Synthesis, characterization, and cancer cell-selective cytotoxicity of mixed-ligand cobalt(III) complexes of 8-hydroxyquinolines and phenanthroline bases.

Transition metal complexes exhibiting selective toxicity towards a broad range of cancer types are highly desirable as potential anticancer agents. Herein, we report the synthesis, characterization, and cytotoxicity studies of six new mixed-ligand cobalt(III) complexes of general formula [Co(B)2(L)](ClO4)2 (1-6), where B is a N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in 1, 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 3, 4), and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 5, 6), and L is the monoanion of 8-hydroxyquinoline (HQ in 1, 3, 5) and 5-chloro-7-iodo-8-hydroxyquinoline (CQ in 2, 4, 6). The X-ray single crystal structures of complexes 1 and 2 as PF6- salts revealed a distorted octahedral CoN5O coordination environment. Complexes demonstrated good stability in an aqueous buffer medium and in the presence of ascorbic acid as a reductant. Cytotoxicity studies using a panel of nine cancer cell lines showed that complex 6, with the dppz and CQ ligands, was significantly toxic against most cancer cell types, yielding IC50 values in the range of 2 to 14 µM. Complexes 1, 3, and 5, containing the HQ ligand, displayed lower toxicity compared to their CQ counterparts. The phenanthroline complexes demonstrated marginal toxicity towards the tested cell lines, while the dpq complexes exhibited moderate toxicity. Interestingly, all complexes demonstrated negligible toxicity towards normal HEK-293 kidney cells (IC50 > 100 µM). The observed cytotoxicity of the complexes correlated well with their lipophilicities (dppz > dpq > phen). The cytotoxicity of complex 6 was comparable to that of the clinical drug cisplatin under similar conditions. Notably, neither the HQ nor the CQ ligands alone demonstrated noticeable toxicity against any of the tested cell lines. The Annexin-V-FITC and DCFDA assays revealed that the cell death mechanism induced by the complexes involved apoptosis, which could be attributed to the metal-assisted generation of reactive oxygen species. Overall, the dppz complex 6, with its remarkable cytotoxicity against a broad range of cancer cells and negligible toxicity toward normal cells, holds significant potential for cancer chemotherapeutic applications.

Superior functionality of niobium pentoxide nano-rod/tripod photocatalyst synthesized using polyethyleneimine as a soft template for the abatement of methylene blue under UV and visible irradiation.

Polyethyleneimine (PEI) capping agent-cum-template-mediated synthesis of niobium oxide nanoparticles is reported to explore its impact on the resultant morphology, porosity, crystallinity, phase complexation, and thus on the photocatalytic activity. The resultant niobium oxides calcined at 800°C and 1000°C crystallized into highly ordered nano-rod/tripod nanostructure with inter-rod angle <120° having orthorhombic phase and heavily agglomerated rod-like nanostructures having monoclinic crystal phase, respectively. Contrary to the expectations, the nano-rod/tripods showed superior photocatalytic degradation kinetics and high adsorption of methylene blue dye in the hydrocolloid than formerly reported monoclinic nanoparticles. The best adsorption capability and photocatalytic activity are observed for the sample calcined at 800°C, resulting in a combined degradation efficiency of 98.8% of methylene blue dye. The adsorption characteristics, stability of the hydrocolloid system, the existence of oxygen vacancies, and the distinct morphology of the photocatalytic nano-rod/tripods are mainly responsible for this behavior. The process and the performance of unique nanostructure over others presents a superior alternative.

Awareness and Attitude of Dental Practitioners on Impact of Music Therapy on Patients Anxiety Level during Various Types of Dental Treatments.

Music therapy plays an important role in reducing the anxiety of patients during various procedures of dental treatments. Dental practitioners should also be aware of the employment of music therapy on patients before various dental treatments to reduce dental anxiety and the feasibility of its implementation in regular dental practice. A questionnaire study was conducted regarding the awareness and attitude of dental practitioners on the impact of music therapy on dental patients, to which 305 participants responded. A comparison was made between the Undergraduates, Postgraduates, Faculties, Interns, and Private practitioners. They were also asked about the drawbacks associated with music therapy. There was a level of agreement amongst participants regarding the awareness of music therapy. But there was a statistically significant difference (p = 0.011) noted across groups. The majority of the participants agreed that it could be incorporated into a regular dental practice as a stress management procedure.

Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma.

