Thieno[2,3-c]isoquinolines: A novel chemotype of antiproliferative agents inducing cellular apoptosis while targeting the G2/M phase and Tubulin

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Marae I.S.; Maklad R.M.; Samir S.; Bakhite E.A.; Sharmoukh W.

Journal: Drug Development Research

Publisher: John Wiley and Sons Inc

Publication Date: 31 March 2023

Volume / Issue: Volume 84 / Issue 4

Pages: 747–766

ISSN: 2724391

DOI: 10.1002/ddr.22054

Scopus: View on Scopus

PubMed: 36999479

Document Type: Article

Access: All Open Access; Bronze Open Access

Authors and Affiliations

Marae I.S., Department of Chemistry, Faculty of Science, Assiut University, Assiut, Egypt; Maklad R.M., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt, Institute of Drug Discovery and Development, Kafrelsheikh University, Kafrelsheikh, Egypt; Samir S., Department of Biochemistry and Molecular Biology, Theodor Bilharz Research Institute, Giza, Egypt; Bakhite E.A., Department of Chemistry, Faculty of Science, Assiut University, Assiut, Egypt; Sharmoukh W., Department of Inorganic Chemistry, National Research Centre, Giza, Egypt

Abstract

In the era of modern synthetic methodology and advanced bio-evaluation techniques and considering the notorious history of hepatocellular carcinoma (HCC), hopeful expectations regarding novel bioactive chemotypes have grown dramatically. Among the widely versatile motifs in drug discovery studies are isoquinoline and thieno[2,3-b]pyridine. Herein, the molecular merging of both motifs evoked thieno[2,3-c]isoquinoline as a novel antiproliferative chemotype being hardly studied against HCC. Accordingly, compound series 4, 5, 7 and 8 were synthesized and bioevaluated against the HepG2 cell line. The role of C7-Ac/C8-OH substituents, C8-C9 unsaturation, 1H-pyrrol-1-yl ring closure at C1-NH2 and C6-Ph p-halo-substitution were biologically studied and successfully furnished the lead 5b while showing safe profile against Vero cells. Further, flow cytometric and Annexin V-FITC/PI apoptotic bio-investigations of 5b unveiled remarkable cell cycle arrest at the G2/M phase besides a 60-fold increase in apoptosis. The use of a DFT conformational study followed by Molecular docking and molecular mechanics/generalized born surface area scoring evoked potential tubulin-targeting activity of 5b at colchicine-binding site, which was confirmed by experimental evidence (Tub Inhib IC50 = 71 µM vs. 14 µM for colchicine). Accordingly, preserving C7-acetyl and optimizing halogen position while preserving [6S,7R]-stereochemistry is crucial for optimum binding to colchicine binding site of tubulin. © 2023 Wiley Periodicals LLC.

Keywords

anticancer; apoptosis; flow cytometry; molecular modeling; thieno[2,3-c]isoquinoline; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Division; Cell Line, Tumor; Cell Proliferation; Chlorocebus aethiops; Colchicine; Drug Screening Assays, Antitumor; Humans; Isoquinolines; Liver Neoplasms; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship; Tubulin; Tubulin Modulators; Vero Cells; 1 amino 2 acetyl 5,8 dimethyl 6 phenyl 6,7 dihydrothieno[2,3 c]isoquinoline; 1 amino 2,7 diacetyl 5,8 dimethyl 8 hydroxy 6 phenyl 6,7,8,9 tetrahydrothieno[2,3 c]isoquinoline; 2 acetyl 5,8 dimethyl 6 phenyl 1 pyrrolyl 6,7 dihydrothieno[2,3 c]isoquinoline; 2,7 diacetyl 5,8 dimethyl 8 hydroxy 6 phenyl 1 (1h pyrrol 1 yl)6,7,8,9 tetrahydrothieno[2,3 c]isoquinoline; antineoplastic agent; fluorescein isothiocyanate; isoquinoline derivative; lipocortin 5; thieno[2,3 b]pyridine derivative; unclassified drug; tubulin modulator; antiproliferative activity; Article; binding site; cell cycle G2 phase; cell cycle M phase; controlled study; drug development; drug synthesis; evoked response; Hep-G2 cell line; human; human cell; liver cell carcinoma; molecular mechanics; stereochemistry; structure activity relation; surface area; Vero cell line; animal; chemical structure; chemistry; drug screening; liver tumor; metabolism; molecular docking; tumor cell line

Citation Information

Scopus Citations: 8

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