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Your search keyword '"Madasu, Chandrashekhar"' showing total 12 results
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12 results on '"Madasu, Chandrashekhar"'

1. Reversible male contraception by targeted inhibition of serine/threonine kinase 33

Author

Ku, Angela F., primary, Sharma, Kiran L., additional, Ta, Hai Minh, additional, Sutton, Courtney M., additional, Bohren, Kurt M., additional, Wang, Yong, additional, Chamakuri, Srinivas, additional, Chen, Ruihong, additional, Hakenjos, John M., additional, Jimmidi, Ravikumar, additional, Kent, Katarzyna, additional, Li, Feng, additional, Li, Jian-Yuan, additional, Ma, Lang, additional, Madasu, Chandrashekhar, additional, Palaniappan, Murugesan, additional, Palmer, Stephen S., additional, Qin, Xuan, additional, Robers, Matthew B., additional, Sankaran, Banumathi, additional, Tan, Zhi, additional, Vasquez, Yasmin M., additional, Wang, Jian, additional, Wilkinson, Jennifer, additional, Yu, Zhifeng, additional, Ye, Qiuji, additional, Young, Damian W., additional, Teng, Mingxing, additional, Kim, Choel, additional, and Matzuk, Martin M., additional

Published
2024
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3. Identification of potent pan-ephrin receptor kinase inhibitors using DNA-encoded chemistry technology.

Author

Madasu, Chandrashekhar, Zian Liao, Parks, Sydney E., Sharma, Kiran L., Bohren, Kurt M., Qiuji Ye, Feng Li, Palaniappan, Murugesan, Zhi Tan, Fei Yuan, Creighton, Chad J., Suni Tang, Masand, Ramya P., Xiaoming Guan, Young, Damian W., Monsivais, Diana, and Matzuk, Martin M.

Subjects
*KINASE inhibitors, *EWING'S sarcoma, *EPHRIN receptors, *CYCLOOXYGENASES, *LIGANDS (Biochemistry)
Abstract

EPH receptors (EPHs), the largest family of tyrosine kinases, phosphorylate downstream substrates upon binding of ephrin cell surface-associated ligands. In a large cohort of endometriotic lesions from individuals with endometriosis, we found that EPHA2 and EPHA4 expressions are increased in endometriotic lesions relative to normal eutopic endometrium. Because signaling through EPHs is associated with increased cell migration and invasion, we hypothesized that chemical inhibition of EPHA2/4 could have therapeutic value. We screened DNA-encoded chemical libraries (DECL) to rapidly identify EPHA2/4 kinase inhibitors. Hit compound, CDD-2693, exhibited picomolar/nanomolar kinase activity against EPHA2 (Ki: 4.0 nM) and EPHA4 (Ki: 0.81 nM). Kinome profiling revealed that CDD-2693 bound to most EPH family and SRC family kinases. Using NanoBRET target engagement assays, CDD-2693 had nanomolar activity versus EPHA2 (IC50: 461 nM) and EPHA4 (IC50: 40 nM) but was a micromolar inhibitor of SRC, YES, and FGR. Chemical optimization produced CDD-3167, having picomolar biochemical activity toward EPHA2 (Ki: 0.13 nM) and EPHA4 (Ki: 0.38 nM) with excellent cell-based potency EPHA2 (IC50: 8.0 nM) and EPHA4 (IC50: 2.3 nM). Moreover, CDD-3167 maintained superior off-target cellular selectivity. In 12Z endometriotic epithelial cells, CDD-2693 and CDD-3167 significantly decreased EFNA5 (ligand) induced phosphorylation of EPHA2/4, decreased 12Z cell viability, and decreased IL-1β-mediated expression of prostaglandin synthase 2 (PTGS2). CDD-2693 and CDD-3167 decreased expansion of primary endometrial epithelial organoids from patients with endometriosis and decreased Ewing's sarcoma viability. Thus, using DECL, we identified potent pan-EPH inhibitors that show specificity and activity in cellular models of endometriosis and cancer. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Discovery of Highly Potent and BMPR2-Selective Kinase Inhibitors Using DNA-Encoded Chemical Library Screening