Cancer stem cells (CSCs) are a small sub-population of cells within a tumor mass proficient of tumor initiation and progression. Distinguishing features possessed by CSCs encompass self-renewal, regeneration and capacity to differentiate. These cells are attributed to the phenomenon of aggression, recurrence and metastasis in neoplasms. Due to their cancer initiating and contributing features, a proper understanding of these CSCs and its microenvironment would aid in better understanding of cancer and designing better targeted therapeutic strategies for improved clinical outcome, thus improving the prognosis. This article dispenses a narrative review of CSCs in the context of head and neck carcinoma under the sub headings of overview of cancer stem cells, methods of isolation of these cells, putative CSC markers of head and neck cancer, signaling pathways used by these cells and their therapeutic implications.

Effect of Angiotensin Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on COVID-19 outcome: A Record Based Observational Study in West Bengal.

BACKGROUND: Since its first identification in December 2019, in WUHAN (CHINA), SARS-COV-2, causative agent of Corona virus pandemic, has affected millions of people worldwide, causing thousands of death. There is much speculation about the interplay between ACEI/ARB and Corona virus infection, as for internalization into host cell SARS-COV-2 binds through S spike protein to ACE-2, aided TMPRSS2. METHODS: A record based observational study has been conducted (data obtained from the clinics of fourteen physicians) in two worst affected districts of West Bengal, to find out the association of ACEI/ARB on patients, suffering from Corona virus infection. The study-protocol has already been approved by Clinical Research Ethics Committee of Calcutta School of Tropical Medicine. (IEC Ref. No: CREC-STM/2020-AS-37) Results: Increasing age, male sex and presence of co-morbidities (viz. Diabetes, COPD) are significantly associated with the occurrence of moderate and severe disease. Drugs (viz. ACEI/ARB), though are associated with less severe disease, have not achieved statistical significance, in the present study. CONCLUSION: Drugs, like ACEI/ARB, should be continued in patients suffering from COVID-19 infection, (if they are already on these drugs).

BODIPY-attached zinc(II) complexes of curcumin drug for visible light assisted photo-sensitization, cellular imaging and targeted PDT.

Boron-dipyrromethene (BODIPY) based photosensitizers as porphyrinoids and curcumin as natural product possess exciting photophysical features suitable for theranostic applications, namely, imaging and photodynamic therapy (PDT). Limited aqueous solubility and insufficient physiological stability, however, reduce their efficacy significantly. We have designed a novel strategy to deliver these two unusable cytotoxins simultaneously in cancer cells and herein, report the synthesis, characterization and imaging-assisted photocytotoxicity of three zinc(II) complexes containing N3-donor dipicolylamine (dpa) ligands (L1-3) and O,O-donor curcumin (Hcur) viz. [Zn(L1)(cur)]Cl (1), [Zn(L2)(cur)]Cl (2) and [Zn(L3)(cur)]Cl (3), where L2 and L3 have pendant fluorescent BODIPY and non-emissive di-iodo-BODIPY moieties. Metal chelation imparted remarkable biological stability (pH ∼7.4) to the respective ligands and induces significant aqueous solubility. These ternary complexes could act as replacements of the existing metalloporphyrin-based PDT photosensitizers as their visible-light photosensitizing ability is reinforced by the dual presence of blue light absorbing curcumin and green light harvesting BODIPY units. Complex 2 having emissive BODIPY unit L2 and curcumin, showed mitochondria selective localization in HeLa, MCF-7 cancer cells and complex 3, the di-iodinated analogue of complex 2, exhibited type-I/II PDT activity via inducing apoptosis through mitochondrial membrane disruption in cancer cells while being significantly nontoxic in dark and to the healthy cells.

BODIPY-linked cis-dichlorido zinc(ii) conjugates: the strategic design of organelle-specific next-generation theranostic photosensitizers.

Dipicolylamine (dpa) based cis-dichlorido zinc(ii) complexes [Zn(L1-3)Cl2] (1-3), where L2 and L3 are non-iodo and di-iodo BODIPY-appended dpa in 2 and 3, and L1 is dpa in control complex 1, were prepared and characterized and their photocytotoxicity was studied. Complexes 2 and 3 were developed as potential substitutes for zinc(ii)-porphyrins/phthalocyanines that are photodynamic therapeutic agents with moderate activity owing to their inherent hydrophobicity and aggregation-induced deactivation mechanism. In our approach, we strategically designed hybrid inorganic-organic zinc-BODIPY conjugates as theranostic photosensitizers. The structurally characterized diamagnetic Zn(ii) cis-dichlorido complexes mimic cisplatin and serve as new-generation photosensitizers with enhanced aqueous solubility and mito-DNA targeting propensity while imparting significant physiological stability to the heavy atom tethered BODIPY ligand, L3. The BODIPY complexes showed a visible band near 500 nm (ε∼ 34 000-44 000 dm3 mol-1 cm-1) and an emission band at 507 nm for 2 in 1% DMSO-Dulbecco's phosphate buffered saline. The labile chlorido ligands (ΛM∼ 200 S m2 mol-1 in 9 : 1 H2O-DMSO) generated positively charged complexes inside the cellular medium enabling them to cross the mitochondrial membrane for this organelle-selective localization and singlet oxygen-mediated apoptotic photocytotoxicity at nanomolar concentrations for 3 in HeLa and MCF-7 cells in light (400-700 nm), while being less active in the dark.

