RESUMEN
Nuclear factor kappa beta (NF-κB) plays a pivotal role in breast cancer, particularly triple-negative breast cancer, by promoting inflammation, proliferation, epithelial-mesenchymal transition, metastasis, and drug resistance. Upregulation of NF-κB boosts vascular endothelial growth factor (VEGF) expression, assisting angiogenesis. The Ru(II) complexes of methyl- and dimethylpyrazolyl-benzimidazole N,N donors inhibit phosphorylation of ser536 in p65 and translocation of the NF-κB heterodimer (p50/p65) to the nucleus, disabling transcription to upregulate inflammatory signaling. The methyl- and dimethylpyrazolyl-benzimidazole inhibit VEGFR2 phosphorylation at Y1175, disrupting downstream signaling through PLC-γ and ERK1/2, ultimately suppressing Ca(II)-signaling. Partial release of the antiangiogenic ligand in a reactive oxygen species-rich environment is possible as per our observation to inhibit both NF-κB and VEGFR2 by the complexes. The complexes are nontoxic to zebrafish embryos up to 50 µM, but the ligands show strong in vivo antiangiogenic activity at 3 µM during embryonic growth in Tg(fli1:GFP) zebrafish but no visible effect on the adult phase.
Asunto(s)
FN-kappa B , Neoplasias de la Mama Triple Negativas , Humanos , Animales , FN-kappa B/metabolismo , Pez Cebra/metabolismo , Factor de Transcripción ReIA/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular , Ligandos , Bencimidazoles/farmacologíaRESUMEN
We report a facile stimuli-responsive strategy to generate reactive oxygen and nitrogen species (ROS and RNS) in the biological milieu from a photocleavable water-soluble block copolymer under visible light irradiation (427 nm, 2.25 mW/cm2). An anthraquinone-based water-soluble polymeric nitric oxide (NO) donor (BCPx-NO) is synthesized, which exhibits NO release in the range of 40-65 µM within 10 h of photoirradiation with a half-life of 30-103 min. Additionally, BCPx-NO produces peroxynitrite (ONOO-) and singlet oxygen (1O2) under photoirradiation. To understand the mechanism of NO release and photolysis of the functional group under blue light, we prepared a small-molecule anthraquinone-based N-nitrosamine (NOD). The cellular investigation of the effect of spatiotemporally controlled ONOO- and 1O2 generation from the NO donor polymeric nanoparticles in a triple negative breast adenocarcinoma (MDA-MB-231) under visible light irradiation (white light, 5.83 mW/cm2; total dose 31.5 J/cm2) showed an IC50 of 0.6 mg/mL. The stimuli-responsive strategy using a photolabile water-soluble block copolymer employed to generate ROS and RNS in a biological setting widens the horizon for their potential in cancer therapy.
Asunto(s)
Neoplasias , Ácido Peroxinitroso , Humanos , Ácido Peroxinitroso/uso terapéutico , Especies Reactivas de Oxígeno/uso terapéutico , Polímeros/uso terapéutico , Especies de Nitrógeno Reactivo/uso terapéutico , Luz , Oxígeno/uso terapéutico , Óxido Nítrico/uso terapéutico , Antraquinonas/uso terapéutico , Neoplasias/tratamiento farmacológicoRESUMEN
N-Nitrosamines are well established motifs to release nitric oxide (NO) under photoirradiation. Herein, a series of amphiphilic N-nitrosamine-based block copolymers (BCPx-NO) are developed to attain controlled NO release under photoirradiation (365 nm, 3.71 mW/cm2). The water-soluble BCPx-NO forms micellar architecture in aqueous medium and exhibits a sustained NO release of 92-160 µM within 11.5 h, which is 36.8-64.0% of the calculated value. To understand the NO release mechanism, a small molecular NO donor (NOD) resembling the NO releasing functional motif of BCPx-NO is synthesized, which displays a burst NO release in DMSO within 2.5 h. The radical nature of the released NO is confirmed by electron paramagnetic resonance (EPR) spectroscopy. The gradual NO release from micellar BCPx-NO enhances antibacterial activity over NOD and exhibits a superior bactericidal effect on Gram-positive Staphylococcus aureus. In relation to biomedical applications, this work offers a comprehensive insight into tuning light-triggered NO release to improve antibacterial activity.
