Abstract
The reaction of cyclohexan-1,3-dione ( 1 ) with ethyl orthoformate ( 2 ) in acetic acid gave the 2-(ethoxymethylene)cyclohexane-1,3-dione ( 3 ). The latter compound was used for further heterocyclization reactions to give thiophene, pyrazole and pyran derivatives. The cytotoxicity of the newly synthesized compound against the six cancer cell lines NUGC, DLDI, HA22T, HEPG2, HONE1 and MCF showed that compounds 5 , 10c , 10d , 13b , 14a , 18b , 18d , 18e and 20b were the most potent compounds. On the other hand, the toxicity of these compounds against shrimp larvae indicated that compounds 7a , 10c , 13b , 14a , 18b and 18d were non toxic against the tested organisms. Inhibition of the most potent compounds towards the tyrosine kinases c-kit, FIT-3, Vascular Endothelial Growth Factor Receptor (VEGFR)-2, Estimated Glomerular Filtration Rate (EGFR) and Platelet-Derived Growth Factor Receptor (PDGFR) revealed that compounds 5 , 10c , 10d , 13b , 18b , 18d , 18e and 20b were of the highest inhibitory effect. The Pim-1 kinase test revealed that compounds 10d , 18b and 20b were of the highest inhibitory effect. In addition, the c-Met enzymatic activities showed that compounds 10c , 10d , 18b , 18e , 19 and 20b showed higher potencies against c-Met kinase than the reference foretinib. On the other hand, compounds 7a , 7b , 10d , 13a , 13b , 14a , 14b , 16a , 16b, 17 , 18a-f , 19 and 20 showed higher inhibition towards PC-3 cell line than the reference SGI-1776. Compounds 10c and 18b were of common potencies and their molecular docking was described. KEY WORDS : Cyclohexane 1,3-dione, Pyrazole, Thiophene, Cytotoxicity, Tyrosine kinases Bull. Chem. Soc. Ethiop. 2018 , 32(2), 285-308. DOI: https://dx.doi.org/10.4314/bcse.v32i2.9
Highlights
Major progress in cancer chemotherapy requires new drugs to eradicate the entire neoplastic diseases in human being
Pyrazole derivatives have been reported in the literature to demonstrate anti-tumor [19] and kinase inhibitions [20]. Motivated by these results and in continuation of our previous work aimed at the synthesis of a new heterocyclic systems for anti-tumor evaluations [21,22,23] we report here the modification of cyclohexan-1,3-dione into a variety of novel condensed pyrazole, thiophene and isoxazole derivatives incorporating the cyclohexane moiety
We studied the activity of the synthesized compounds towards PC-3 prostate cancer cell line, results are demonstrated through Table 3
Summary
Major progress in cancer chemotherapy requires new drugs to eradicate the entire neoplastic diseases in human being. Many planar heteroaromatic derivatives have shown anti-proliferative activity in vitro and some of them are important anticancer drugs [8,9,10]. Some of these types of compounds have the indazole nucleus which is a structural component of a large number of biologically active natural and unnatural compounds. The high anti-proliferative activity of nitrogen containing heterocycles in two human breast cancer cell lines (MDAMB 231 and MCF-7) was reported and the authors were able to show that the tubulin is the primary target of these agents inhibiting its polymerization [11,12,13].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
