322399-31-5Relevant academic research and scientific papers
Design and synthesis of new 1,6-dihydropyrimidin-2-thio derivatives targeting VEGFR-2: Molecular docking and antiproliferative evaluation
Abdel-Aziz, Mohamed,Abdel-Aziz, Salah A.,Abdelrahman, Kamal S.,Gouda, Ahmed M.,Marzouk, Adel A.,Wanas, Amira S.,Youssif, Bahaa G. M.
, (2020)
A series of new 1,6-dihydropyrimidin-2-thiol derivatives (scaffold A) as VEGFR-2 inhibitors has been designed and synthesized. Compounds 3a, 3b, 3e and 4b have been selected for in vitro anticancer screening by the National Cancer Institute. Compound 3e showed remarkable anticancer activity against most of the cell lines tested, where a complete cell death against leukemia, non-small cell lung cancer, colon, CNS, melanoma, and breast cancer cell lines was observed. In vitro five dose tests showed that compound 3e had high activity against most of the tested cell lines with GI50 ranging from 19 to 100 μM and selectivity ratios ranging between 0.75 and 1.71 at the GI50 level. VEGFR-2-kinase was tested against 3a, 3b, 3e, 4b and sorafenib was used as a reference. Compounds 3a and 3e were the most potent analogues with IC50 values of 386.4 nM and 198.7 nM against VEGFR-2, respectively, in comparison to sorafenib (IC50 = 0.17 nM). The results of the docking study showed a good fitting of the new compounds to the active site of VEGFR-2 with binding free energies in the range of ?9.80 to ?11.25 kcal/mol compared to ?12.12 kcal/mol for sorafenib. Compounds 4a-e with the hydroxyimino group had a higher affinity to VEGFR-2 than their parent derivatives 3a-e.
Discovery of Potent and Selective 2-(Benzylthio)pyrimidine-based DCN1-UBC12 Inhibitors for Anticardiac Fibrotic Effects
He, Zhang-Xu,An, Qi,Wei, Bo,Zhou, Wen-Juan,Wei, Bing-Fei,Gong, Yun-Peng,Zhang, Xin,Gao, Ge,Dong, Guan-Jun,Huo, Jin-Ling,Zhang, Xin-Hui,Yang, Fei-Fei,Liu, Hong-Min,Ma, Li-Ying,Zhao, Wen
, p. 163 - 190 (2022/01/11)
DCN1, a co-E3 ligase, interacts with UBC12 and activates cullin-RING ligases (CRLs) by catalyzing cullin neddylation. Although DCN1 has been recognized as an important therapeutic target for human diseases, its role in the cardiovascular area remains unknown. Here, we first found that DCN1 was upregulated in isolated cardiac fibroblasts (CFs) treated by angiotensin (Ang) II and in mouse hearts after pressure overload. Then, structure-based optimizations for DCN1-UBC12 inhibitors were performed based on our previous work, yielding compound DN-2. DN-2 specifically targeted DCN1 at molecular and cellular levels as shown by molecular modeling studies, HTRF, cellular thermal shift and co-immunoprecipitation assays. Importantly, DN-2 effectively reversed Ang II-induced cardiac fibroblast activation, which was associated with the inhibition of cullin 3 neddylation. Our findings indicate a potentially unrecognized role of DCN1 inhibition for anticardiac fibrotic effects. DN-2 may be used as a lead compound for further development.
Novel cyanothiouracil and cyanothiocytosine derivatives as concentration-dependent selective inhibitors of U87MG glioblastomas: Adenosine receptor binding and potent PDE4 inhibition
Sahin, Zafer,Biltekin, Sevde Nur,Yurttas, Leyla,Berk, Barkin,?zhan, Ya?mur,Sipahi, Hande,Gao, Zhan-Guo,Jacobson, Kenneth A.,Demirayak, ?eref
, (2021/01/12)
Thiouracil and thiocytosine are important heterocyclic pharmacophores having pharmacological diversity. Antitumor and antiviral activity is commonly associated with thiouracil and thiocytosine derivatives, which are well known fragments for adenosine receptor affinity with many associated pharmacological properties. In this respect, 33 novel compounds have been synthesized in two groups: 24 thiouracil derivatives (4a-x) and 9 thiocytosine derivatives (5a-i). Antitumor activity of all the compounds was determined in the U87 MG glioblastoma cell line. Compound 5e showed an anti-proliferative IC50 of 1.56 μM, which is slightly higher activity than cisplatin (1.67 μM). The 11 most active compounds showed no signficant binding to adenosine A1, A2A or A2B receptors at 1 μM. Brain tumors express high amounts of phosphodiesterases. Compounds were tested for PDE4 inhibition, and 5e and 5f showed the best potency (5e: 3.42 μM; 5f: 0.97 μM). Remakably, those compounds were also the most active against U87MG. However, the compounds lacked a cytotoxic effect on the HEK293 healthy cell line, which encourages further investigation.
Novel 2-thiopyrimidine derivatives as CDK2 inhibitors: Molecular modeling, synthesis, and anti-tumor activity evaluation
Fathalla, Omar Abd El-Fattah M.,Ismail, Mohamed A. H.,Anwar, Manal M.,Abouzid, Khaled A. M.,Ramadan, Aisha A. K.
, p. 659 - 673 (2013/04/10)
A novel series of pyrimidine-benzenesulfonamide derivatives as potential cyclin-dependent kinase 2 inhibitors were designed depending upon the molecular docking simulation study. This study was preceded by modification and optimization of the lead compound 4-(2-amino-4-methylthiazol-5-yl)-N-(3- nitrophenyl) pyrimidin-2-amine. The target proposed compounds were synthesized using the derivative 6-(3,4-dimethoxyphenyl)-4-oxo-2-thioxo-1,2,3,4- tetrahydropyrimidine-5-carbonitrile (1) as a key starting compound. Some of the synthesized derivatives were selected as representative examples to evaluate their anti-proliferative activity against cultured human Hela cell line using doxorubicin as a reference drug and the results obtained were correlated with the data of molecular modeling simulation study. The structures of the novel derivatives were confirmed on the bases of micro-analytical and spectral data.
Novel dihydropyrimidines and its pyrazole derivatives: Synthesis and pharmacological screening
Ramesh,Bhalgat, Chetan M.
experimental part, p. 1882 - 1891 (2011/05/06)
In the present study, we have synthesized novel dihydropyrimidines (1a-j), their dimethylated adducts (2a-j), and hydrazine derivatives (3a-j) of 2a-j and subsequently their pyrazole derivatives (4a-j). Elemental analysis, IR, 1H NMR and mass s
