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Bioorg Chem. 2018 Oct;80:545-554. doi: 10.1016/j.bioorg.2018.06.033. Epub 2018 Jun 30.

Tetrahydroindolocarbazoles (THICZs) as new class of urokinase (uPA) inhibitors: Synthesis, anticancer evaluation, DNA-damage determination, and molecular modelling study.

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Department of Applied Organic Chemistry, National Research Centre, 12622 Dokki, Giza, Egypt; Chemistry Department, Faculty of Sciences, King Khaled University, Saudi Arabia.
Chemistry Department, Faculty of Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates.
Chemistry Department, Faculty of Science, Al Azhar University, Cairo, Egypt.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt. Electronic address:
Biochemistry Department, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki 12622, Giza, Egypt.
Cell Biology Department, National Research Centre, 12622-Dokki, Egypt.
Department of Applied Organic Chemistry, National Research Centre, 12622 Dokki, Giza, Egypt. Electronic address:


Tetrahydroindolocarbazoles (THICZs) with versatile substituents, have been designed, synthesized, structure characterized, then investigated for their in-vitro anticancer screening, urokinase inhibition (uPA) evaluated, DNA-damage determination was further explored. Compounds 5, 8, 10 and 17 displayed the most promising antitumor activities against the breast cancer cell line as compared to the standard drug, doxorubicin with IC50 = 5.24 ± 0.37, 4.00 ± 0.52, 7.20 ± 0.90 and 9.60 ± 1.10 µg/ml (versus 3.30 ± 0.48 µg/ml for doxorubicin). Compounds 5, 8, 10 and 17 represents the most significant uPA inhibitors of our study with IC50 of 3.80, 2.70. 4.75, 10.80 (ng/ml) respectively. The expression levels of CDKN2A gene were decreased in 8, 10 and 17 cell lines as compared to those in positive control samples. Cell lines treated with 5, 8, 10 and 17 clearly observed a high score of damaged DNA cells. A deeper examination revealed that our hetroaromatics showed an extensive hydrogen bonding interactions that is required in the S pocket which is important for activity Arg 217, Gly 219, Gly 216, Lys 143 and Ser 190. So we present THICZs as promising uPA inhibitors expected as significant promise for further development as anti-invasiveness drugs.


Breast cancer; DNA damage and molecular modelling; Tetrahydroindolocarbazoles; Urokinase inhibition

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