Toreshettahally R. Swaroop

Synthesis of 1,2-benzisoxazole tethered 1,2,3-triazoles that exhibit anticancer activity in acute myeloid leukemia cell lines by inhibiting histone deacetylases, and inducing p21 and tubulin acetylation

1,2,3-Triazole-based heterocycles have previously been shown to possess significant anticancer activity in various tumor models. In the present study, we attached a 1,2,3-triazole moiety to the third position of a 1,2-benzisoxazole heterocycle via copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) with various alkynes and established for the title compounds significant antiproliferative effect against human acute myeloid leukemia (AML) cells. Among the tested compounds, 3-(4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl)benzo[d]isoxazole (PTB) was found to be the most potent antiproliferative agent with an IC50 of 2 μM against MV4-11 cells using MTT assay. Notably, PTB induced cytotoxicity in MOLM13, MOLM14 and MV4-11 cells with selectivity over normal bone marrow cells (C57BL/6). Furthermore, PTB was found to induce cytotoxicity by increasing apoptosis of AML cells (MOLM13, MOLM14 and MV4-11) as well as sub-G1 cell population and apoptotic cells at submicromolar concentrations, as shown by flow cytometry and Annexin-V staining, respectively. On the protein level we suggested histone deacetylases (HDACs) as the potential protein target of those compounds in silico, and the predicted target was next experimentally validated by measuring the variations in the levels of p21, cyclin D and acetylation of histone H3 and tubulin. Molecular docking analysis of the title compounds with the second deacetylase domain of HDAC6 displayed high degree of shape complementarity to the binding site of the enzyme, forming multiple molecular interactions in the hydrophobic region as well as a hydrogen bond to the phenol side-chain of Tyr-782. Thus, 1,2,3-triazole derivatives appear to represent a class of novel, biologically active ligands against histone deacetylases which deserve to be further evaluated in their applications in the cancer field.

Novel synthetic bisbenzimidazole that targets angiogenesis in Ehrlich ascites carcinoma bearing mice

Cancer is a leading cause of death in developed countries and second cause in developing countries. Herein we are reporting the synthesis of novel bisbenzimidazole derivatives and their anticancer properties. Among the newly synthesized bisbenzimidazoles, 3-(4-flurophenylsulfonyl)-1,7-dimethyl-2-propyl-1H,3H-2,5-bibenzo[d]imidazole (FDPB) presented as a potent antiproliferative agent against HeLa, HCT116 and A549 cells with selectivity over normal Vero cells (IC50 >50 μM). Additionally, we evaluated the efficacy of lead compound against Ehrlich ascites tumor (EAT) bearing mice for its antitumor and antiangiogenic properties. Our lead compound significantly reduced the cell viability, body weight, ascites volume and downregulated the formation of neovasculature and production of Vascular Endothelial Growth Factor (VEGF).

A New Ibuprofen Derivative Inhibits Platelet Aggregation and ROS Mediated Platelet Apoptosis

Thrombocytopenia is a serious issue connected with the pathogenesis of several human diseases including chronic inflammation, arthritis, Alzheimers disease, cardiovascular diseases (CVDs) and other oxidative stress-associated pathologies. The indiscriminate use of antibiotics and other biological drugs are reported to result in thrombocytopenia, which is often neglected during the treatment regime. In addition, augmented oxidative stress induced by drugs and pathological conditions has also been shown to induce thrombocytopenia, which seems to be the most obvious consequence of elevated rate of platelet apoptosis. Thus, blocking oxidative stress-induced platelet apoptosis would be of prime importance in order to negotiate thrombocytopenia and associated human pathologies. The current study presents the synthesis and platelet protective nature of novel ibuprofen derivatives. The potent anti-oxidant ibuprofen derivative 4f was selected for the study and the platelet protective efficacy and platelet aggregation inhibitory property has been demonstrated. The compound 4f dose dependently mitigates the oxidative stress-induced platelet apoptosis in both platelet rich plasma and washed platelets. The platelet protective nature of compound 4f was determined by assessing various apoptotic markers such as ROS generation, cytosolic Ca2+ levels, PS externalization, cytochrome C translocation, Caspase activation, mitochondrial membrane depolarization, cytotoxicity, LDH leakage and tyrosine phosphorylation of cytosolic proteins. Furthermore, compound 4f dose dependently ameliorated agonist induced platelet aggregation. Therefore, compound 4f can be estimated as a potential candidate in the treatment regime of pathological disorders associated with platelet activation and apoptosis. In addition, compound 4f can be used as an auxiliary therapeutic agent in pathologies associated with thrombocytopenia.

