202197-25-9Relevant articles and documents
Natural Product Neopeltolide as a Cytochrome bc1 Complex Inhibitor: Mechanism of Action and Structural Modification
Zhu, Xiao-Lei,Zhang, Rui,Wu, Qiong-You,Song, Yong-Jun,Wang, Yu-Xia,Yang, Jing-Fang,Yang, Guang-Fu
, (2019/03/19)
The marine natural product neopeltolide was isolated from a deep-water sponge specimen of the family Neopeltidae. Neopeltolide has been proven to be a new type of inhibitor of the cytochrome bc1 complex in the mitochondrial respiration chain. However, its detailed inhibition mechanism has remained unknown. In addition, neopeltolide is difficult to synthesize because of its very complex chemical structure. In the present work, the binding mode of neopeltolide was determined for the first time by integrating molecular docking, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations, which showed that neopeltolide is a Qo site inhibitor of the bc1 complex. Then, according to guidance via inhibitor-protein interaction analysis, structural modification was carried out with the aim to simplify the chemical structure of neopeltolide, leading to the synthesis of a series of new neopeltolide derivatives with much simpler chemical structures. The calculated binding energies (ΔGcal) of the newly synthesized analogues correlated very well (R2 = 0.90) with their experimental binding free energies (ΔGexp), which confirmed that the computational protocol was reliable. Compound 45, bearing a diphenyl ether fragment, was successfully designed and synthesized as the most potent candidate (IC50 = 12 nM) against porcine succinate cytochrome c reductase. The molecular modeling results indicate that compound 45 formed a π-π interaction with Phe274 and two hydrogen bonds with Glu271 and His161. The present work provides a new starting point for future fungicide discovery to overcome the resistance that the existing bc1 complex inhibitors are facing.
Novel series of 6-(2-substitutedacetamido)-4-anilinoquinazolines as EGFR-ERK signal transduction inhibitors in MCF-7 breast cancer cells
Ismail, Rania S.M.,Abou-Seri, Sahar M.,Eldehna, Wagdy M.,Ismail, Nasser S.M.,Elgazwi, Sara M.,Ghabbour, Hazem A.,Ahmed, Mahmoud Salama,Halaweish, Fathi T.,Abou El Ella, Dalal A.
, p. 782 - 796 (2018/06/29)
Epidermal growth factor receptor (EGFR) signaling pathway has been previously investigated for its significant role in the progression of different types of malignant tumors, where development of small molecules targeting EGFR is well known strategy for design of antitumor agents. Herein, we report the design and synthesis of two series of 6-(2-substitutedacetamido)-4-anilinoquinazolines (6a-x and 13a-d) as EGFR inhibitors. All the newly synthesized quinazoline derivatives were in vitro evaluated for their anti-proliferative activity towards MCF-7 (Breast Cancer) and HepG2 (Hepatocellular carcinoma) cell lines. In particular, compound 6n showed significant inhibitory activity against MCF-7 and HepG2 cell lines (IC50 = 3 and 16 μM, respectively), compared to that of Erlotinib (IC50 = 20 and 25 μM, respectively). Western blotting of 6n at MCF-7 cell line revealed the dual inhibitory activity of 6n towards diminishing the phosphorylated levels for EGFR and ERK. Also, ELISA assay confirmed the anti-EGFR activity of compound 6n (IC50 = 0.037 μM). Finally, a molecular docking study showed the potential binding mode of 6n within the ATP catalytic binding site of EGFR, exhibiting similar binding mode to EGFR inhibitor Erlotinib.
Discovery of anilino-furo[2,3-d]pyrimidine derivatives as dual inhibitors of EGFR/HER2 tyrosine kinase and their anticancer activity
Hossam, Monia,Lasheen, Deena S.,Ismail, Nasser S.M.,Esmat, Ahmed,Mansour, Ahmed M.,Singab, Abdel Nasser B.,Abouzid, Khaled A.M.
, p. 330 - 348 (2017/12/28)
Being responsible for the development of many cancer types, EGFR (Epidermal Growth Factor Receptor) and HER2 (Human Epidermal growth factor Receptor 2) were the focus of this study where a series of novel 4-anilino-furo[2,3-d]pyrimidine derivatives was designed, synthesized and biologically evaluated. Modification of the solvent accessible 5-position side chain greatly affected the in-vitro EGFR/HER2 inhibitory activity. Three derivatives bearing 5-carboxylic acid side chain, namely the 3-chloroanilino derivative (8c), the 3-bromoaniline (8d) and the lapatinib analogue (10) demonstrated the most significant submicromolar EGFR inhibition. Surprisingly, the in-vitro assay of the ester 7h and its acid analogue 10 showed a significant variation of results between the antiproliferative activity against A549 cell line (IC50 0.5 and 21.4 μM) respectively and EGFR inhibitory activity (18% and 100%) respectively, suggesting that 7h might be a prodrug for 10. This assumption was also affirmed by the in-vivo results, where the in-vivo antitumor assessment against EAC (Ehrlich Ascites Carcinoma) solid tumor model revealed that 7h and 8d (10 mg/kg dose) exhibited antitumor activity comparable to that of gefitinib at the same dose, exhibiting TGI% of 67%, 71% and 70%, respectively. This effect could be explained, at least partly, via activation of apoptosis, where 7h and 8d caused more than 2-fold increase of caspase 3 and cytochrome c expression than the control group which is comparable to that of gefitinib-treated group. Finally, 7h was the most effective apoptotic inducer, resulting in a significant elevation in annexin V–FITC-positive apoptotic cells (both early and late apoptosis) by 25 and 79-folds, respectively, compared to control, which is higher than that of gefitinib (22 and 61-folds, respectively).
