Design, synthesis, crystal structures and biological evaluation of some 1,3-thiazolidin-4-ones as dual CDK2/EGFR potent inhibitors with potential apoptotic antiproliferative effects
A series of novel thiazolidine-4-one derivatives was synthesized by reacting 1,4-disubstituted hydrazine carbothioamides with diethyl azodicarboxylate. The structures were confirmed by spectroscopic data as well as single-crystal X-ray analyses. The antiproliferative activity of the synthesized comp...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-11-01
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| Series: | Arabian Journal of Chemistry |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878535222005962 |
| _version_ | 1797990468433215488 |
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| author | Hendawy N. Tawfeek Alaa A. Hassan S. Bräse M. Nieger Yaser A. Mostafa Hesham A.M. Gomaa Bahaa G.M. Youssif Essmat M. El-Shreef |
| author_facet | Hendawy N. Tawfeek Alaa A. Hassan S. Bräse M. Nieger Yaser A. Mostafa Hesham A.M. Gomaa Bahaa G.M. Youssif Essmat M. El-Shreef |
| author_sort | Hendawy N. Tawfeek |
| collection | DOAJ |
| description | A series of novel thiazolidine-4-one derivatives was synthesized by reacting 1,4-disubstituted hydrazine carbothioamides with diethyl azodicarboxylate. The structures were confirmed by spectroscopic data as well as single-crystal X-ray analyses. The antiproliferative activity of the synthesized compounds was investigated against four human cancer cell lines using an MTT assay. Compounds 5d, 5e, and 5f revealed the most potent antiproliferative activity with GI50 values ranging from 0.70 µM to 1.20 µM, compared to doxorubicin GI50 value = 1.10 µM. Compounds 5d, 5e, and 5f were further investigated for their inhibitory activities against CDK2 and EGFR as potential targets for their molecular mechanism. Compounds 5e and 5f have showed potent inhibitory activity to CDK2 enzyme with IC50 values of 18 and 14 nM, which is more potent than the reference dinaciclib (IC50 = 20 nM). Moreover, compounds 5e and 5f were the most potent EGFR inhibitors, with IC50 values of 93 and 87 nM, respectively, compared to the reference erlotinib (IC50 = 70 nM). In addition, the most potent derivatives were tested for their apoptotic activity against caspases 3, 8, and 9, and the results showed that compounds 5d, 5e, and 5f revealed a greater increase in active caspases 3,8 and 9 than doxorubicin. Also, compounds 5d, 5e, and 5f elevated cytochrome C levels in the MCF-7 human breast cancer cell line by about 15.5, 15.8, and 16.5 times, respectively. Finally, a molecular docking study was performed to investigate the binding sites of these compounds within the active sites of CDK2 and EGFR targets, and the results confirmed that the most potent CDK2 and EGFR inhibitor 5h also have showed the highest docking score. |
| first_indexed | 2024-04-11T08:37:03Z |
| format | Article |
| id | doaj.art-c1cf0f9517054a93a50d4eb5a1322099 |
| institution | Directory Open Access Journal |
| issn | 1878-5352 |
| language | English |
| last_indexed | 2024-04-11T08:37:03Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Arabian Journal of Chemistry |
| spelling | doaj.art-c1cf0f9517054a93a50d4eb5a13220992022-12-22T04:34:19ZengElsevierArabian Journal of Chemistry1878-53522022-11-011511104280Design, synthesis, crystal structures and biological evaluation of some 1,3-thiazolidin-4-ones as dual CDK2/EGFR potent inhibitors with potential apoptotic antiproliferative effectsHendawy N. Tawfeek0Alaa A. Hassan1S. Bräse2M. Nieger3Yaser A. Mostafa4Hesham A.M. Gomaa5Bahaa G.M. Youssif6Essmat M. El-Shreef7Unit of Occupational of Safety and Health, Administration Office of Minia University, El-Minia 61519, Egypt; Chemistry Department, Faculty of Science, Minia University, El-Minia 61519, EgyptChemistry Department, Faculty of Science, Minia University, El-Minia 61519, EgyptInstitute of Biological and Chemical Systems, IBCS-FMS, Karlsruhe Institute of Technology, 76131 Karlsruhe, GermanyDepartment of Chemistry, University of Helsinki, PO