LMCT transition-based red-light photochemotherapy using a tumour-selective ferrocenyl iron(iii) coumarin conjugate.

A rationally designed iron(iii) complex (2a) with pendant ferrocene and naturally occurring coumarin (esculetin) shows LMCT transition-based mitochondria-targeted red-light (600-720 nm) induced apoptotic toxicity against cancer cells but remains innocuous in the dark and to normal cells.

Crystal structure, DNA crosslinking and photo-induced cytotoxicity of oxovanadium(IV) conjugates of boron-dipyrromethene.

Cis-dichloro-oxovanadium(IV) complexes [VO(L1/L2)Cl2], where L1 is N-(4-(5,5-difluoro-1,3,7,9-tetramethyl-5H-4ʎ4,5ʎ4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)benzyl)-1-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)methanamine in 1 and L2 is N-(4-(5,5-difluoro-2,8-diiodo-1,3,7,9-tetramethyl-5H-4ʎ4,5ʎ4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)benzyl)-1-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)methanamine in 2) having 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene as boron-dipyrromethene (BODIPY) appended dipicolylamine bases were prepared, characterized and their photocytotoxicity studied. X-ray crystal structure of 1 showed distorted octahedral geometry with a VIVON3Cl2 core having Cl-V-Cl angle of 91.93(4)°. The complexes showed variable solution conductivity properties. They were non-electrolytes in dry DMF at 25 °C but showed 1:1 electrolytic behavior in an aqueous medium due to dissociation of one chloride ligand as evidenced from the mass spectral study. Complexes 1 and 2 showed absorption bands at 500 and 535 nm, respectively. The calf thymus DNA melting study revealed their interaction through DNA crosslinking on exposure to light which was further confirmed from the alkaline agarose gel electrophoresis using plasmid supercoiled pUC19 DNA. Complex 2 showed disruption of the mitochondrial membrane potential in the JC-1 (1,1',3,3'-tetraethyl-5,5',6,6'-tetrachloroimidacarbocyanine iodide) assay. The complexes were photocytotoxic in visible light (400-700 nm, power: 10 J cm-2) in cervical cancer HeLa and breast cancer MCF-7 cells. Complex 2 having a photoactive diiodo­boron-dipyrromethene moiety gave a singlet oxygen quantum yield (ΦΔ) value of ~0.6. It showed singlet oxygen mediated apoptotic photodynamic therapy activity with remarkably low IC50 (half maximal inhibitory concentration) value of ~0.15 µM. The cis-disposition of chlorides gave a cis-divacant 4-coordinate intermediate structure from the density functional theory (DFT) study thus mimicking the DNA crosslinking property of cisplatin.

Photocytotoxic copper(II) complexes of N-salicylyl-l-tryptophan and phenanthroline bases.

Four ternary copper(II) complexes of N-salicylyl-l-Tryptophan (Sal-TrpH) and phenanthroline bases of general formula [Cu(Sal-Trp)(L)], where L is 1,10-phenanthroline (phen, 1), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 2), dipyrido[3,2-a:2',3'-c]phenazine (dppz, 3) and 2-(anthracen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (aip, 4), were synthesized and fully characterized. The complexes were evaluated for their affinity for biomolecules and photocytotoxic activities. Single crystal X-ray diffraction studies of complex 1 revealed that it has a square pyramidal CuN3O2 core with the phenolate oxygen of salicylaldehyde occupying the axial coordination site in the solid state. Complexes 1-4 displayed the Cu(II)-Cu(I) redox couples at ~-0.3 V vs. Ag/AgCl reference electrode in DMF-0.1 M [Bun4N](ClO4). A Cu(II)-based weak d-d band ~650 nm and a moderately strong ligand to metal charge transfer band at ~430 nm were observed in DMF-Tris-HCl buffer (pH 7.2) (1:4 v/v). The complexes are efficient binders to calf thymus DNA and model proteins such as bovine serum albumin and lysozyme. They cleave supercoiled plasmid DNA efficiently when exposed to 446 and 660 nm laser radiation. They are cytotoxic to HeLa (human cervical cancer) and MCF-7 (human breast cancer) cells showing significant enhancement of cytotoxicity upon photo-excitation with low energy visible light. The complexes are found to kill cancer cells through generation of reactive oxygen species (ROS) as confirmed by DCFDA (2',7'-dichlorofluorescin diacetate) assay. The apoptotic cell death induced by complex 4 was confirmed by Annexin V-Fluorescein isothiocyanate-Propidium iodide assay. Confocal microscopic images using 4 showed its primary cytosolic localization in the HeLa and MCF-7 cells.