Author

Modukuri, Ram K., primary, Monsivais, Diana, additional, Li, Feng, additional, Palaniappan, Murugesan, additional, Bohren, Kurt M., additional, Tan, Zhi, additional, Ku, Angela F., additional, Wang, Yong, additional, Madasu, Chandrashekhar, additional, Li, Jian-Yuan, additional, Tang, Suni, additional, Miklossy, Gabriella, additional, Palmer, Stephen S., additional, Young, Damian W., additional, and Matzuk, Martin M., additional

Published
2023
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9. Design, synthesis, anti-inflammatory, cytotoxic and cell based studies of some novel side chain analogues of myrrhanones A & B isolated from the gum resin of Commiphora mukul

Author

Uppuluri Venkata Mallavadhani, Sistla Ramakrishna, Madasu Chandrashekhar, and Karri Shailaja

Subjects
medicine.drug_class, Stereochemistry, Interleukin-1beta, Anti-Inflammatory Agents, Antineoplastic Agents, Apoptosis, 01 natural sciences, Biochemistry, Anti-inflammatory, HeLa, DU145, Cell Line, Tumor, Plant Gums, Drug Discovery, medicine, Humans, Cytotoxic T cell, Cytotoxicity, Commiphora, Molecular Biology, IC50, Membrane Potential, Mitochondrial, Molecular Structure, U937 cell, biology, Tumor Necrosis Factor-alpha, 010405 organic chemistry, Chemistry, Organic Chemistry, biology.organism_classification, G1 Phase Cell Cycle Checkpoints, Triterpenes, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Cell culture, Drug Screening Assays, Antitumor, Reactive Oxygen Species, Resins, Plant
Abstract

Myrrhanones A (1) and B (2), isolated from the gum resin of Commiphora mukul, were reported to exhibit anticancer and anti-inflammatory activities. In view of their interesting skeletal features and biological activities they have been chemically modified by exploiting their side chain functionalities to synthesise 29 diverse analogues. All the synthesized analogues were screened for their cytotoxic potential against a panel of five human cancer cell lines which include DU145 (Prostate), HT-29 (Colon), MCF-7 (Breast), Hela (Cervical) and U87MG (Glioblastoma) along with a normal cell line (L132). The synthesized analogues were also screened for anti-inflammatory activity against TNF-α and IL-1β using LPS induced inflammation model employing U937 cells. The biological screening results revealed that compounds 4b (piperidine analogue), 9d (linear aliphatic four member amide analogue) and 9i (N-methyl piperazine analogue) displayed significant cytotoxic activity against MCF-7, HT-29 and DU145 [IC50 (μM): 4.65 ± 1.28, 5.48 ± 0.13 and 6.63 ± 1.39] respectively. These analogues were further taken up for apoptotic assay, which confirmed that compounds 4b, 9d and 9i induced apoptosis in MCF-7, HT-29, DU145 cells and arrested in G0/G1 phase. Further, compounds 9c and 9g found to exhibit good anti-inflammatory activity against TNF-α with IC50 (μM) values of 10.02 ± 2.13 and 10.53 ± 0.48 respectively, while compound 2 exhibited strong inhibitory activity against both TNF-α (IC50: 9.39 ± 0.44 μM) and IL-1β (IC50: 12.15 ± 1.36 μM).

Published
2019

11. Novel triazole hybrids of myrrhanone C, a natural polypodane triterpene: Synthesis, cytotoxic activity and cell based studies

Author

Madasu Chandrashekhar, Uppuluri Venkata Mallavadhani, Vadithe Lakshma Nayak, and Sistla Ramakrishna