Asunto(s)
Óxido Nítrico , Staphylococcus aureus , Óxido Nítrico/química , Polímeros/farmacología , Micelas , Antibacterianos/farmacología , Antibacterianos/químicaRESUMEN
The aggressiveness and recurrence of cancer is linked to cancer stem cells (CSCs), but drugs targeting CSCs may not succeed in the clinic due to the lack of a distinct CSC subpopulation. Clinical Pt(II) drugs can increase stemness. We screened 15 RuII or IrIII complexes with mesalazine or 3-aminobenzoate Schiff bases of the general formulas [Ru(p-cym)L]+, [Ru(p-cym)L], and [Ir(Cp*)L]+ (L = L1-L9) and found three complexes (2, 12, and 13) that are active against oral squamous cell carcinoma (OSCC) CSCs. There is a putative oncogenic role of transcription factors (viz. NOTCH1, SOX2, c-MYC) to enhance the stemness. Our work shows that imidazolyl-mesalazine ester-based RuII complexes inhibit growth of CSC-enriched OSCC 3D spheroids at low micromolar doses (2 µM). Complexes 2, 12, and 13 reduce stemness gene expression and induce differentiation markers (Involucrin, CK10) in OSCC 3D cultures. The imidazolyl-mesalazine ester-based RuII complex 13 shows the strongest effect. Downregulating c-MYC suggests that RuII complexes may target c-MYC-driven cancers.
Asunto(s)
Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Mesalamina/metabolismo , Mesalamina/farmacología , Línea Celular Tumoral , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/metabolismo , Diferenciación Celular , Antineoplásicos/farmacología , Antineoplásicos/metabolismo , Neoplasias de Cabeza y Cuello/patología , Células Madre NeoplásicasRESUMEN
Lipoic acid (LA) and dihydrolipoic acid (DHLA) are well established antioxidants to scavenge reactive oxygen species (ROS). However, they are carboxylates with ≈4.7 pKa making them negatively charged at physiological pH (7.4) reducing their passive diffusion through cell membranes. LA is known to be capable of reducing protein fibrillation. Incorporation of LA and especially DHLA in polymer side chains are scarce. Herein, the first examples of the anti-amyloidogenic effect of LA and DHLA incorporated into the side-chain of a block copolymer with a water-soluble poly(polyethylene glycol methyl ether methacrylate) (PPEGMA) segment are presented. The resultant polymers show improved ROS scavenging activity and improved ability to reduce insulin fibrillation compared to free LA and DHLA. Furthermore, the resultant polymers are also capable of disintegrating preformed insulin firbrils. Interestingly, polymers with dihydro-lipoate moieties showed 93% free radical scavenging activity with 91% anti-fibrillating efficacies for insulin protein confirmed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay and Thioflavin T (ThT) dye binding study, respectively. Further, the antioxidant polymers increase the cell viability against fibrillar insulin aggregates that may be involved in the etiology of several diseases. Overall, this work reveals that antioxidant polymer-based therapeutic agents can serve as a powerful modulation strategy for developing novel drugs in future against amyloid-related disorders.