Design, synthesis and biological evaluation of salicylamide analogues as epidermal growth factor receptor tyrosine kinase inhibitors
Liu, Yang,Li, Yijing,Liu, Jianzhen,Yang, Limin,Li, Pengzhan,Zhao, Guisen
, p. 314 - 323 (2016/04/04)
Blocking epidermal growth factor receptor (EGFR) has been the hotspot in the field of cancer therapy. Based on the fact that salicylanilides possess well inhibitory activity against EGFR tyrosine kinase, a series of salicylamide analogs bearing 4'-substitution were designed to explore new candidates exhibiting improved efficacy against EGFR. Many of the synthesized compounds inhibited EGFR in the micromolar range, especially compounds 15a and 15b (IC50 = 0.27 μM and 1.1μM, respectively). We report our findings as a basis for further development in salicylamide analogues as EGFR inhibitors.
Design and Synthesis of 4-Anilinothieno[2,3-d]pyrimidine-Based Compounds as Dual EGFR/HER-2 Inhibitors
Abd El Hadi, Soha R.,Lasheen, Deena S.,Hassan, Mahmoud A.,Abouzid, Khaled A. M.
, p. 827 - 847 (2016/11/09)
Dual inhibition of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER-2) is an attractive cancer therapeutic approach. In this study, new series of 4-anilinothieno[2,3-d]pyrimidines were designed, synthesized, and tested as dual EGFR/HER-2 kinase inhibitors. Five compounds (8a, 8b, 8e–g) demonstrated low to submicromolar inhibition of both kinases with IC50 values of 1.2, 0.6, 0.3, 0.2, 0.4 μM and 8.2, 3.4, 1.3, 0.5, 2.7 μM for the EGFR and HER-2, respectively. Introduction of a 5,6-tetramethylene moiety into the thienopyrimidine core bearing a 4-(3-fluorobenzyloxy)-3-chloroaniline tail resulted in a favorable increase in both the EGFR and HER-2 inhibitory activities. Compound 8f (IC50 EGFR/HER-2: 0.2/0.5 μM) also exhibited significant cell growth inhibition on some specific NCI cell lines, especially ovarian, breast, non-small-cell lung cancer, and renal cancer cell lines.
PROTOZOAN PARASITE GROWTH INHIBITORS
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Paragraph 0145; 0146; 0154, (2015/11/10)
Compounds and methods for inhibiting growth of a protozoan parasite. Methods of treating a protozoan parasite infection in a subject by administering a therapeutically effective amount of a compound as disclosed herein. The compounds and methods can be us
Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
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Page/Page column 41, (2015/12/18)
A pharmaceutical formulation comprising the compound of formula
Kinase scaffold repurposing for neglected disease drug discovery: Discovery of an efficacious, lapatanib-derived lead compound for trypanosomiasis
Patel, Gautam,Karver, Caitlin E.,Behera, Ranjan,Guyett, Paul J.,Sullenberger, Catherine,Edwards, Peter,Roncal, Norma E.,Mensa-Wilmot, Kojo,Pollastri, Michael P.
, p. 3820 - 3832 (2013/06/27)
Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei. Because drugs in use against HAT are toxic and require intravenous dosing, new drugs are needed. Initiating lead discovery campaigns b
Optimization and SAR for dual ErbB-1/ErbB-2 tyrosine kinase inhibition in the 6-furanylquinazoline series
Petrov, Kimberly G.,Zhang, Yue-Mei,Carter, Malcolm,Cockerill, G. Stuart,Dickerson, Scott,Gauthier, Cassandra A.,Guo, Yu,Mook Jr., Robert A.,Rusnak, David W.,Walker, Ann L.,Wood, Edgar R.,Lackey, Karen E.
, p. 4686 - 4691 (2007/10/03)
Synthetic modifications on a 6-furanylquinazoline scaffold to optimize the dual ErbB-1/ErbB-2 tyrosine kinase inhibition afforded consistent SAR whereby a 4-(3-fluorobenzyloxy)-3-haloanilino provided the best enzyme potency and cellular selectivity. Changes made to the 6-furanyl group had little impact on the enzyme activity, but appeared to dramatically affect the cellular efficacy. The discovery of lapatinib emerged from this work.
Anilinoquinazaolines as protein tyrosine kianse inhibitors
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Page/Page column 46, (2008/06/13)
Heteroaromatic compounds are described, methods for their preparation, pharmaceutical compositions containing them, methods of use, and their use in medicines. In particular, the invention relates to quinazoline and pyridopyrimidine derivatives which exhibit protein tyrosine kinase inhibition.
