New Genetic Bomb Trigger: Design, Synthesis, Molecular Dynamics Simulation, and Biological Evaluation of Novel BIBR1532-Related Analogs Targeting Telomerase against Non-Small Cell Lung Cancer

Telomeres serve a critical function in cell replication and proliferation at every stage of the cell cycle. Telomerase is a ribonucleoprotein, responsible for maintaining the telomere length and chromosomal integrity of frequently dividing cells. Although it is silenced in most human somatic cells, telomere restoration occurs in cancer cells because of telomerase activation or alternative telomere lengthening. The telomerase enzyme is a universal anticancer target that is expressed in 85–95% of cancers. BIBR1532 is a selective non-nucleoside potent telomerase inhibitor that acts by direct noncompetitive inhibition. Relying on its structural features, three different series were designed, and 30 novel compounds were synthesized and biologically evaluated as telomerase inhibitors using a telomeric repeat amplification protocol (TRAP) assay. Target compounds 29a, 36b, and 39b reported the greatest inhibitory effect on telomerase enzyme with IC50 values of 1.7, 0.3, and 2.0 μM, respectively, while BIBR1532 displayed IC50 = 0.2 μM. Compounds 29a, 36b, and 39b were subsequently tested using a living-cell TRAP assay and were able to penetrate the cell membrane and inhibit telomerase inside living cancer cells. Compound 36b was tested for cytotoxicity against 60 cancer cell lines using the NCI (USA) procedure, and the % growth was minimally impacted, indicating telomerase enzyme selectivity. To investigate the interaction of compound 36b with the telomerase allosteric binding site, molecular docking and molecular dynamics simulations were used. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Authors
Tawfik H.O.1 , El-Hamaky A.A.1 , El-Bastawissy E.A.1 , Shcherbakov K.A.2 , Veselovsky A.V. 2 , Gladilina Y.A. 2 , Zhdanov D.D. 2, 3 , El-Hamamsy M.H.1
Journal
Publisher
MDPI AG
Number of issue
4
Language
English
Status
Published
Number
481
Volume
15
Year
2022
Organizations
  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt
  • 2 Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya St. 10/8, Moscow, 119121, Russian Federation
  • 3 Department of Biochemistry, Peoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya St. 6, Moscow, 117198, Russian Federation
Keywords
2-Amino-3-cyanothiophene; BIBR1532; inhibitors; lung cancer; molecular dynamics simulation; telomerase enzyme; TRAP assay
Date of creation
06.07.2022
Date of change
06.07.2022
Short link
https://repository.rudn.ru/en/records/article/record/83692/
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