Asunto(s)
Antioxidantes , Ácido Tióctico , Antioxidantes/farmacología , Antioxidantes/química , Especies Reactivas de Oxígeno , Insulina , Neuroprotección , Ácido Tióctico/farmacologíaRESUMEN
OBJECTIVE: To compare the characteristics and short-term outcomes in extremely preterm infants, who developed necrotizing enterocolitis (NEC) following a packed red blood cell transfusion (pRBC) within 48 h (TANEC), with those who developed NEC beyond 48 h (non-TANEC). SETTING: A single-center retrospective cohort study in a Tertiary neonatal intensive care unit in the UK over a 5-year period. PATIENTS AND METHODS: Extremely premature infants (23-27 weeks gestation) were selected. TANEC and non-TANEC incidence were calculated from the confirmed NEC group (defined as modified Bell's stage II and beyond). The characteristics and short-term outcomes of infants with TANEC in the first 8 weeks of life were compared to infants with non-TANEC. RESULTS AND INTERPRETATION: Incidence of confirmed NEC was 14% (28/207). On further subgroup analysis of the confirmed NEC cases, 46% (13/28) of infants were identified with TANEC and 54% (15/28) with non-TANEC. The incidence of TANEC did not correlate with the number of antecedent pRBC transfusions or the pre-transfusion median hemoglobin (Hb) levels. There were no significant differences in characteristics between the TANEC and non-TANEC groups. Infants within the TANEC group required more intensive neonatal care support, greater surgical intervention (p-value 0.043) with loss of gut integrity and an increase in number of TPN dependency days (p-value 0.014). CONCLUSIONS: A significantly worse clinical course and short-term outcome was observed in the TANEC group when compared with the non-TANEC group.
Asunto(s)
Enterocolitis Necrotizante , Enfermedades del Recién Nacido , Enfermedades del Prematuro , Recién Nacido , Humanos , Enterocolitis Necrotizante/etiología , Enterocolitis Necrotizante/complicaciones , Recien Nacido Extremadamente Prematuro , Enfermedades del Prematuro/epidemiología , Enfermedades del Prematuro/etiología , Enfermedades del Prematuro/terapia , Estudios Retrospectivos , Factores de Riesgo , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Diffuse parenchymal lung disease (DPLD) is not an uncommon problem in clinical practice. Although the exact prevalence of DPLD in India is not known, the relative etiological distribution in DPLD in India has been reported. There has been no information as regards the seasonality of the disease. PATIENTS AND METHODS: The archive of the Institute of Pulmocare and Research, Kolkata, was searched for the number of new patients registered at the outpatient department to a single consultant (practicing in the same style on appointment only) over years from 2009 to 2019. The attendance (absolute and relative) was arranged year wise and then month wise to look for the annual and seasonal trends, if any. RESULTS: A total of 2226 patients were registered from 2009 to 2019. There has been a steady increase in both the absolute number (104 in 2009 to 204 in 2019) and the relative percentage of attendance (4.36% in 2009 to 6.9% in 2019) of new registration of DPLD patients over the years. Regarding seasonal variation, two consistent peaks in attendance have been observed as December-January and April-May over the years with dips in February and September; the first being more consistent then the latter. CONCLUSIONS: The increase in relative attendance in the DPLD patients over the years needs further investigation to establish a rising trends in incidence and prevalence of DPLD. The unequivocal trend in seasonal variation needs attention and further research.
