Chakrabhavi Dhananjaya Mohan
University of Mysore
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Featured researches published by Chakrabhavi Dhananjaya Mohan.
Journal of Biological Chemistry | 2014
Chakrabhavi Dhananjaya Mohan; Hanumantharayappa Bharathkumar; Krishna C. Bulusu; Vijay Pandey; Shobith Rangappa; Julian E. Fuchs; Muthu K. Shanmugam; Xiaoyun Dai; Feng Li; Amudha Deivasigamani; Kam M. Hui; Alan Prem Kumar; Peter E. Lobie; Andreas Bender; Basappa; Gautam Sethi; Kanchugarakoppal S. Rangappa
Background: Constitutive activation of STAT3 is associated with the progression of hepatocellular carcinoma (HCC), and abrogation of STAT3 signaling is a potential target for HCC treatment. Results: A novel azaspirane modulates the JAK-STAT pathway in HCC. Conclusion: The lead compound induces apoptosis by down-regulating STAT3 signaling. Significance: This investigation reports a novel inhibitor of the JAK-STAT pathway with the potential to target various cancers. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates genes involved in cell growth, proliferation, and survival, and given its association with many types of cancers, it has recently emerged as a promising target for therapy. In this work, we present the synthesis of N-substituted azaspirane derivatives and their biological evaluation against hepatocellular carcinoma (HCC) cells (IC50 = 7.3 μm), thereby identifying 2-(1-(4-(2-cyanophenyl)1-benzyl-1H-indol-3-yl)-5-(4-methoxy-phenyl)-1-oxa-3-azaspiro(5,5) undecane (CIMO) as a potent inhibitor of the JAK-STAT pathway with selectivity over normal LO2 cells (IC50 > 100 μm). The lead compound, CIMO, suppresses proliferation of HCC cells and achieves this effect by reducing both constitutive and inducible phosphorylation of JAK1, JAK2, and STAT3. Interestingly, CIMO displayed inhibition of Tyr-705 phosphorylation, which is required for nuclear translocation of STAT3, but it has no effect on Ser-727 phosphorylation. CIMO accumulates cancer cells in the sub-G1 phase and decreases STAT3 in the nucleus and thereby causes down-regulation of genes regulated via STAT3. Suppression of STAT3 phosphorylation by CIMO and knockdown of STAT3 mRNA using siRNA transfection displayed a similar effect on the viability of HCC cells. Furthermore, CIMO significantly decreased the tumor development in an orthotopic HCC mouse model through the modulation of phospho-STAT3, Ki-67, and cleaved caspase-3 in tumor tissues. Thus, CIMO represents a chemically novel and biologically in vitro and in vivo validated compound, which targets the JAK-STAT pathway as a potential cancer treatment.
Bioorganic & Medicinal Chemistry | 2015
Nanjundaswamy Ashwini; Manoj Garg; Chakrabhavi Dhananjaya Mohan; Julian E. Fuchs; Shobith Rangappa; Sebastian Anusha; Toreshettahally R. Swaroop; Kodagahalli Sathya Rakesh; Deepika Kanojia; Vikas Madan; Andreas Bender; H. Phillip Koeffler; Basappa; Kanchugarakoppal S. Rangappa
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.
Journal of Biological Chemistry | 2014
Hosadurga K. Keerthy; Chakrabhavi Dhananjaya Mohan; Kodappully Sivaraman Siveen; Julian E. Fuchs; Shobith Rangappa; Mahalingam S. Sundaram; Feng Li; Kesturu S. Girish; Gautam Sethi; Basappa; Andreas Bender; Kanchugarakoppal S. Rangappa
Background: TNF-α-induced NF-κB pathway is associated with the progression of several cancers and abrogation of TNF signaling a potential target for cancer treatment. Results: Novel biscoumarin inhibits TNF signaling in vitro and in vivo in IBD model. Conclusion: The lead compound interrupts the trimeric structure of TNF to achieve this effect. Significance: This study introduces a novel TNF inhibitor with the potential to target pro-inflammatory diseases. TNF is a pleotropic cytokine known to be involved in the progression of several pro-inflammatory disorders. Many therapeutic agents have been designed to counteract the effect of TNF in rheumatoid arthritis as well as a number of cancers. In the present study we have synthesized and evaluated the anti-cancer activity of novel biscoumarins in vitro and in vivo. Among new compounds, BIHC was found to be the most cytotoxic agent against the HepG2 cell line while exhibiting less toxicity toward normal hepatocytes. Furthermore, BIHC inhibited the proliferation of various hepatocellular carcinoma (HCC) cells in a dose- and time-dependent manner. Subsequently, using in silico target prediction, BIHC was predicted as a TNF blocker. Experimental validation was able to confirm this hypothesis, where BIHC could significantly inhibit the recombinant mouse TNF-α binding to its antibody with an IC50 of 16.5 μm. Furthermore, in silico docking suggested a binding mode of BIHC similar to a ligand known to disrupt the native, trimeric structure of TNF, and also validated with molecular dynamics simulations. Moreover, we have demonstrated the down-regulation of p65 phosphorylation and other NF-κB-regulated gene products upon BIHC treatment, and on the phenotypic level the compound shows inhibition of CXCL12-induced invasion of HepG2 cells. Also, we demonstrate that BIHC inhibits infiltration of macrophages to the peritoneal cavity and suppresses the activity of TNF-α in vivo in mice primed with thioglycollate broth and lipopolysaccharide. We comprehensively validated the TNF-α inhibitory efficacy of BIHC in an inflammatory bowel disease mice model.
