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Development of pyrolo[2,3-c]pyrazole, pyrolo[2,3-d]pyrimidine and their bioisosteres as novel CDK2 inhibitors with potent in vitro apoptotic anti-proliferative activity: Synthesis, biological evaluation and molecular dynamics investigations.
Azmy, Eman M; Hagras, Mohamed; Ewida, Menna A; Doghish, Ahmed S; Gamil Khidr, Emad; El-Husseiny, Ahmed A; Gomaa, Maher H; Refaat, Hanan M; Ismail, Nasser S M; Nassar, Ibrahim F; Lashin, Walaa H.
Afiliación
  • Azmy EM; Chemistry Department, Faculty of Women, Ain Shams University, Heliopolis, Egypt.
  • Hagras M; Department of Pharmaceutical Organic Chemistry, College of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
  • Ewida MA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Future University in Egypt, Cairo 11835, Egypt.
  • Doghish AS; Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
  • Gamil Khidr E; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
  • El-Husseiny AA; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt; Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City 11829, Cairo, Egypt.
  • Gomaa MH; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
  • Refaat HM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Future University in Egypt, Cairo 11835, Egypt.
  • Ismail NSM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Future University in Egypt, Cairo 11835, Egypt. Electronic address: Nasser.saad@fue.edu.eg.
  • Nassar IF; Faculty of Specific Education, Ain Shams University, 365 Ramsis Street, Abassia, Cairo, Egypt.
  • Lashin WH; Chemistry Department, Faculty of Women, Ain Shams University, Heliopolis, Egypt.
Bioorg Chem ; 139: 106729, 2023 10.
Article en En | MEDLINE | ID: mdl-37467621
Inhibiting the CDK2/cyclin A2 enzyme has been validated in multiple clinical manifestations related to multiple types of cancer. Herein, novel series of pyrolo[2,3-c]pyrazole, pyrolo[2,3-c]isoaxazole and pyrolo[2,3-d]pyrimidine, pyrolo[3,2-c]pyridine & indole based analogs were designed, synthesized and biologically evaluated for their in vitro antiproliferative activity where the obtained results revealed that most of the newly synthesized compounds showed significant cytotoxic activity towards MCF-7 (breast cancer cell lines) and HepG-2 (hepatocellular carcinoma) with IC50 ranging from 3.20 µM to 10.05 µM & from 2.18 µM to 13.49 µM, respectively, compared to that of Sorafenib (IC50 9.76 & 13.19 µM, respectively). The in vitro inhibitory profile of the most promising compounds (9, 11, 14, 15, 16, 17 and 20) towards CDK2/CyclinA2 was evaluated. Compounds 14 & 15 exhibited potent inhibitory profile against CDK2 with (IC50 0.11 and 0.262 µM, respectively comparable to Sorafenib IC50 0.184 µM. Western blotting of 14 & 15 at MCF-7 cell line confirmed the diminishing activity on CDK2. Furthermore, both compounds exserted a significant cell cycle arrest and apoptosis. Moreover, the normal cell line cytotoxicity for both compounds revealed low cytotoxic results in normal cells rather than cancer cells. Molecular docking and dynamic simulation validated the potentiality of the newly synthesized compounds to have high binding affinity within CDK2 binding pocket. 3DQSAR pharmacophore, in-silico ADME/TOPKAT studies and drug-likeness showed proper pharmacokinetic properties and helped in structure requirements prediction. The obtained model and pattern of substitution could be used for further development of CDK2 inhibitors.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Simulación de Dinámica Molecular / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Bioorg Chem Año: 2023 Tipo del documento: Article País de afiliación: Egipto Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Simulación de Dinámica Molecular / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Bioorg Chem Año: 2023 Tipo del documento: Article País de afiliación: Egipto Pais de publicación: Estados Unidos