RESUMEN
Eight new ruthenium(II) complexes of N,N-chelating pyrazolylbenzimidazole ligands of the general formula [RuII(p-cym)(L)X]+ [where the ligand L is 2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole (L1) substituted at the 4 position of the pyrazole ring by Cl (L2), Br (L3), or I (L4) and X = Cl- and I-] were synthesized and characterized using various analytical techniques. Complexes 1 and 3 were also characterized by single-crystal X-ray crystallography, and they crystallized as a monoclinic crystal system in space groups P21/n and P21/c, respectively. The complexes display good solution stability at physiological pH 7.4. The iodido-coordinated pyrazolylbenzimidazole ruthenium(II) p-cymene complexes (2, 4, 6, and 8) are more resistant toward hydrolysis and have less tendency to form monoaquated complexes in comparison to their chlorido analogues (1, 3, 5, and 7). The halido-substituted 2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole ligands, designed as organic-directing molecules, inhibit vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation. In addition, the ruthenium(II) complexes display a potential to bind to DNA bases. The cytotoxicity profile of the complexes (IC50 ca. 9-12 µM for 4-8) against the triple-negative breast cancer cells (MDA-MB-231) show that most of the complexes are efficient. The lipophilicity and cellular accumulation data of the complexes show a good correlation with the cytotoxicity profile of 1-8. The representative complexes 3 and 7 demonstrate the capability of arresting the cell cycle in the G2/M phase and induce apoptosis. The inhibition of VEGFR2 phosphorylation with the representative ligands L2 and L4 and the corresponding metal complexes 3 and 7 in vitro shows that the organic-directing ligands and their complexes inhibit VEGFR2 phosphorylation. Besides, L2, L4, 3, and 7 inhibit the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and proto-oncogene tyrosine-protein kinase (Src), capable of acting downstream of VEGFR2 as well as independently. Compounds L2, L4, 3, and 7 have a lesser effect on ERK1/2 and more prominently affect Src phosphorylation. We extended the study for L2 and 3 in the Tg(fli1:gfp) zebrafish model and found that L2 is more effective in vivo compared to 3 in inhibiting angiogenesis.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Bencimidazoles/química , Bencimidazoles/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Neovascularización Fisiológica/efectos de los fármacos , Fosforilación/efectos de los fármacos , Pirazoles/química , Pirazoles/farmacología , Rutenio/química , Rutenio/farmacología , Células Tumorales Cultivadas , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Pez CebraRESUMEN
Half-sandwich RuII complexes, [(YZ)RuII (η6 -arene)(X)]+, (YZ=chelating bidentate ligand, X=halide), with N,N and N,O coordination (1-9) show significant antiproliferative activity against the metastatic triple-negative breast carcinoma (MDA-MB-231). 3-aminobenzoic acid or its methyl ester is used in all the ligands while varying the aldehyde for N,N and N,O coordination. In the N,N coordinated complex the coordinated halide(X) is varied for enhancing stability in solution (X=Cl, I). Rapid aquation and halide exchange of the pyridine analogues, 2 and 3, in solution are a major bane towards their antiproliferative activity. Presence of free -COOH group (1 and 4) make complexes hydrophilic and reduces toxicity. The imidazolyl 3-aminobenzoate based N,N coordinated 5 and 6 display better solution stability and efficient antiproliferative activity (IC50 ca. 2.3-2.5â µM) compared to the pyridine based 2 and 3 (IC50 >100â µM) or the N,O coordinated complexes (7-9) (IC50 ca. 7-10â µM). The iodido coordinated, 6, is resistant towards aquation and halide exchange. The N,O coordinated 7-9 underwent instantaneous aquation at pHâ 7.4 generating monoaquated complexes stable for at least 6â h. Complexes 5 and 6, bind to 9-ethylguanine (9-EtG) showing propensity to interact with DNA bases. The complexes may kill via apoptosis as displayed from the study of 8. The change in coordination mode and the aldehyde affected the solution stability, antiproliferative activity and mechanistic pathways. The N,N coordinated (5 and 6) exhibit arrest in the G2/M phase while the N,O coordinated 8 showed arrest in the G0/G1 phase.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Rutenio/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , metaminobenzoatos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Rutenio/química , Bases de Schiff/química , Bases de Schiff/farmacología , Neoplasias de la Mama Triple Negativas/patología , Células Tumorales Cultivadas , metaminobenzoatos/químicaRESUMEN
Gasotransmitters belong to the subfamily of endogenous gaseous signaling molecules, which find a wide range of biomedical applications. Among the various gasotransmitters, nitric oxide (NO) has an enormous effect on the cardiovascular system. Apart from this, NO showed a pivotal role in neurological, respiratory, and immunological systems. Moreover, the paradoxical concentration-dependent activities make this gaseous signaling molecule more interesting. The gaseous NO has negligible stability in physiological conditions (37 °C, pH 7.4), which restricts their potential therapeutic applications. To overcome this issue, various NO delivering carriers were reported so far. Unfortunately, most of these NO donors have low stability, short half-life, or low NO payload. Herein, we review the synthesis of NO delivering motifs, development of macromolecular NO donors, their advantages/disadvantages, and biological applications. Various NO detection analytical techniques are discussed briefly, and finally, a viewpoint about the design of polymeric NO donors with improved physicochemical characteristics is predicted.