Bioorganic & Medicinal Chemistry Letters | 2015
Mahabaleshwaraiah Neelgundmath; Koragere Rajashekar Dinesh; Chakrabhavi Dhananjaya Mohan; Feng Li; Xiaoyun Dai; Kodappully Sivaraman Siveen; Shardul Paricharak; Daniel J. Mason; Julian E. Fuchs; Gautam Sethi; Andreas Bender; Kanchugarakoppal S. Rangappa; Obelannavar Kotresh; Basappa
Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor worldwide, and is the third most common cause of cancer related death. Constitutive activation of NF-κB is the underlying mechanism behind tumorigenesis and this protein regulates the expression of genes involved in proliferation, survival, drug resistance, angiogenesis and metastasis. The design of inhibitors which suppress NF-κB activation is therefore of great therapeutic importance in the treatment of HCC. In this study, we investigated the effect of newly synthesized coumarin derivatives against HCC cells, and identified (7-Carbethoxyamino-2-oxo-2H-chromen-4-yl)methylpyrrolidine-1 carbodithioate (CPP) as lead compound. Further, we evaluated the effect of CPP on the DNA binding ability of NF-κB, CXCL12-induced cell migration and invasion, and the regulated gene products in HCC cells. We found that CPP induced cytotoxicity in three HCC cells in a time and dose dependent manner, and suppressed the DNA binding ability of NF-κB. CPP significantly decreased the CXCL12-induced cell migration and invasion. More evidently, CPP inhibits the expression of NF-κB targeted genes such as cyclin D1, Bcl-2, survivin, MMP12 and C-Myc. Furthermore, the molecular docking analysis suggested that CPP interacts with the p50 binding domain of the p65 subunit, scoring best among the 26 docked coumarin derivatives of this study. Thus, we are reporting CPP as a potent inhibitor of the pro-inflammatory pathway in Hepatocellular carcinoma.
PLOS ONE | 2014
Hosadurga K. Keerthy; Manoj Garg; Chakrabhavi Dhananjaya Mohan; Vikas Madan; Deepika Kanojia; Rangappa Shobith; Shivananju Nanjundaswamy; Daniel J. Mason; Andreas Bender; Basappa; Kanchugarakoppal S. Rangappa; H. Phillip Koeffler
The anti-apoptotic protein Bcl-2 is a well-known and attractive therapeutic target for cancer. In the present study the solution-phase T3P-DMSO mediated efficient synthesis of 2-amino-chromene-3-carbonitriles from alcohols, malanonitrile and phenols is reported. These novel 2-amino-chromene-3-carbonitriles showed cytotoxicity in human acute myeloid leukemia (AML) cell lines. Compound 4g was found to be the most bioactive, decreasing growth and increasing apoptosis of AML cells. Moreover, compound 4g (at a concentration of 5 µM) increased the G2/M and sub-G1 (apoptosis) phases of AML cells. The AML cells treated with compound 4g exhibited decreased levels of Bcl-2 and increased levels of caspase-9. In silico molecular interaction analysis showed that compound 4g shared a similar global binding motif with navitoclax (another small molecule that binds Bcl-2), however compound 4g occupies a smaller volume within the P2 hot spot of Bcl-2. The intermolecular π-stacking interaction, direct electrostatic interactions, and docking energy predicted for 4g in complex with Bcl-2 suggest a strong affinity of the complex, rendering 4g as a promising Bcl-2 inhibitor for evaluation as a new anticancer agent.
RSC Advances | 2014
Sebastian Anusha; B. S. Anandakumar; Chakrabhavi Dhananjaya Mohan; G. P. Nagabhushana; B. S. Priya; Kanchugarakoppal S. Rangappa; Basappa; Chandrappa G. T
Bismuth oxide was synthesized via simple, rapid and energy efficient solution combustion synthesis (SCS) by employing sucrose as a fuel. This SCS-Bi2O3 was characterized by analytical techniques such as PXRD, SEM, EDX, UV-Visible and BET surface area measurement. Using the prepared SCS-Bi2O3, several classes of heterocyclic compounds were synthesized in good yields via Suzuki-coupling reaction in aqueous medium. Interestingly, the recovered SCS-Bi2O3 could be reused three times without a significant loss of catalytic activity. Further, the synthesized compounds were tested for cytotoxic activity against a human hepatoma cancer cell line (HepG2). Among these, compound 3n effectively inhibited the proliferation of these cells with an IC50 value of 8.4 μM. Thus, this paper describes the preparation of highly effective Bi2O3, which can be used for synthesizing various classes of heterocycles, including those having anti-cancer property.
