- Development of pyridazine derivatives as potential EGFR inhibitors and apoptosis inducers: Design, synthesis, anticancer evaluation, and molecular modeling studies
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Novel hybrids of pyridazine-pyrazoline were synthesized aiming to develop new antiproliferative candidates. All compounds were submitted to the National Cancer Institute (NCI), USA, and many were proved to have significant antiproliferative activity. In addition, in vitro studies of the epidermal growth factor receptor (EGFR) inhibition showed that compounds IXn, IXg, IXb and IXl exhibited excellent inhibitory effect (IC50 = 0.65, 0.75, 0.82 and 0.84 μM, respectively) compared to Erlotinib (IC50 = 0.95 μM). The mechanistic effectiveness in cell cycle progression, apoptotic induction and gene regulation were assessed for the promising compounds IXg and IXn due to their significant EGFR inhibition. Flow cytometeric analysis indicated that compounds IXg and IXn result in increased cell numbers in phase G2/M, suggesting cell cycle arrest in phase G2/M in UO-31cells. Furthermore, real time PCR assay illustrated that compounds IXg and IXn elevated Bax/Bcl2 ratio which confirmed the mechanistic pathway of them. Moreover, the apoptotic induction of UO-31 renal cancer cells was enhanced effectively through activation of caspase-3 by compounds IXg and IXn. On the other hand, molecular docking study was performed to investigate binding mode of interaction of compounds with EGFR-PK in the active site with the aim of rationalizing its promising inhibitory activity. Finally, based on the aforementioned findings, compounds IXg and IXn could be considered as effective apoptosis modulators and promising leads for future development of new anti-renal cancer agents.
- Ahmed, Marwa F.,Santali, Eman Y.,Mohi El-Deen, Eman M.,Naguib, Ibrahim A.,El-Haggar, Radwan
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- CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF
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Disclosed herein are small molecule calpain modulator compositions, pharmaceutical compositions, the use and preparation thereof.
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Paragraph 1172
(2018/04/17)
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- Synthesis and cytotoxic activities of some pyrazoline derivatives bearing phenyl pyridazine core as new apoptosis inducers
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The cyclization of chalcones 3a-3u with 3-hydrazinyl-6-phenylpyridazine 7 under basic condition led to the formation of new pyrazoline derivatives 8a-8u. All final compounds were characterized by spectral and elemental analyses. They were screened for their antiproliferative activities against A549 (lung), HepG-2 (liver), CaCo-2 (intestinal) and MCF-7 (breast) cancer cell lines. Some of the synthesized compounds exhibited promising antiproliferative activities especially compound 8k with IC50values of 8.33, 1.67 and 10?μM against HepG-2, MCF-7 and CaCo-2 cancer cell lines, respectively. Moreover, their antiproliferative activity was due to apoptosis rather than necrosis induction except compound 8h which exhibited equal apoptotic and necrotic properties. Compound 8k showed 5 fold increase in caspase-3 activity indicating that the apoptosis proceeds via caspase-3 activation.
- George, Riham F.,Fouad, Marwa A.,Gomaa, Iman E.O.
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- REGULATION OF PROTEIN SYNTHESIS
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A composition and method for inhibiting proliferation of a tumor cell compared to a non-tumor cell. Also described are methods of screening for a composition that inhibits cap-dependent translation compared to cap-independent translation of proteins
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Page/Page column 45
(2010/06/19)
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- Design, synthesis and analgesic properties of novel conformationally-restricted N-acylhydrazones (NAH)
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A set of six azaheterocycles were designed as conformationnaly-constrained N-acylhydrazones and tested as analgesics.
- Kuemmerle, Arthur E.,Vieira, Marina M.,Schmitt, Martine,Miranda, Ana L.P.,Fraga, Carlos A.M.,Bourguignon, Jean-Jacques,Barreiro, Eliezer J.
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scheme or table
p. 4963 - 4966
(2010/03/24)
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- Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase
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Tumorigenesis is a multistep process in which oncogenes play a key role in tumor formation, growth, and maintenance. MET was discovered as an oncogene that is activated by its ligand, hepatocyte growth factor. Deregulated signaling in the c-Met pathway ha
- Albrecht, Brian K.,Harmange, Jean-Christophe,Bauer, David,Berry, Loren,Bode, Christiane,Boezio, Alessandro A.,Chen, April,Choquette, Deborah,Dussault, Isabelle,Fridrich, Cary,Hirai, Satoko,Hoffman, Doug,Larrow, Jay F.,Kaplan-Lefko, Paula,Lin, Jasmine,Lohman, Julia,Long, Alexander M.,Moriguchi, Jodi,O'Connor, Anne,Potashman, Michele H.,Reese, Monica,Rex, Karen,Siegmund, Aaron,Shah, Kavita,Shimanovich, Roman,Springer, Stephanie K.,Teffera, Yohannes,Yang, Yajing,Zhang, Yihong,Bellon, Steven F.
