4651-91-6Relevant articles and documents
Discovery of potent dual egfr/her2 inhibitors based on thiophene scaffold targeting h1299 lung cancer cell line
Elrayess, Ranza,Abdel Aziz, Yasmine M.,Elgawish, Mohamed Saleh,Elewa, Marwa,Yassen, Asmaa S. A.,Elhady, Sameh S.,Elshihawy, Hosam A.,Said, Mohamed M.
, p. 1 - 21 (2021)
Dual targeting of epidermal growth factor receptor (EGFR) and human EGFR-related receptor 2 (HER2) is a proven approach for the treatment of lung cancer. With the aim of discov-ering effective dual EGFR/HER2 inhibitors targeting non-small cell lung cancer cell line H1299, three series of thieno[2,3-d][1,2,3]triazine and acetamide derivatives were designed, synthesized, and biologically evaluated. The synthesized compounds displayed IC50 values ranging from 12 to 54 nM against H1299, which were superior to that of gefitinib (2) at 40 μM. Of the synthesized com-pounds, 2-(1H-pyrazolo[3,4-b]pyridin-3-ylamino)-N-(3-cyano4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (21a) achieved the highest in vitro cytotoxic activity against H1299, with an IC50 value of 12.5 nM in situ, and 0.47 and 0.14 nM against EGFR and HER2, respectively, values comparable to the IC50 of the approved drug imatinib (1). Our synthesized compounds were promising, demonstrating high selectivity and affinity for EGFR/HER2, especially the hinge region forming a hydrophobic pocket, which was mediated by hydrogen bonding as well as hydrophobic and electrostatic inter-actions, as indicated by molecular modeling. Moreover, the designed compounds showed good affinity for T790M EGFR, one of the main mutants resulting in acquired drug resistance. Furthermore, both pharmacokinetic and physicochemical properties of the designed compounds were within the appropriate range for human usage as predicted by the in Silico ADME study. The designed compound (21a) might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR/HER2.
Synthesis and cytotoxicity of novel thiophene, pyran and pyridine derivatives
Wardakhan, Wagnat W.,Samir, Eman M.,El-Arab, Elham E.
, p. 259 - 270 (2018)
The reaction of 2-amino-3-cyano-tetrahydrobenzothiophene 3 with ethyl acetoacetate gave the amide derivatives 5. The reactivity of 5 toward a variety of chemical reagents was studied to give pyrans, pyridines, thiophenes and the thiazoles and their fused derivatives. The structures of the newly synthesized products were confirmed on the basis of their respective analytical and spectral data. The antitumor evaluations of the synthesized compounds against the three cancer cell lines MCF-7, NCI-H460 and SF-268 showed that compounds 9a, 9c, 12a and 14 were of the highest potencies against the three cancer cell lines among the tested compounds.
Synthesis of novel 5-aryl/hetarylidenyl 3-(2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-2-thioxothiazolidin-4-ones
Mendoza, Kimberly,Kamila, Sukanta,Biehl, Edward R.
, p. 741 - 753 (2014)
The synthesis of a variety of novel 5-substituted titled compounds containing a priviledged rhodanine scaffold is described. The synthesis involves a microwave (MW) assisted Knoevenagel condensation of 3-(2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-2-thioxothiazolidin-4-one with suitably substituted aromatic aldehydes. However, these condensations fail with aliphatic aldehydes. The 2-thioxothiazolidin-4-one (rhodanine) precursor was prepared by the condensation of 2-thioxothiazolidin-4-one-di-(carboxymethyl)trithiocarbonyl and 4,5,6,7-tetrahydrobenzo[4,5]thienyl[2,3-d]-2-methylpyrimidin-4-amine in the presence of K2CO3.
Design, synthesis and biological evaluation of novel (E)-2-benzylidene-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)hydrazine-1-carboxamide derivatives as α-glucosidase inhibitors
Fang, Lei,Jiang, Cheng-Shi,Li, Yue,Song, Zhiling,Wang, Kai-Ming,Xie, Hong-Xu,Zhang, Jin-He,Zhang, Juan,Zhu, Kong-Kai
supporting information, (2021/10/20)
In this present study, a series of novel (E)-2-benzylidene-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)hydrazine-1-carboxamide derivatives against α-glucosidase were designed and synthesized, and their biological activities were evaluated in vitro and in vivo. Most of the designed analogues exhibited better inhibitory activity than the marketed acarbose, especially the most potent compound 7 with an IC50 value of 9.26 ± 1.84 μM. The direct binding of 7 and 8 with α-glucosidase was confirmed by fluorescence quenching experiments, and the kinetic and molecular docking studies revealed that 7 and 8 inhibited α-glucosidase in a non-competitive manner. Cytotoxicity bioassay indicated compounds 7 and 8 were non-toxic towards LO2 and HepG2 at 100 μM. Furthermore, both compounds were demonstrated to have in vivo hypoglycemic activity by reducing the blood glucose levels in sucrose-treated rats.
Discovery of thieno[2,3-d]pyrimidine-based derivatives as potent VEGFR-2 kinase inhibitors and anti-cancer agents
El-Metwally, Souad A.,Abou-El-Regal, Mohsen M.,Eissa, Ibrahim H.,Mehany, Ahmed B.M.,Mahdy, Hazem A.,Elkady, Hazem,Elwan, Alaa,Elkaeed, Eslam B.
, (2021/05/10)
Vascular endothelial growth factor-2 (VEGFR-2) is considered one of the most important factors in tumor angiogenesis, and consequently a number of anticancer therapeutics have been developed to inhibit VEGFR-2 signaling. Accordingly, eighteen derivatives of thieno[2,3-d]pyrimidines having structural characteristics similar to VEGFR-2 inhibitors were designed and synthesized. Anticancer activities of the new derivatives were assessed against three human cancer cell lines (HCT-116, HepG2, and MCF-7) using MTT. Sorafenib was used as positive control. Compounds 17c-i, and 20b showed excellent anticancer activities against HCT-116 and HepG2 cell lines, while compounds 17i and 17g was found to be active against MCF-7 cell line. Compound 17f exhibited the highest cytotoxic activities against the examined cell lines, HCT-116 and HepG2, with IC50 values of 2.80 ± 0.16 and 4.10 ± 0.45 μM, respectively. Aiming at exploring the mechanism of action of these compounds, the most active cytotoxic derivatives were in vitro tested for their VEGFR-2 inhibitory activity. Compound 17f showed high activity against VEGFR-2 with an IC50 value of 0.23 ± 0.03 μM, that is equal to that of reference, sorafenib (IC50 = 0.23 ± 0.04 μM). Molecular docking studies also were performed to investigate the possible binding interactions of the target compounds with the active sites of VEGFR-2. The synthesized compounds were analyzed for their ADMET and toxicity properties. Results showed that most of the compounds have low to very low BBB penetration levels and they have non-inhibitory effect against CYP2D6. All compounds were predicted to be non-toxic against developmental toxicity potential model except compounds 17b and 20b.