PLOS ONE | 2016
Chakrabhavi Dhananjaya Mohan; Venkatachalaiah Srinivasa; Shobith Rangappa; Lewis H. Mervin; Surender Mohan; Shardul Paricharak; Sefer Baday; Feng Li; Muthu K. Shanmugam; Arunachalam Chinnathambi; Mohamed E. Zayed; Sulaiman Ali Alharbi; Andreas Bender; Gautam Sethi; Basappa; Kanchugarakoppal S. Rangappa
Overactivation of PI3K/Akt/mTOR is linked with carcinogenesis and serves a potential molecular therapeutic target in treatment of various cancers. Herein, we report the synthesis of trisubstituted-imidazoles and identified 2-chloro-3-(4, 5-diphenyl-1H-imidazol-2-yl) pyridine (CIP) as lead cytotoxic agent. Naïve Base classifier model of in silico target prediction revealed that CIP targets RAC-beta serine/threonine-protein kinase which comprises the Akt. Furthermore, CIP downregulated the phosphorylation of Akt, PDK and mTOR proteins and decreased expression of cyclin D1, Bcl-2, survivin, VEGF, procaspase-3 and increased cleavage of PARP. In addition, CIP significantly downregulated the CXCL12 induced motility of breast cancer cells and molecular docking calculations revealed that all compounds bind to Akt2 kinase with high docking scores compared to the library of previously reported Akt2 inhibitors. In summary, we report the synthesis and biological evaluation of imidazoles that induce apoptosis in breast cancer cells by negatively regulating PI3K/Akt/mTOR signaling pathway.
Bioorganic & Medicinal Chemistry Letters | 2015
Rangaswamy Roopashree; Chakrabhavi Dhananjaya Mohan; Toreshettahally R. Swaroop; Swamy Jagadish; Byregowda Raghava; Kyathegowdanadoddi Srinivas Balaji; Shankar Jayarama; Basappa; Kanchugarakoppal S. Rangappa
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).
Bioorganic & Medicinal Chemistry Letters | 2015
Hanumantharayappa Bharathkumar; Chakrabhavi Dhananjaya Mohan; Hanumappa Ananda; Julian E. Fuchs; Feng Li; Shobith Rangappa; Mohan Surender; Krishna C. Bulusu; Kesturu S. Girish; Gautam Sethi; Andreas Bender; Basappa; Kanchugarakoppal S. Rangappa
A new, simple, and microwave-assisted, solution-phase T3P®-DMSO mediated method for the preparation of a novel class of estrogen receptor alpha (ERα) ligands based on the 2-phenylquinoline scaffold was developed. Furthermore, the novel ERα ligands were tested for their bioactivity against ERα-positive and ERα-negative cell lines. The ligand (entry 4), with amine and nitro group substitution at C4 position, displayed significant cytotoxicity against MCF-7 and HepG2 cells with an IC50 value of 6 and 11μM, respectively. On the other hand, ERα-negative cells displayed resistance to quinolines induced cytotoxicity with an IC50 value >100Mm and they does not induce cytotoxicity in normal breast epithelial cells. Molecular docking analyses suggest a consistent binding mode for these ERα ligands in the ligand binding domain of the human ERα and predict the ligands to occupy the hydrophobic cavity in a similar fashion as estradiol or GW2368.
RSC Advances | 2014
Hanumantharayappa Bharathkumar; Shardul Paricharak; K. R. Dinesh; Kodappully Sivaraman Siveen; Julian E. Fuchs; Shobith Rangappa; Chakrabhavi Dhananjaya Mohan; Nima Mohandas; Alan Prem Kumar; Gautam Sethi; Andreas Bender; Basappa; Kanchugarakoppal S. Rangappa
Hepatocellular carcinoma, a fatal liver cancer, affects 600 000 people annually and ranks third in cancer-related lethality. In this work we report the synthesis and related biological activity of novel dihydropyrimidones. Among the tested compounds, 5-acetyl-4-(1H-indol-3-yl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (4g) was found to be most active towards the HepG2 cell line (IC50 = 17.9 μM), being at the same time 7.6-fold selective over normal (LO2) liver cells (IC50 = 136.9 μM). Subsequently, we identified peroxisome proliferator-activated receptor γ as a target of compound 4g using an in silico approach, and confirmed this mode-of-action experimentally.