Pyriplatin-Boron-Dipyrromethene Conjugates for Imaging and Mitochondria-Targeted Photodynamic Therapy.

Monofunctional pyriplatin analogues cis-[Pt(NH3)2(L)Cl](NO3) (1-3) having boron-dipyrromethene (BODIPY) pendants (L) with 1,3,5,7-tetramethyl-8-(4-pyridyl)-4,4'-difluoroboradiazaindacene moieties were designed and synthesized, and their photocytotoxic properties were studied. The Pt-BODIPY conjugates displayed an absorption band within 505-550 nm and a green emissive band near 535 nm in 1% DMSO/DMEM (Dulbecco's modified Eagle's medium) buffer. Complex cis-[Pt(NH3)2(4-Me-py)Cl](NO3) (4) was used as a control for determining the structural aspects by X-ray crystallography. The mono- and diiodinated BODIPY complexes 2 and 3 showed generation of singlet oxygen on light activation as evidenced from the 1,3-diphenylisobenzofuran (DPBF) titration experiments. The cytotoxicity of the BODIPY complexes was tested against A549 (human lung cancer), MCF-7 (human breast cancer), and HaCaT (human skin keratinocyte) cells in dark and visible light (400-700 nm, 10 J cm-2). While complexes 2 and 3 showed excellent photocytotoxicity (IC50 ≈ 0.05 µM), they remained essentially nontoxic in the dark (IC50 > 100 µM). The emissive bands of 1 and 2 were used for cellular imaging by confocal microscopy study, which showed their mitochondrial localization. This was further supported by platinum estimation from isolated mitochondria and mitochondrial depolarization through a JC-1 assay. The photomediated apoptotic cell death was evidenced from flow cytometric assays, annexin-V/FITC-PI (fluorescein isothiocyanate-propidium iodide) and cell cycle arrest in sub-G1 and G2/M phases. The complexes bind to 9-ethylguanine as a model nucleobase to form monoadducts. A mechanistic study on DNA photocleavage activity using pUC19 DNA showed singlet oxygen as the reactive oxygen species (ROS). The combination of photodynamic therapy with DNA cross-linking property enhanced the anticancer potential of the monofunctional BODIPY-conjugates of pyriplatins.

Elucidating efficacy of biomass derived nanocomposites in water and wastewater treatment.

In the present study, two synthesis methods of nanocomposites-one involving a mixture of biomass and the other using chemical modification were investigated to evaluate practical application of green approach in pollution control, specifically for water and wastewater treatment. Newer multifunctional superparamagnetic nanocomposites using biomaterials such as unripened fruit of Cassia fistula (Golden shower) and Aloe vera were developed as an example of green approach while chemical modification was illustrated using n-octanol. Two specific model applications were studied for the developed materials-dye removal (Methyl Blue and Congo Red) and disinfection-demonstrating antimicrobial property. To elucidate the multifunctional character, the texture, morphology and composition of the prepared bionanocomposites were studied. The surface area values were 6.2 and 9.8 m2/g for Aloe vera and octanol based nanocomposites while the average pore diameters were 1.79 nm and 5.7 nm respectively, indicating presence of highly developed micropores in the first material having a honeycomb shape and the later showing excellent staircase type formation with larger pores. A very high dye removal to the extent of 100% was obtained that can be attributed largely to the functionalities imparted from Cassia fistula compared to ingredients from Aloe vera and octanol. The nanomaterials could be completely separated with absolute ease by applying simple magnetic field. Also, successful application of the developed materials in disinfection, removal of E. coli, was demonstrated with a very high efficiency of over 95%. The biomass derived nanocomposites exhibit excellent pollutant removal and disinfection properties, even at very low nanoparticle content; octanol based material indicating ∼5 times lowered cost, while the Aloe vera based bionanocomposites have potential for cost reduction to the extent of 10 times as compared to only magnetite nanoparticles, thereby highlighting techno-economical alternative in water and wastewater treatment.

Mitochondria-localizing BODIPY-copper(ii) conjugates for cellular imaging and photo-activated cytotoxicity forming singlet oxygen.