Asunto(s)
Portadores de Fármacos/química , Gasotransmisores/análisis , Donantes de Óxido Nítrico/administración & dosificación , Óxido Nítrico/análisis , Diseño de Fármacos , Gasotransmisores/metabolismo , Semivida , Humanos , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/química , Donantes de Óxido Nítrico/farmacocinética , Polímeros/químicaRESUMEN
Morpholine motif is an important pharmacophore and, depending on the molecular design, may localize in cellular acidic vesicles. To understand the importance of the presence of pendant morpholine in a metal complex, six bidentate N,O-donor ligands with or without a pendant morpholine unit and their corresponding ruthenium(II) p-cymene complexes (1-6) are synthesized, purified, and structurally characterized by various analytical methods including X-ray diffraction. Complexes 2-4 crystallized in the P21/c space group, whereas 5 and 6 crystallized in the P1Ì space group. The solution stability studies using 1H NMR support instantaneous hydrolysis of the native complexes to form monoaquated species in a solution of 3:7 (v/v) dimethyl sulfoxide-d6 and 20 mM phosphate buffer (pH* 7.4, containing 4 mM NaCl). The monoaquated complexes are stable for at least up to 24 h. The complexes display excellent in vitro antiproliferative activity (IC50 ca. 1-14 µM) in various cancer cell lines, viz., MDA-MB-231, MiaPaCa2, and Hep-G2. The presence of the pendant morpholine does not improve the dose efficacy, but rather, with 2-[[(2,6-dimethylphenyl)imino]methyl]phenol (HL1) and its pendant morpholine analogue (HL3) giving complexes 1 and 3, respectively, the antiproliferative activity was poorer with 3. MDA-MB-231 cells treated with the complexes show that the acidic vesicles remain acidic, but the population of acidic vesicles increases or decreases with time of exposure, as observed from the dispersed red puncta, depending on the complex used. The presence of the 2,6-disubstituted aniline and the naphthyl group seems to improve the antiproliferative dose. The complex treated MDA-MB-231 cells show that cathepsin D, which is otherwise present in the cytosolic lysosomes, translocates to the nucleus as a result of exposure to the complexes. Irrespective of the presence of a morpholine motif, the complexes do not activate caspase-3 to induce apoptosis and seem to favor the necrotic pathway of cell killing.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacología , Cimenos/química , Morfolinas/química , Rutenio/química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Técnicas de Química Sintética , Complejos de Coordinación/química , Humanos , Modelos Moleculares , Conformación MolecularRESUMEN
Platinum(IV) complexes of orotic acid selectively target liver cancer cells displaying enhanced activity and higher uptake in Hep G2. The comparatively higher expression of Organic Anion Transporter 2 (OAT2) in Hep G2 and decrease in toxicity in the presence of OAT2 inhibitor suggest its involvement in the uptake of the complexes. They are resistant to sequestration by the copper transporter ATP7B, unlike cisplatin and oxaliplatin.