Subjects
Stereochemistry, Triazole, 010402 general chemistry, 01 natural sciences, Structure-Activity Relationship, chemistry.chemical_compound, Triterpene, Cell Line, Tumor, Drug Discovery, Humans, Structure–activity relationship, MTT assay, Cell Proliferation, Membrane Potential, Mitochondrial, Pharmacology, chemistry.chemical_classification, Biological Products, Cell Death, Dose-Response Relationship, Drug, Molecular Structure, Bicyclic molecule, 010405 organic chemistry, Chemistry, Cell growth, Cell Cycle, Organic Chemistry, General Medicine, Triazoles, Cell cycle, Antineoplastic Agents, Phytogenic, Triterpenes, 0104 chemical sciences, Biochemistry, Apoptosis, Drug Screening Assays, Antitumor
Abstract

The 3-keto functionality in ring A of myrrhanone C, a natural bicyclic triterpene has been chemically modified and synthesized 27 novel triazole hybrids belonging to two different series in very good to excellent yields (66-83%). The synthesized compounds were thoroughly characterized by their spectroscopic data (IR, (1)H&(13)C NMR, HRMS). All the synthesized compounds were evaluated for their cytotoxic potential against a panel of five human cancer cell lines by employing MTT assay using doxorubicin as the standard. In general the synthesized compounds showed anticancer activity against almost all the cell lines screened. Interestingly, the oxime based triazoles (4a-4n) showed higher activity than the benzylidene triazoles (6a-6m). Most significantly compound 4a showed potent activity against all the tested cell lines, especially against lung cancer (A-549) with an IC 50 of 6.16 μm. In view of their significant activity against lung cancer cell lines, compounds 4a and 4l were subjected to detailed biological studies, which revealed that they arrested cell cycle in G2/M phase and induced cell death by apoptosis that was further confirmed by Hoechst staining, measurement of mitochondrial membrane potential (ΔΨm) and Annexin V-FITC assay. These compounds will serve as lead molecules in the development of potent anticancer drug candidates especially for lung cancer.

Published
2016

12. Synthesis and anticancer activity of novel fused pyrimidine hybrids of myrrhanone C, a bicyclic triterpene of Commiphora mukul gum resin

Author

Vadithe Lakshma Nayak, Madasu Chandrashekhar, Uppuluri Venkata Mallavadhani, and Sistla Ramakrishna

Subjects
Pyrimidine, Stereochemistry, Antineoplastic Agents, Apoptosis, Biology, Catalysis, Inorganic Chemistry, HeLa, chemistry.chemical_compound, Mice, Triterpene, Cell Line, Tumor, Drug Discovery, Animals, Humans, MTT assay, Physical and Theoretical Chemistry, Molecular Biology, Commiphora, Cell Proliferation, chemistry.chemical_classification, Bicyclic molecule, Molecular Structure, Cell growth, Organic Chemistry, General Medicine, biology.organism_classification, Triterpenes, Pyrimidines, chemistry, Cell culture, MCF-7 Cells, Resins, Plant, Information Systems, HeLa Cells
Abstract

Myrrhanone C [8(R)-3-oxo-8-hydroxypolypoda-13E,17E,21-triene], a bicyclic triterpene isolated from the gum resin of Commiphora mukul, has been chemically transformed to synthesize a series of ten novel pyrimidine hybrids in good to excellent yields. The synthesized compounds (2-22) were evaluated for their anticancer potential against a panel of six cancer cell lines, namely A-549 (lung), Hela (cervical), MCF-7 (breast), ACHN (renal), Colo-205 (colon) and B-16 (mouse melanoma) by employing the MTT assay. In general, the synthesized compounds showed significant anticancer activity against all the cancer cell lines tested. Interestingly, the pyrimidine hybrids 18 and 19 showed good activity against the A-549, MCF-7, B-16, Colo-205 and ACHN cancer cell lines with [Formula: see text] values between 7.7-37.8 [Formula: see text]M. Most significantly, compounds 19 (IC[Formula: see text]: 7.7 [Formula: see text]M) and 18 (IC[Formula: see text]: 9.5 [Formula: see text]M) showed about five- and six-fold enhanced activities, respectively, compared to the parent myrrhanone C (1) against A-549 cell line. Flow cytometric analysis revealed that compounds 18 and 19 induced apoptosis in A-549 cells and arrested the cell growth in the G0/G1 phase.

Published
2015

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