Kothanahally S. Sharath Kumar

Antiproliferative and tumor inhibitory studies of 2,3 disubstituted 4-thiazolidinone derivatives

4-Thiazolidinone derivatives were synthesized using T3P®-DMSO media as a cyclodehydrating agent. All the molecules were tested for their cytotoxicity against leukemic cell lines. The compound 3-(4-bromophenyl)-2-(4-(dimethylamino)phenyl)thiazolidin-4-one (4e) with electron donating substituent at para position of phenyl ring displayed considerable cytotoxicity against Reh and Nalm6 cells with an IC50 value of 11.9 and 13.5 μM, respectively. Furthermore, the compound 4e tested for tumor regression studies induced by EAC in Swiss albino mouse. Both in vitro and in vivo results suggested significant antiproliferative activity of compound 4e in Reh cells and mouse tumor tissue treated with compound 4e showed multifocal areas of necrosis and numerous number of apoptotic cells.

ZrO2-supported Cu(II)–β-cyclodextrin complex: construction of 2,4,5-trisubstituted-1,2,3-triazoles via azide–chalcone oxidative cycloaddition and post-triazole alkylation

An efficient one-pot three-component stepwise approach for the synthesis of N-2-substituted-1,2,3-triazoles from chalcones, sodium azide and esters has been developed using a recoverable and reusable ZrO2 nanoparticle-supported Cu(II)–β-cyclodextrin complex as a catalyst. N-2 alkylation of triazoles using different aryl–alkyl esters without any additives has been achieved for the first time. The one-pot operation, atom-economical nature, regioselectivity and good yields are the noteworthy features of this protocol. The reusability of the prepared nanocatalyst was successfully examined four times without any appreciable loss in catalytic activity.

ZrO2-β-cyclodextrin catalyzed synthesis of 2,4,5-trisubstituted imidazoles and 1,2-disubstituted benzimidazoles under solvent free conditions and evaluation of their antibacterial study

A series of 2,4,5-trisubstituted imidazoles and 1,2-disubstituted benzimidazoles catalyzed by ZrO2-supported-β-cyclodextrin (ZrO2-β-CD) under solvent free conditions have been synthesized and characterized by spectral methods. The nanoparticles (ZrO2-β-CD), prepared by a simple one-pot-coprecipitation method and were characterized by PXRD, SEM, and TEM techniques. The nano (ZrO2-β-CD) particles were found to be an effective heterogeneous reusable catalyst for the effective synthesis of imidazoles and benzimidazoles under solvent free conditions and all of the synthesized derivatives were evaluated for their antibacterial activity against six bacterial strains.

Synthesis and characterization of novel oxazines and demonstration that they specifically target cyclooxygenase 2.

In the present study, we used solution combustion synthesis-bismuth oxide (Bi2O3) as catalyst for the simple and efficient synthesis of 1,2-oxazine based derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazoles, 1-arylpiperazine and carbazoles. (4aR,8aR)-4-(4-Methoxyphenyl)-3-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,2]oxazine was found to be the most potent compound with a high degree of selectivity in inhibition towards COX2 (1.7 μM) over COX1 (40.4 μM) demonstrating the significance of 1,2-oxazine derivatives in developing COX2 specific inhibitors. Molecular docking analyses demonstrated that an isoleucine residue in the active site of COX1 is responsible for lower affinity to COX1 and increased potency towards COX2. Overall, our study reveals that the new 1,2-oxazine-based small molecules qualify as lead structures in developing COX2-specific inhibitors for anti-inflammatory therapy.

A novel benzimidazole derivative binds to the DNA minor groove and induces apoptosis in leukemic cells

DNA minor groove binders are an important class of chemotherapeutic agents. These small molecule inhibitors interfere with various cellular processes like DNA replication and transcription. Several benzimidazole derivatives showed affinity towards the DNA minor groove. In this study we show the synthesis and biological studies of a novel benzimidazole derivative (MH1), that inhibits topoisomerase II activity and in vitro transcription. UV-visible and fluorescence spectroscopic methods in conjunction with Hoechst displacement assay demonstrate that MH1 binds to DNA at the minor groove. Cytotoxic studies showed that leukemic cells are more sensitive to MH1 compared to cancer cells of epithelial origin. Further, we find that MH1 treatment leads to cell cycle arrest at G2/M, at early time points in Molt4 cells. Finally multiple cellular assays demonstrate that MH1 treatment leads to reduction in MMP, induction of apoptosis by activating CASPASE 9 and CASPASE 3. Thus our study shows MH1, a novel DNA minor groove binder, induces cytotoxicity efficiently in leukemic cells by activating the intrinsic pathway of apoptosis.

Easy access for the synthesis of 2-aryl 2,3-dihydroquinazolin-4(1H)-ones using gem-dibromomethylarenes as synthetic aldehyde equivalent

One step synthesis of 2,3-dihydroquinazolin-4(1H)-ones from gem-dibromomethylarenes using 2-aminobenzamide is described. Gem-dibromomethylarenes are used as aldehyde equivalent for the efficient synthesis of 2,3-dihydroquinazolin-4(1H)-ones, this synthesis takes shorter reaction time with quick isolation and excellent product yield.