Asunto(s)
Antineoplásicos/farmacología , Hipoxia de la Célula/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Compuestos Organoplatinos/farmacología , Ácido Orótico/farmacología , Profármacos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Estructura Molecular , Transportadores de Anión Orgánico Sodio-Independiente/antagonistas & inhibidores , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Ácido Orótico/química , Profármacos/síntesis química , Profármacos/química , Relación Estructura-ActividadRESUMEN
Sulfonamides have a broad range of therapeutic applications, which include the inhibition of various isoforms of carbonic anhydrases (CAs). Among the various CA isoforms, CA IX is overexpressed in tumors and regulates the pH of the tumor microenvironment. Herein we present five new ruthenium(II) p-cymene complexes (1-5) of Schiff base ligands (L1-L4) of 4-(2-aminoethyl)benzenesulfonamide by varying the aldehyde to enhance the selective cytotoxicity toward cancer cells. All of the complexes are stable to aquation for the observed period of 24 h except 1, which aquated within 1 h, but the monoaquated species is stable for 24 h. The two imidazole derivatives, 1 and 2, are cytotoxic to the cancer cells MDA-MB-231 and MIA PaCa-2 but not to the noncancerous cells CHO and MDCK. The enhanced toxicity in hypoxia against MDA-MB-231 may be due to the greater expression of CA IX in hypoxia, as per the immunofluorescence data. The most cytotoxic complexes, 1 and 2, are lipophilic, whereas 3-5 show high hydrophilicity and are not cytotoxic up to 200 µM. Complexes 1 and 2 also show a higher cellular accumulation in MDA-MB-231 than the nontoxic yet solution-stable complex 5. The cytotoxic complexes bind with the model nucleobase 9-ethylguanine but have slow reactivity toward cellular tripeptide glutathione. Both 1 and 2 induce apoptosis by depolarizing the mitochondrial membrane potential and arrest the cell cycle in the SubG1 phase.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Cimenos/farmacología , Imidazoles/farmacología , Rutenio/farmacología , Sulfonamidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Cimenos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Imidazoles/química , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Estructura Molecular , Rutenio/química , Bases de Schiff/química , Bases de Schiff/farmacología , Relación Estructura-Actividad , Sulfonamidas/química , Células Tumorales CultivadasRESUMEN
Platinum-based complexes are one of the most successful chemotherapeutic agents having a significant ground in cancer chemotherapy despite their side effects. During the past few decades, Ru(II) complexes have been emerging as efficient alternatives owing to their promising activities against platinum-resistant cancer. The pathway of action, lipophilicity, and cytotoxicity of a Pt or Ru complex may be tuned by varying the attached ligands, the coordination mode, and the leaving group. In this work, we report a family of Pt(II) and Ru(II) complexes (1-5) of three N,O and N,N donor-based trimethoxyanilines containing Schiff bases with the general formula [PtII(L)(DMSO)Cl], [RuII(L)(p-cymene)Cl], [RuII(L)(p-cymene)Cl]+, and [PtII(L)Cl2]. All of the complexes are characterized by different analytical techniques. 1H NMR and electrospray ionization mass spectrometry (ESI-MS) data suggest that the N,O-coordinated Pt(II) complexes undergo slower aquation compared to the Ru(II) analogues. The change of the coordination mode to N,N causes the Ru complexes to be more inert to aquation. The N,O-coordinating complexes show superiority over N,N-coordinating complexes by displaying excellent in vitro antiproliferative activity against different aggressive cancer cells, viz., triple-negative human metastatic breast adenocarcinoma MDA-MB-231, human pancreatic carcinoma MIA PaCa-2, and hepatocellular carcinoma Hep G2. In vitro cytotoxicity studies suggest that Pt(II) complexes are more effective than their corresponding Ru(II) analogues, and the most cytotoxic complex 3 is 10-15 times more toxic than the clinical drugs cisplatin and oxaliplatin against MDA-MB-231 cells. Cellular studies show that all of the N,O-coordinated complexes (1-3) initiate disruption of the microtubule network in MDA-MB-231 cells in a dose-dependent manner within 6 h of incubation and finally lead to the arrest of the cell cycle in the G2/M phase and render apoptotic cell death. The disruption of the microtubule network affects the agility of the cytoskeleton rendering inhibition of tyrosine phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), a key step in angiogenesis. Complexes 1 and 2 inhibit VEGFR2 phosphorylation in a dose-dependent fashion. Among the Pt(II) and Ru(II) complexes, the former displays higher cytotoxicity, a stronger effect on the cytoskeleton, better VEGFR2 inhibition, and strong interaction with the model nucleobase 9-ethylguanine (9-EtG).
