Design, Synthesis, In Vitro, and In Silico Studies of New N5-Substituted-pyrazolo[3,4- d]pyrimidinone Derivatives as Anticancer CDK2 Inhibitors

Waheed A Zaki; Selwan M El-Sayed; Mohamed Alswah; Ahmed El-Morsy; Ashraf H Bayoumi; Abrahman S Mayhoub; Walaa H Moustafa; Aeshah A Awaji; Eun Joo Roh; Ahmed H E Hassan; Kazem Mahmoud

doi:10.3390/ph16111593

Design, Synthesis, In Vitro, and In Silico Studies of New N⁵-Substituted-pyrazolo[3,4- d]pyrimidinone Derivatives as Anticancer CDK2 Inhibitors

Pharmaceuticals (Basel). 2023 Nov 11;16(11):1593. doi: 10.3390/ph16111593.

Authors

Waheed A Zaki¹, Selwan M El-Sayed², Mohamed Alswah¹, Ahmed El-Morsy^{1

3}, Ashraf H Bayoumi¹, Abrahman S Mayhoub^{1

4}, Walaa H Moustafa⁵, Aeshah A Awaji⁶, Eun Joo Roh^{7

8}, Ahmed H E Hassan², Kazem Mahmoud⁹

Affiliations

¹ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
² Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
³ Pharmaceutical Chemistry Department, College of Pharmacy, The Islamic University, Najaf 54001, Iraq.
⁴ Nanoscience Program, University of Science and Technology, Zewail City of Science and Technology, October Gardens, 6th of October, Giza 12578, Egypt.
⁵ Microbiology and Immunology Department, Faculty of Pharmacy, Helwan University, Cairo 19448, Egypt.
⁶ Department of Biology, Faculty of Science, University College of Taymaa, University of Tabuk, Tabuk 71491, Saudi Arabia.
⁷ Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
⁸ Division of Bio-Medical Science & Technology, University of Science and Technology, Daejeon 34113, Republic of Korea.
⁹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City 11829, Egypt.

Abstract

CDK2 is a key player in cell cycle processes. It has a crucial role in the progression of various cancers. Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are two common cancers that affect humans worldwide. The available therapeutic options suffer from many drawbacks including high toxicity and decreased specificity. Therefore, there is a need for more effective and safer therapeutic agents. A series of new pyrazolo[3,4-d]pyrimidine analogs was designed, synthesized, and evaluated as anticancer agents against the CRC and HCC cells, HCT116, and HepG2, respectively. Pyrazolo[3,4-d]pyrimidinone derivatives bearing N⁵-2-(4-halophenyl) acetamide substituents were identified as the most potent amongst evaluated compounds. Further evaluation of CDK2 kinase inhibition of two potential cytotoxic compounds 4a and 4b confirmed their CDK2 inhibitory activity. Compound 4a was more potent than the reference roscovitine regarding the CDK2 inhibitory activity (IC₅₀ values: 0.21 and 0.25 µM, respectively). In silico molecular docking provided insights into the molecular interactions of compounds 4a and 4b with important amino acids within the ATP-binding site of CDK2 (Ile10, Leu83, and Leu134). Overall, compounds 4a and 4b were identified as interesting CDK2 inhibitors eliciting antiproliferative activity against the CRC and HCC cells, HCT116 and HepG2, respectively, for future further investigations and development.

Keywords: CDK2; anticancer agents; colorectal cancer; liver cancer; pyrazolo[3,4-d]pyrimidine analogs.

Abstract

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