Synthesis and antiproliferative studies of curcumin pyrazole derivatives

A series of curcumin pyrazole derivatives (3a–e) were synthesized. The chemical structures were determined by 1H and 13C NMR spectroscopic techniques and their purity was confirmed by LC–MS and melting point determination. The compounds were screened for anticancer effects on different cancer cell lines by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay. The analogs demonstrated growth inhibitory effect on MCF-7, HeLa, and K562 cell lines with significant IC50 values. Compound 3b exhibited a high degree of cytotoxicity against cancer cells and minimum growth inhibitory effects against normal cells HEK293T and hence further, cell cycle analysis and mitochondrial membrane potential studies (JC-1 assay) were conducted by utilizing flow cytometry against K562 cells. This compound effectively arrested cell cycle progression at SubG1 phase and cells exhibited decreased membrane potential in a concentration-dependent manner with fluorescence shifting from red to green. Our findings suggest that compound 3b could be a promising anticancer agent since it effectively inhibited cell proliferation and can be selected for further in vitro and in vivo investigations.

Novel oxolane derivative DMTD mitigates high glucose-induced erythrocyte apoptosis by regulating oxidative stress

&NA; Chronic hyperglycemia is one of the characteristic conditions associated with Diabetes Mellitus (DM), which often exerts deleterious effects on erythrocyte morphology and hemodynamic properties leading to anemia and diabetes‐associated vascular complications. High glucose‐induced over production of reactive oxygen species (ROS) can alter the blood cell metabolism and biochemical functions subsequently causing eryptosis (red blood cell death), yet another complication of concern in DM. Therefore, blocking high glucose‐induced oxidative damage and subsequent eryptosis is of high importance in the better management of DM and associated vascular complications. In this study, we synthesized an oxolane derivative 1‐(2,2‐dimethyltetrahydrofuro[2,3][1,3]dioxol‐5‐yl)ethane‐1,2‐diol (DMTD), and demonstrated its efficacy to mitigate hyperglycemia‐induced ROS generation and subsequent eryptosis. We showed that DMTD effectively inhibits high glucose‐induced ROS generation, intracellular calcium levels, phosphaditylserine (PS) scrambling, calpain and band 3 activation, LDH leakage, protein glycation and lipid peroxidation, meanwhile enhances the antioxidant indices, osmotic fragility and Na+/K+‐ATPase activity in erythrocytes. DMTD dose dependently decreased the glycated hemoglobin level and enhances the glucose utilization by erythrocytes in vitro. Further, DMTD alleviated the increase in ROS production, intracellular Ca2 + level and PS externalization in the erythrocytes of human diabetic subjects and enhanced the Na+/K+‐ATPase activity. Taken together, the synthesized oxolane derivative DMTD could be a novel synthetic inhibitor of high glucose‐induced oxidative stress and eryptosis. Considering the present results DMTD could be a potential therapeutic to treat DM and associated complications and open new avenues in developing synthetic therapeutic targeting of DM‐associated complications. Graphical abstract Figure. No caption available. HighlightsChronic hyperglycemia exerts deleterious effects on erythrocytes leading to anemia.High glucose induced ROS instigates eryptosis and associated vascular complications.Novel oxolane derived DMTD ameliorates hyperglycemia induced ROS ensuing eryptosis.DMTD inhibits hyperglycemia induced Ca2 + levels, PS scrambling & calpain activation.DMTD a promising therapeutic candidate to treat hyperglycemia induced eryptosis.

Regioselective synthesis and biological studies of novel 1-aryl-3, 5-bis (het) aryl pyrazole derivatives as potential antiproliferative agents

Pyrazole moiety represents an important category of heterocyclic compound in pharmaceutical and medicinal chemistry. The novel 1-aryl-3, 5-bis (het) aryl pyrazole derivatives were synthesized with complementary regioselectivity. The chemical structures were confirmed by IR, 1H NMR, 13C NMR, and mass spectral analysis. The chemical entities were screened in various cancer cell lines to assess their cell viability activity. Results showed that the compound 3-(1-(4-bromophenyl)-5-phenyl-1H-pyrazol-3-yl) pyridine (5d) possessed maximum cytotoxic effect against breast cancer and leukemic cells. The cytotoxicity was confirmed by live–dead cell assay and cell cycle analysis. Mitochondrial membrane potential, Annexin V-FITC staining, DNA fragmentation, Hoechst staining, and western blot assays revealed the ability of compound 5d to induce cell death by activating apoptosis in cancer cells. Thus, the present study demonstrates that compound 5d could be an attractive chemical entity for the development of small molecule inhibitors for treatment of leukemia and breast cancer.

A trisubstituted pyrazole derivative reduces DMBA-induced mammary tumor growth in rats by inhibiting estrogen receptor-α expression

Aberrant expression of estrogen receptor alpha (ER-α) is observed in many pathological complications like breast cancer, endometrial cancer, and in osteoporosis. ER-α plays a vital role in the initiation and progression of breast cancer and confers chemo and radioresistance to the cancer cells by upregulating expression of anti-apoptotic proteins. The synthetic pyrazole derivative 3-(1-(4-bromophenyl)-5-phenyl-1H-pyrazol-3-yl)pyridine (compound 5d) displays significant cytotoxicity against mammary carcinoma cells. Molecular docking studies revealed that compound 5d binds to ligand binding domain of (ER-α). In vivo studies were carried out to investigate ER-α expression by immunohistochemistry and quantitative RT-PCR, which revealed reduction of ER-α in tumor cells upon treatment with compound 5d indicating its ER-α antagonistic effect. Our study ascertains compound 5d as a potent inhibitor of mammary carcinoma cells.