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Microtúbulos/metabolismo , Bases de Schiff/farmacología , Moduladores de Tubulina/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Citoesqueleto/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Fosforilación/efectos de los fármacos , Platino (Metal)/química , Rutenio/química , Bases de Schiff/síntesis química , Moduladores de Tubulina/síntesis químicaRESUMEN
Hck, a Src family nonreceptor tyrosine kinase (SFK), has recently been established as an attractive pharmacological target to improve pulmonary function in COVID-19 patients. Hck inhibitors are also well known for their regulatory role in various malignancies and autoimmune diseases. Curcumin has been previously identified as an excellent DYRK-2 inhibitor, but curcumin's fate is tainted by its instability in the cellular environment. Besides, small molecules targeting the inactive states of a kinase are desirable to reduce promiscuity. Here, we show that functionalization of the 4-arylidene position of the fluorescent curcumin scaffold with an aryl nitrogen mustard provides a stable Hck inhibitor (Kd = 50 ± 10 nM). The mustard curcumin derivative preferentially interacts with the inactive conformation of Hck, similar to type-II kinase inhibitors that are less promiscuous. Moreover, the lead compound showed no inhibitory effect on three other kinases (DYRK2, Src, and Abl). We demonstrate that the cytotoxicity may be mediated via inhibition of the SFK signaling pathway in triple-negative breast cancer and murine macrophage cells. Our data suggest that curcumin is a modifiable fluorescent scaffold to develop selective kinase inhibitors by remodeling its target affinity and cellular stability.
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Curcumina/farmacología , Diseño de Fármacos , Células Epiteliales/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-hck/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Clonación Molecular , Curcumina/análogos & derivados , Curcumina/síntesis química , Estabilidad de Medicamentos , Células Epiteliales/enzimología , Células Epiteliales/patología , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Regulación de la Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Células HEK293 , Células HT29 , Humanos , Ratones , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-abl/genética , Proteínas Proto-Oncogénicas c-abl/metabolismo , Proteínas Proto-Oncogénicas c-hck/química , Proteínas Proto-Oncogénicas c-hck/genética , Proteínas Proto-Oncogénicas c-hck/metabolismo , Células RAW 264.7 , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Familia-src Quinasas/genética , Familia-src Quinasas/metabolismo , Quinasas DyrKRESUMEN
The Covid-19 is a highly contagious disease which becomes a serious global health concern. The residents living in areas with high population density, such as big or metropolitan cities, have a higher probability to come into close contact with others and consequently any contagious disease is expected to spread rapidly in dense areas. However, recently, after analyzing Covid-19 cases in the USA researchers at the Johns Hopkins Bloomberg School of Public Health, London school of economics, and IZA-Institute of Labour Economics conclude that the spread of Covid-19 is not linked with population density. Here, we investigate the influence of population density on Covid-19 spread and related mortality in the context of India. After a detailed correlation and regression analysis of infection and mortality rates due to Covid-19 at the district level, we find moderate association between Covid-19 spread and population density.