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supporting information; experimental part
p. 2879 - 2882
(2009/05/30)
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- Synthesis, antitubercular, antifungal and antibacterial activities of 6-substituted phenyl-2-(3′-substituted phenyl pyridazin-6′-yl)-2,3, 4,5-tetrahydropyridazin-3-one
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A series of 6-substituted phenyl-2-(3′-substituted phenyl pyridazin-6′-yl)-2,3,4,5-tetrahydropyridazin-3-ones has been synthesized. An appropriate aromatic hydrocarbon reacts with succinic anhydride in presence of AlCl3 to yield β-aroyl propionic acid. The corresponding acid was cyclized with hydrazine hydrate to give 6-(substituted aryl)-2,3,4,5- tetrahydro-3-pyridazinone, which was heated on steam bath with phosphorus( V) oxychloride to yield 3-chloro 6-substituted phenyl pyridazine. This intermediate after reaction with hydrazine hydrate was converted into 3-hydrazino-6- substituted phenyl pyridazine. The resulting product was converted into 6-substituted phenyl-2-(3′-substituted phenyl pyridazin-6′-yl)-2,3, 4,5-tetrahydropyridazin-3-one by reacting with substituted aroyl propionic acid. Spectral data (IR, NMR, mass spectra) confirmed the structures of the synthesized compounds. The synthesized compounds were investigated for their in vitro antitubercular, antifungal and antibacterial activities. The results indicated that the synthesized compounds have mild to potent activities with reference to their appropriate reference standards.
- Islam, Mojahidul,Siddiqui, Anees A.,Rajesh, Ramadoss
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experimental part
p. 353 - 362
(2009/04/11)
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- Discovery of a 3-amino-6-phenyl-pyridazine derivative as a new synthetic antineuroinflammatory compound
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Excessive glial activation, with overproduction of cytokines and oxidative stress products, is detrimental and a hallmark of neurodegenerative disease pathology. Suppression of glial activation is a potential therapeutic approach, and protein kinases are targets of some antiinflammatory drugs. To address an unmet need for selective inhibitors of glial activation, we developed a novel 3-amino-6-phenylpyridazine derivative that selectively blocks increased IL-1β, iNOS, and NO production by activated glia, without inhibition of potentially beneficial glial functions.
- Mirzoeva, Salida,Sawkar, Anu,Zasadzki, Magdalena,Guo, Ling,Velentza, Anastasia V.,Dunlap, Vincent,Bourguignonl, Jean-Jacques,Ramstrom, Helena,Haiech, Jacques,Van Eldik, Linda J.,Watterson
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p. 563 - 566
(2007/10/03)
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- Synthesis and Structure-Activity Relationships of Series of Aminopyridazine Derivatives of γ-Aminobutyric Acid Acting as Selective GABA-A Antagonists
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We have recently shown that an aryloaminopyridazine derivarive of GABA, SR 95103 , is a selective and competitive GABA-A receptor antagonist.In order to further explore the structural requirements for GABA receptor affinity, we synthesized a series of 38 compounds by attaching various pyridazinic structures to GABA or GABA-like side chains.Most of the compounds displaced GABA from rat brain membranes.All the active compounds antagonized the GABA-elicited enhancement of diazepam binding, strongly suggesting that all these compounds are GABA-A receptor antagonists.None of the compounds that displaced GABA from rat brain membranes interacted with other GABA recognition sites (GABA-B receptor, GABA uptake binding site, glutamate decarboxylase, GABA-transaminase).They did not interact with the Cl- ionophore associated with the GABA-A receptor and did not interact with the benzodiazepine, strychnine, and glutamate binding sites.Thus these compounds appear to be specific GABA-A receptor antagonists.In terms of structure-activity, it can be concluded that a GABA moiety bearing a positive charge is necessary for optimal GABA-A receptor recognition.Additional binding sites are tolerated only if they are part of a charge-delocalized amidinic or guanidinic system.If this delocalization is achieved by linking a butyric acid moiety to the N(2) nitrogen of a 3-aminopyridazine, GABA-antagonistic character is produced.The highest potency (ca.250 times bicuculline) was observed when an aromatic ? system, bearing electron-donating substituents, was present on the 6-position of the pyridazine ring.
- Wermuth, Camille-Georges,Bourguignon, Jean-Jacques,Schlewer, Gilbert,Gies, Jean-Pierre,Schoenfelder, Angele,et al.
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p. 239 - 249
(2007/10/02)
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- Reactions of 3-Chloropyridazines with Some Nucleophilic Reagents
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3-Chloro-6-phenylpyridazine (1a) and its 4-methyl derivative (1b) react with sodamide, hydrazines, 3-aminopyridazines and phenothiazine in polar and non-polar solvents as well as by fusion to give different products.The structures assigned to the products have been confirmed by their IR spectra.
- Moustafa, A. H.,Kaddah, A. M.,Shams, N. A.
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p. 1084 - 1086
(2007/10/02)
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