Towards breast cancer targeting: Synthesis of tetrahydroindolocarbazoles, antibreast cancer evaluation, uPA inhibition, molecular genetic and molecular modelling studies

• Published in: Bioorganic chemistry Vol. 93; p. 103332
• Main Authors: Ahmed, Entesar M., Sarhan, Alaadin E., El-Naggar, Dina H., Khattab, Reham R., El-Naggar, Mohamed, El-Messery, Shahenda M., Hassan, Ghada S., Mounier, Marwa M., Mahmoud, Khaled, Ali, Neama I., Mahrous, Karima F., Ali, Mamdouh M., El Sayed, Mardia T.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-12-2019
• Subjects: Breast cancer; DNA genetics; Molecular modelling studies; Tetrahydroindolocarbazoles; Urokinase inhibition; DNA genetics; Molecular modelling studies; Tetrahydroindolocarbazoles; Breast cancer; Urokinase inhibition
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103332

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•New series of tetrahydroindolocarbazole derivatives has been synthesized.•Compound 11 expressed GI% values of 99.9% against MCF7 breast cancer cell line compared to Doxurubucin.•Compound 11 showed a remarkable decrease of uPA level to 3.5 ng/ml compared to DOX.•Compounds 5, 11 and 15 showed significant decrease in expression of MTAP and CDKN2A.•Compounds 5, 11 showed remarkable binding uPA active site via hydrogen binding interactions.
A series of some new tetrahydroindolocarbazole derivatives has been synthesized. The structure of the synthesized compounds has been confirmed by different spectroscopic techniques such as IR, NMR, elemental analysis and mass spectrometry. The target compounds were evaluated for their antitumor activity against breast cancer cell line MCF-7, their GI% and their LC50 have been determined. Six of the synthesized compounds exhibited GI% values against MCF-7 cell lines exceeding 70% ranging from 71.9 to 85.0% in addition that compound 11 expressed GI% values of 99.9% and considered the most active derivatives among the synthesized ones. Compound 11 showed a remarkable decrease of u PA level to 3.5 ng/ml compared to DOX. Compound 5, 11 and 15 showed significant decrease in expression of MTAP and CDKN2A, in addition to a remarkable decrease in DNA damage comet assay method. Molecular modeling studies were performed to interpretate the behavior of active ligands as uPA inhibitors.