case revealed class II mixed-valence behavior of the oxidized asymmetric system 5(3+) with about equal contributions from a radical bridge formulation. In comparison to the analogues with the deprotonated 1,4-diaminoanthraquinone isomer the centrosymmetric H2L(2-) bridge shows anodically shifted redox potentials and weaker electronic coupling between the chelate sites.