Discovery of tropinone-thiazole derivatives as potent caspase 3/7 activators, and noncompetitive tyrosinase inhibitors with high antiproliferative activity: Rational design, one-pot tricomponent synthesis, and lipophilicity determination.
Eur J Med Chem
; 175: 162-171, 2019 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-31082763
ABSTRACT
We have designed novel tropinone-thiazole derivatives that showed high antiproliferative activity against a variety of cancer cell lines via caspase 3/7 activation mechanism. Among the derivatives, compounds 3b-3h were found to exhibit high activity against human leukemia (MV4-11), human lung carcinoma (A549), human breast carcinoma (MCF-7), and skin melanoma (B16-F10) cancer cell lines, with IC50 values of 5.43-11.06⯵M. The lead compound 3g increases caspase 3/7 activity in A549â¯cells 25 times more than the control, and 2 times more than reference drug camptothecin. We have also found that tropinone-thiazole derivatives exhibit high tyrosinase inhibitory activity. The lead compounds 3g and 3h showed tyrosinase inhibition effect, with IC50 values 3.22 and 3.51⯵M, respectively. These inhibitory activities are 22 times higher than the activity of kojic acid (IC50 72.27⯵M) and 120 times higher than activity of ascorbic acid (IC50 386.5⯵M). For compounds 3g and 3h, the experimentally determined lipophilicity correlates very well with their enzymatic activities. These data suggest that presented compounds could constitute lead anticancer drug candidates.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Tiazóis
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Tropanos
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Monofenol Mono-Oxigenase
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Ativadores de Enzimas
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Proliferação de Células
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Inibidores Enzimáticos
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Caspase 3
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Caspase 7
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Descoberta de Drogas
Limite:
Animals
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Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Polônia