Box 55, A. I. Virtasen aukio 1, 00014 Helsinki, FinlandPharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, EgyptPharmacology Department, College of Pharmacy, Jouf University, Sakaka 72314, Saudi ArabiaPharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt; Corresponding author.Chemistry Department, Faculty of Science, Minia University, El-Minia 61519, EgyptA series of novel thiazolidine-4-one derivatives was synthesized by reacting 1,4-disubstituted hydrazine carbothioamides with diethyl azodicarboxylate. The structures were confirmed by spectroscopic data as well as single-crystal X-ray analyses. The antiproliferative activity of the synthesized compounds was investigated against four human cancer cell lines using an MTT assay. Compounds 5d, 5e, and 5f revealed the most potent antiproliferative activity with GI50 values ranging from 0.70 µM to 1.20 µM, compared to doxorubicin GI50 value = 1.10 µM. Compounds 5d, 5e, and 5f were further investigated for their inhibitory activities against CDK2 and EGFR as potential targets for their molecular mechanism. Compounds 5e and 5f have showed potent inhibitory activity to CDK2 enzyme with IC50 values of 18 and 14 nM, which is more potent than the reference dinaciclib (IC50 = 20 nM). Moreover, compounds 5e and 5f were the most potent EGFR inhibitors, with IC50 values of 93 and 87 nM, respectively, compared to the reference erlotinib (IC50 = 70 nM). In addition, the most potent derivatives were tested for their apoptotic activity against caspases 3, 8, and 9, and the results showed that compounds 5d, 5e, and 5f revealed a greater increase in active caspases 3,8 and 9 than doxorubicin. Also, compounds 5d, 5e, and 5f elevated cytochrome C levels in the MCF-7 human breast cancer cell line by about 15.5, 15.8, and 16.5 times, respectively. Finally, a molecular docking study was performed to investigate the binding sites of these compounds within the active sites of CDK2 and EGFR targets, and the results confirmed that the most potent CDK2 and EGFR inhibitor 5h also have showed the highest docking score.http://www.sciencedirect.com/science/article/pii/S1878535222005962Huisgen cycloaddition1,3-Thiazolidin-4-onesCDK2EGFRDiethyl azodicarboxylate |
| spellingShingle | Hendawy N. Tawfeek Alaa A. Hassan S. Bräse M. Nieger Yaser A. Mostafa Hesham A.M. Gomaa Bahaa G.M. Youssif Essmat M. El-Shreef Design, synthesis, crystal structures and biological evaluation of some 1,3-thiazolidin-4-ones as dual CDK2/EGFR potent inhibitors with potential apoptotic antiproliferative effects Arabian Journal of Chemistry Huisgen cycloaddition 1,3-Thiazolidin-4-ones CDK2 EGFR Diethyl azodicarboxylate |
| title | Design, synthesis, crystal structures and biological evaluation of some 1,3-thiazolidin-4-ones as dual CDK2/EGFR potent inhibitors with potential apoptotic antiproliferative effects |
| title_full | Design, synthesis, crystal structures and biological evaluation of some 1,3-thiazolidin-4-ones as dual CDK2/EGFR potent inhibitors with potential apoptotic antiproliferative effects |
| title_fullStr | Design, synthesis, crystal structures and biological evaluation of some 1,3-thiazolidin-4-ones as dual CDK2/EGFR potent inhibitors with potential apoptotic antiproliferative effects |
| title_full_unstemmed | Design, synthesis, crystal structures and biological evaluation of some 1,3-thiazolidin-4-ones as dual CDK2/EGFR potent inhibitors with potential apoptotic antiproliferative effects |
| title_short | Design, synthesis, crystal structures and biological evaluation of some 1,3-thiazolidin-4-ones as dual CDK2/EGFR potent inhibitors with potential apoptotic antiproliferative effects |
| title_sort | design synthesis crystal structures and biological evaluation of some 1 3 thiazolidin 4 ones as dual cdk2 egfr potent inhibitors with potential apoptotic antiproliferative effects |
| topic | Huisgen cycloaddition 1,3-Thiazolidin-4-ones CDK2 EGFR Diethyl azodicarboxylate |
| url | http://www.sciencedirect.com/science/article/pii/S1878535222005962 |
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