2. Academic Validation
  3. An investigative study of antitumor properties of a novel thiazolo[4,5-d]pyrimidine small molecule revealing superior antitumor activity with CDK1 selectivity and potent pro-apoptotic properties

An investigative study of antitumor properties of a novel thiazolo[4,5-d]pyrimidine small molecule revealing superior antitumor activity with CDK1 selectivity and potent pro-apoptotic properties

  • Bioorg Med Chem. 2020 Sep 1;28(17):115633. doi: 10.1016/j.bmc.2020.115633.
Sameh H Mohamed 1,  Hossam R Elgiushy 2,  Heba Taha 3,  Sherif F Hammad 4,  Nageh A Abou-Taleb 2,  Khaled A M Abouzid 5,  Hussein Al-Sawaf 6,  Zeinab Hassan 3
Affiliations

Affiliations

  • 1 Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr 11829, Cairo, Egypt. Electronic address: [email protected].
  • 2 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, Ain Helwan 11795, Cairo, Egypt.
  • 3 Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Ain Helwan 11795, Helwan, Cairo, Egypt.
  • 4 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, Ain Helwan 11795, Cairo, Egypt; Basic and Applied Sciences Institute, Egypt-Japan University of Science and Technology (E-JUST), New Borg El-Arab City, 21934 Alexandria, Egypt.
  • 5 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia 11566, Cairo, Egypt; Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, Egypt.
  • 6 Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr 11829, Cairo, Egypt.
PMID: 32773088 DOI: 10.1016/j.bmc.2020.115633
Abstract

New thiazolo[4,5-d]pyrimidine analogues were synthesized and biologically assessed in-vitro for their antineoplastic activity. The growth inhibitory effects of these compounds were assessed through the National Cancer Institute-United States of America (NCI-USA) Anticancer screening program. Compound5(7-Chloro-3-(2,4-dimethoxyphenyl)-5-methylthiazolo[4,5-d]pyrimidine-2(3H)-thione) was found to have a potent and broad-spectrum cytotoxic action against NCI panel with GI50 (50% growth inhibition concentration) mean graph midpoint (MG-MID) = 2.88 µM. MTT assay was used to determine IC50 values of the most potent agent against HCT-116 colorectal carcinoma and WI-38 human lung fibroblast cell lines; 5.33 µM ± 0.69 and 21.69 µM ± 1.04, respectively. Flow cytometric analysis revealed that compound5triggered Apoptosis and G2/M cell cycle arrest. The ability of compound5to inhibit CDK1 (Cyclin-Dependent Kinase 1)/Cyclin B complex was evaluated, and its IC50 value was 97 nM ± 2.33. Moreover, according to the gene expression analysis, compound5up-regulated p53, Bax, cytochrome c, caspases-3,-8 and-9 besides down-regulated Bcl-2. In conclusion, compound5exerted a potent pro-apoptotic activity through the activation of the intrinsic apoptotic pathway and arrested the cell cycle at the G2/M phase.

Keywords

Anticancer activity; Apoptosis; Cell cycle arrest; Thiazolo[4,5-d]pyrimidine.

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