3,5-Disubstituted Isoxazole Derivatives: Potential Inhibitors of Inflammation and Cancer

The products of arachidonic acid metabolism by lipoxygenase (LOX) and cyclooxygenase (COX) significantly contribute to inflammation and carcinogenesis. Particularly, overproduction of leukotrienes and prostaglandins contribute to tumor growth by inducing formation of new blood vessels that sustain tumor cell viability and growth. Hence, search for novel anticancer drug via inhibition of LOX and COX enzymes constitutes an impressive strategy till date. In this context, a series of isoxazole derivatives were synthesized and screened for their anti-inflammatory activity via LOX and COX inhibition. Among these, 3-(3-methylthiophen-2-yl)-5-(3,4,5-trimethoxyphenyl)isoxazole (2b) showed significant inhibitory activity toward LOX and COX-2. Additionally, 2b showed a good inhibition of tumor growth, peritoneal angiogenesis, and ascite formation in Ehrlich ascites carcinoma (EAC) cell mouse model. Further, the in silico molecular studies also revealed that the compound 2b binds to the catalytic domain of LOX and COX-1 and COX-2 strongly with high atomic contact energy (ACE) score compared to standard drug. These initial pharmacological data support the fact that the compound 2b serves as the basis in developing anti-inflammatory and anticancer agents.

Transition-metal-free solid phase synthesis of 1,2-disubstituted 4-quinolones via the regiospecific synthesis of enaminones

Herein, the transition-metal-free economical solid phase synthesis of 1,2-disubstituted 4-quinolones has been developed via the novel regiospecific synthesis of enaminones. Notably, a wide range of enaminones were synthesized via a silica-supported solid-phase reaction in good to excellent yields. The transformation of enaminones to 1,2-disubstituted 4-quinolones and N-methyl-2-aryl-4-quinolone alkaloid was achieved in high yield via an alumina-supported solid phase reaction. In addition, all the synthesized compounds were isolated directly in their pure form from the reaction mixture using an easy workup procedure.

Synthesis and cholinesterase inhibition activity of new pyrrolopyrimidine derivatives

Cholinesterase plays a vital role in the decline of cholinergic transmission and thus can contribute to the development of Alzheimer’s disease (AD). Thus, compounds that can inhibit acetylcholinesterase (AChe) and butyrylcholinesterase (BuChe) are the potential drugs for the treatment of AD. A series of novel pyrrolopyrimidine derivatives was synthesized and evaluated for their inhibitory activity against cholinesterase by Ellman method. Among the ten newly synthesized compounds, 4-(4-((4-(difluoromethoxy)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzoate was the most potent molecule identified with the IC50 values of 18 µM and 17 µM on AChe and BuChe respectively.

A sequential one-pot tandem approach for the synthesis of 4-tosyl-5-aryloxazoles from carboxylic acids

An efficient method for the synthesis of 4-tosyl-5-aryloxazoles directly from aromatic carboxylic acids has been reported. The method involves the conversion of aromatic carboxylic acids to tosyl carboxylates by treating with tosyl chloride in the presence of potassium carbonate and its subsequent reaction with tosylmethyl isocyanide in the presence of sodium hydride to get 4-tosyl-5-aryloxazoles.Graphical Abstract:4, 5 di-substituted oxazoles were synthesized via an efficient method directly from aromatic carboxylic acids. The presented method involves the conversion of aromatic carboxylic acids to tosyl carboxylates by treating with tosyl chloride in the presence of potassium carbonate and its subsequent reaction with tosylmethyl isocyanide in the presence of sodium hydride yielding 4-tosyl-5-aryloxazoles.

Pro-apoptotic activity of novel 4-anilinoquinazoline derivatives mediated by up-regulation of bax and activation of poly (ADP-ribose) phosphatase in ehrlich ascites carcinoma cells

Quinazolines are very important class of heterocyclic compounds with antitumor properties. In search of novel anti-tumour agents, a series of 4-anilinoquinazolines were synthesized and characterized using proton and carbon-13 nuclear magnetic resonance, Fourier transform infrared and mass spectroscopic techniques. These compounds were evaluated for their cytotoxic effect on Ehrlish Ascities Carcinoma cells using 3-(4,5-Dimethylthiazol- 2-Yl)-2,5-Diphenyltetrazolium Bromide against Ehrlish ascities carcinoma cell lines. Among the tested compounds, compound N-(3-((6,7-dimethoxyquinazoline-4-yl)amino)phenyl)-4-nitrobenzene sulfonamide compound exhibited more potent activity with an IC50 value of 10.29 ± 1.14 μM against EAC cell line. In vivo studies using compound N-(3-((6,7-dimethoxyquinazoline-4-yl)amino)phenyl)-4-nitrobenzene sulfonamide showed that there was reduction in the body weight, ascites volume and decrease in cell number. Mice treated with compound N-(3- ((6,7-dimethoxyquinazoline-4-yl)amino)phenyl)-4-nitrobenzene sulfonamide showed higher survivability compared with that of control treated mice. The cells treated with compound N-(3-((6,7-dimethoxyquinazoline-4-yl)amino) phenyl)-4-nitrobenzene sulfonamide also exhibited typical morphological changes of apoptotic damages. Further, compound N-(3-((6,7-dimethoxyquinazoline-4-yl)amino)phenyl)-4-nitrobenzene sulfonamide induced tumour cell death by activating proapoptotic protein Bax which activates caspase-3 and activated caspase –3 cleaves poly (ADP- ribose) polymerase causes DNA fragmentation. Thus, our results strongly conclude that our compound 4G acts as a anticancer agent by inducing apoptosis in Ehrlish ascites carcinoma cells.