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Acetaminofén/uso terapéutico , Conducto Arterioso Permeable/tratamiento farmacológico , Recien Nacido Prematuro , Unidades de Cuidado Intensivo Neonatal/estadística & datos numéricos , Uso Fuera de lo Indicado/estadística & datos numéricos , Acetaminofén/administración & dosificación , Cálculo de Dosificación de Drogas , Humanos , Recién Nacido , Pautas de la Práctica en Medicina , Reino UnidoRESUMEN
OBJECTIVES: To assess the effect of rituximab (RTX) on the lung function parameters in SSc interstitial lung disease (SSc-ILD) patients. METHODS: PubMed and Embase were searched to identify studies on SSc-ILD treated with RTX, confined to a predefined inclusion and exclusion criteria. A systematic review and meta-analysis were performed on the included studies on changes in forced vital capacity (FVC) and diffusion capacity of carbon monoxide (DLCO) from baseline to 6 and 12 months of follow-up. RESULTS: A total of 20 studies (2 randomized controlled trials, 6 prospective studies, 5 retrospective studies and 7 conference abstracts) were included (n = 575). RTX improved FVC from baseline by 4.49% (95% CI 0.25, 8.73) at 6 months and by 7.03% (95% CI 4.37, 9.7) at 12 months. Similarly, RTX improved DLCO by 3.47% (95% CI 0.99, 5.96) at 6 months and 4.08% (95% CI 1.51, 6.65) at 12 months. In the two studies comparing RTX with other immunosuppressants, improvement of FVC by 6 months in the RTX group was 1.03% (95% CI 0.11, 1.94) greater than controls. At the 12 month follow-up, RTX treatment was similar to controls in terms of both FVC and DLCO. Patients treated with RTX had a lower chance of developing infections compared with controls [odds ratio 0.256 (95% CI 0.104, 0.626), I2 = 0%, P = 0.47). CONCLUSIONS: Treatment with RTX in SSc-ILD was associated with a significant improvement of both FVC and DLCO during the first year of treatment. RTX use was associated with lower infectious adverse events.
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Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Rituximab/uso terapéutico , Esclerodermia Sistémica/complicaciones , Humanos , Factores Inmunológicos/uso terapéutico , Enfermedades Pulmonares Intersticiales/etiología , Esclerodermia Sistémica/tratamiento farmacológicoRESUMEN
We report [RuII(L)(η6-p-cym)Cl] (1 and 2) and [PtII(L)(DMSO)Cl] (3 and 4) complexes, where L is a chelate imine ligand derived from chloroethylamine and salicylaldehyde (HL1) or o-vanillin (HL2). The complexes were characterized by single-crystal X-ray diffraction and other analytical techniques. The 1H nuclear magnetic resonance data show that both the Ru(II) and Pt(II) complexes start forming the aquated complex within an hour. The aquated complexes are stable at least up to 24 h. The complexes bind to the N7 of the model nucleobase 9-ethylguanine (9-EtG). Interaction with calf thymus (CT) DNA shows moderate binding interactions with binding constants, Kb (3.7 ± 1.2) × 103 M-1 and (4.3 ± 1.9) × 103 M-1 for 1 and 3, respectively. The complexes exhibit significant antiproliferative activity against human pancreas ductal adenocarcinoma (Mia PaCa-2), triple negative metastatic breast adenocarcinoma (MDA-MB-231), hepatocellular carcinoma (Hep G2), and colorectal adenocarcinoma (HT-29) cell lines. The studies show that with the same ligand the Pt(II) complexes are more potent than the Ru(II) complexes. The in vitro potencies of all the complexes toward pancreatic cancer cell line MIA PaCa-2 are more than cisplatin (CDDP). The Pt(II) and Ru(II) complexes show similar binding constants with CT-DNA, but the reactivity of the Pt(II) complex 3 with 9-EtG is faster and their overall cell killing pathways are different. This is evident from the arrest of the cell cycle by the Ru(II) complex 1 in the G2/M phase in contrast to the SubG1 phase arrest by the Pt(II) complex 3. The immunoblot study shows that 3 increases cyclin D and Bcl-2 expression in MDA-MB-231 due to the SubG1 phase arrest where these proteins express in greater quantities. However, both 1 and 3 kill in the apoptotic pathway via dose-dependent activation of caspase 3. Complex 3 depolarizes the mitochondria more efficiently than 1, suggesting its higher preference for the intrinsic pathway of apoptosis. Our work reveals that the same bidentate ligand with a change of the metal center, viz, Pt(II) or Ru(II), imparts significant variation in cytotoxic dosage and pathway of action due to specific intrinsic properties of a metal center (viz, coordination geometry, solution stability) manifested in a complex.