Tetrahydroindolocarbazoles (THICZs) as new class of urokinase (uPA) inhibitors: Synthesis, anticancer evaluation, DNA-damage determination, and molecular modelling study.
Bioorg Chem
; 80: 545-554, 2018 10.
Article
em En
| MEDLINE
| ID: mdl-30014922
ABSTRACT
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 IC50â¯=â¯5.24⯱â¯0.37, 4.00⯱â¯0.52, 7.20⯱â¯0.90 and 9.60⯱â¯1.10⯵g/ml (versus 3.30⯱â¯0.48⯵g/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.
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Base de dados:
MEDLINE
Assunto principal:
Carbazóis
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Ativador de Plasminogênio Tipo Uroquinase
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Neoplasias
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Antineoplásicos
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article