Synthesis of novel dimeric compounds containing triazole using click method and their selective antiproliferative and proapoptotic potential via mitochondrial apoptosis signaling

• Published in: Medicinal chemistry research Vol. 29; no. 4; pp. 643 - 655
• Main Authors: Karabulut, H. R. Ferhat, Karatavuk, Ali Osman, Ozyildirim, Hasan, Doğanlar, Oğuzhan, Doğanlar, Zeynep Banu
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-04-2020; Springer Nature B.V
• Subjects: Annexin V; Antiproliferatives; Apoptosis; Biochemistry; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cell Biology; Cell death; Cell proliferation; Cell viability; Cellular structure; Cervical cancer; Cytotoxicity; Dimers; Embryo fibroblasts; Mitochondria; Original Research; Pharmacology/Toxicology; Pyridines; Synthesis; Toxicity; Triazoles; HeLa; Click chemistry; Gene expression; MCF-7; Lithocholic acid
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-020-02510-x

In this study, the main aim was synthesis of dimeric compounds, which contain lithocholic acid and a triazole structure to investigate the selective cellular and molecular antiproliferative and proapoptotic potential of these products in healthy embryonic fibroblast (MEF), cervix cancer (HeLa), and breast cancer (MCF-7) cells. Four ester (
5a
–
d
) and five dimeric (
6a
–
d, 7
) out of nine novel compounds were obtained. First of all, lithocholic acid was converted to methyl lithocholate and then it was reacted with certain alkynoic acids (
a
–
d
) to obtain its alkynoate derivatives (
5a
–
d
). Finally, these compounds were converted to dimers (
6a
–
d
) by using 2,6-bis(azidomethyl)pyridine via the click method. Our result indicate that, treatment with dimeric compounds can selectively decrease the cell viability and proliferation in cervix cancer HeLa and breast cancer MCF-7 cells, except 7 which caused a strong cytotoxicity on healthy MEF cells. According to MTT assay, Nucblue cell stain and Annexin V/Propodium iodide molecular probe staining, 100 µM concentrations of the dimeric compounds was sufficient in inducing death and apoptotic cell ratio in HeLa and MCF-7 breast cancer cells selectively. In brief, the present study indicates that most effective dimeric compounds are
6a
and
6b
, which have the highest IC
50
(345.8–342.6 µM) value on healthy cell and the lowest IC
50
value in both cervix (49.2–36.9 µM) and breast (23.0–66.1 µM) cancer cells especially long-term treatment and which triggers apoptosis pathway specifically.