2. Academic Validation
  3. Newly synthesized 6-substituted piperazine/phenyl-9-cyclopentyl containing purine nucleobase analogs act as potent anticancer agents and induce apoptosis via inhibiting Src in hepatocellular carcinoma cells

Newly synthesized 6-substituted piperazine/phenyl-9-cyclopentyl containing purine nucleobase analogs act as potent anticancer agents and induce apoptosis via inhibiting Src in hepatocellular carcinoma cells

  • RSC Med Chem. 2023 Nov 10;14(12):2658-2676. doi: 10.1039/d3md00440f.
Ebru Bilget Guven 1 2,  Irem Durmaz Sahin 3 4,  Duygu Altiparmak 1,  Burak Servili 5,  Sebnem Essiz 2 5,  Rengul Cetin-Atalay 6 7,  Meral Tuncbilek 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University 06560, Yenimahalle Ankara Turkey [email protected].
  • 2 Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Kadir Has University 34083, Cibali-Fatih Istanbul Turkey.
  • 3 Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University 06800, Bilkent Ankara Turkey.
  • 4 School of Medicine, Koc University 34450, Sarıyer İstanbul Turkey.
  • 5 Graduate School of Science and Engineering, Bioinformatics and Genetics Program, Kadir Has University Fatih 34083 Istanbul Turkey.
  • 6 Cancer System Biology Laboratory, CanSyL, Graduate School of Informatics, Middle East Technical University 06800 Ankara Turkey.
  • 7 Section of Pulmonary and Critical Care Medicine, The University of Chicago Chicago IL 60637 USA.
PMID: 38107180 DOI: 10.1039/d3md00440f
Abstract

Newly synthesized 6-substituted piperazine/phenyl-9-cyclopentyl-containing purine nucleobase analogs were tested for their in vitro Anticancer activity against human Cancer cells. Compounds 15, 17-24, 49, and 56 with IC50 values less than 10 μM were selected for further examination on an enlarged panel of liver Cancer cell lines. Experiments revealed that compound 19 utilizes its high cytotoxic potential (IC50 < 5 μM) to induce Apoptosis in vitro. Compound 19 displayed a KINOMEscan selectivity score S35 of 0.02 and S10 of 0.01 and demonstrated a significant selectivity against anaplastic lymphoma kinase (ALK) and Bruton's tyrosine kinase (Btk) over Other kinases. Compounds 19, 21, 22, 23, and 56 complexed with ALK, Btk, and (discoidin domain-containing receptor 2) DDR2 were analyzed structurally for binding site interactions and binding affinities via molecular docking and molecular dynamics simulations. Compounds 19 and 56 displayed similar interactions with the activation loop of the kinases, while only compound 19 reached toward the multiple subsites of the active site. Cell cycle and signaling pathway analyses exhibited that compound 19 decreases phosho-Src, phospho-Rb, cyclin E, and CDK2 levels in liver Cancer cells, eventually inducing Apoptosis.

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