Copper(ii) acetylacetonates of N,N,N-donor dipicolylamine (dpa) ligands, viz. [Cu(L1)(acac)]ClO4 (1), [Cu(L2)(acac)]ClO4 (2) and [Cu(L3)(acac)]ClO4 (3), where L1 is benzyldipicolylamine (bzdpa), L2 and L3 are non-iodinated and diiodinated BODIPY (borondipyrromethene) ligands and Hacac is acetylacetone, were synthesized and characterized and their photocytotoxicity was studied. The BODIPY complex 2, structurally characterized by X-ray crystallography, has copper(ii) in a distorted square-pyramidal geometry (degree of trigonality, τ5 = 0.28). The one-electron paramagnetic and redox active copper(ii) complexes displayed 1 : 1 electrolytic behaviour in polar organic solvents. The BODIPY complexes 2 and 3 showed respective visible bands at 498 and 539 nm in 5% DMSO-phosphate buffered saline (PBS). Complex 2 displayed an emission band at 511 nm in 5% DMSO-PBS (λex = 465 nm) with a fluorescence quantum yield (ΦF) value of 0.15. Cellular imaging using this complex showed significant mitochondrial localization in HeLa and MCF-7 cancer cells. Complex 3 with a diiodo-BODIPY moiety was non-emissive (ΦF = 0.01) but acted as an efficient photosensitizer with a singlet oxygen quantum yield value of 0.59 (ΦΔ). Complex 3 showed a remarkable PDT effect with apoptotic cell death due to singlet oxygen giving IC50 values within 0.04-0.06 µM in HeLa and MCF-7 cells using visible light (400-700 nm), while being less toxic in the dark.

Curcumin "Drug" Stabilized in Oxidovanadium(IV)-BODIPY Conjugates for Mitochondria-Targeted Photocytotoxicity.

Ternary oxidovanadium(IV) complexes of curcumin (Hcur), dipicolylamine (dpa) base, and its derivatives having pendant noniodinated and di-iodinated boron-dipyrromethene (BODIPY) moiety (L1 and L2, respectively), namely, [VO(dpa)(cur)]ClO4 (1), [VO(L1)(cur)]ClO4 (2), and [VO(L2)(cur)]ClO4 (3) and their chloride salts (1a-3a) were prepared, characterized, and studied for anticancer activity. The chloride salts were used for biological studies due to their aqueous solubility. Complex 1 was structurally characterized by single-crystal X-ray crystallography. The complex has a VO2+ moiety bound to dpa ligand showing N,N,N-coordination in a facial mode, and curcumin is bound in its mono-anionic enolic form. The V-O(cur) distances are 1.950(18) and 1.977(16) Å, while the V-N bond lengths are 2.090(2), 2.130(2), and 2.290(2) Å. The bond trans to V═O is long due to trans effect. The complexes are stable in a solution phase over a long period of time of 48 h without showing any apparent degradation of the curcumin ligand. The diiodo-BODIPY ligand (L2) or Hcur alone showed limited solution stability in dark. The emissive BODIPY (L1) containing complex 2a showed preferential mitochondrial localization in MCF-7 cells in cellular imaging experiments. The cytotoxicity of the complexes was studied by MTT assay. The BODIPY complex 3a showed excellent photodynamic therapy effect in visible light (400-700 nm) giving IC50 values of 2-6 µM in HeLa and MCF-7 cancer cells, while being less toxic in dark (∼100 µM). The cell death was apoptotic in nature involving reactive oxygen species (ROS). Mechanistic data from pUC19 DNA photocleavage studies revealed photogenerated ROS as primarily 1O2 from the BODIPY moiety and ·OH radicals from the curcumin ligand.

Discovering vesicle traffic network constraints by model checking.

A eukaryotic cell contains multiple membrane-bound compartments. Transport vesicles move cargo between these compartments, just as trucks move cargo between warehouses. These processes are regulated by specific molecular interactions, as summarized in the Rothman-Schekman-Sudhof model of vesicle traffic. The whole structure can be represented as a transport graph: each organelle is a node, and each vesicle route is a directed edge. What constraints must such a graph satisfy, if it is to represent a biologically realizable vesicle traffic network? Graph connectedness is an informative feature: 2-connectedness is necessary and sufficient for mass balance, but stronger conditions are required to ensure correct molecular specificity. Here we use Boolean satisfiability (SAT) and model checking as a framework to discover and verify graph constraints. The poor scalability of SAT model checkers often prevents their broad application. By exploiting the special structure of the problem, we scale our model checker to vesicle traffic systems with reasonably large numbers of molecules and compartments. This allows us to test a range of hypotheses about graph connectivity, which can later be proved in full generality by other methods.