Your browser doesn't support javascript.
loading
Design, synthesis, and anticancer activity of some novel 1H-benzo[d]imidazole-5-carboxamide derivatives as fatty acid synthase inhibitors.
Singh, Shailendra; Paul, Subarno; Brás, Natércia F; Kundu, Chanakya N; Karthikeyan, Chandrabose; Moorthy, N S Hari Narayana.
Afiliación
  • Singh S; Cancept Therapeutics Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Lalpur, Amarkantak, (MP) 484887, India. Electronic address: singh26shail@gmail.com.
  • Paul S; School of Biotechnology, KIIT deemed to be University, Campus-11, Patia, Bhubaneswar, Orissa 751024, India. Electronic address: subarno.biotech@gmail.com.
  • Brás NF; LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal.
  • Kundu CN; School of Biotechnology, KIIT deemed to be University, Campus-11, Patia, Bhubaneswar, Orissa 751024, India. Electronic address: cnkundu@kiitbiotech.ac.in.
  • Karthikeyan C; Cancept Therapeutics Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Lalpur, Amarkantak, (MP) 484887, India. Electronic address: karthikeyan_c@igntu.ac.in.
  • Moorthy NSHN; Cancept Therapeutics Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Lalpur, Amarkantak, (MP) 484887, India. Electronic address: hari.nmoorthy@gmail.com.
Bioorg Chem ; 138: 106658, 2023 09.
Article en En | MEDLINE | ID: mdl-37331170
Multiple malignancies exhibit aberrant FASN expression, associated with enhanced de novo lipogenesis to meet the metabolic demands of rapidly proliferating tumour cells. Furthermore, elevated FASN expression has been linked to tumour aggressiveness and poor prognosis in a variety of malignant tumours, making FASN is an attractive target for anticancer drug discovery. Herein, we report the de novo design and synthesis of (2-(2-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperazin-1-yl)methanone derivatives as novel FASN inhibitors with potential therapeutic applications in breast and colorectal cancers. Twelve (2-(2-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperazin-1-yl)methanone derivatives (CTL) were synthesized and evaluated for FASN inhibition and cytotoxicity against colon cancer (HCT-116, Caco-2 cell lines), breast cancer (MCF-7 cell line) and normal cell line (HEK-293). Compounds CTL-06 and CTL-12 were chosen as the most promising lead molecules based on FASN inhibition and selective cytotoxicity profiles against colon and breast cancer cell lines. Compounds CTL-06 and CTL-12 demonstrate promising FASN inhibitory activity at IC50 of 3 ± 0.25 µM and 2.5 ± 0.25 µM when compared to the FASN inhibitor orlistat, which has an IC50 of 13.5 ± 1.0 µM. Mechanistic investigations on HCT-116 revealed that CTL-06 and CTL-12 treatment led to cell cycle arrest in Sub-G1/S phase along with apoptosis induction. Western blot studies indicated that CTL-06 and CTL-12 inhibited FASN expression in a dose-dependent manner. CTL-06 and CTL-12 treatment of HCT-116 cells enhanced caspase-9 expression in a dose-dependent manner, while upregulating proapoptotic marker Bax and downregulating antiapoptotic Bcl-xL. Molecular docking experiments of CTL-06 and CTL-12 with FASN enzyme revealed the mode of binding of these analogues in the KR domain of the enzyme.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Antineoplásicos Límite: Female / Humans Idioma: En Revista: Bioorg Chem Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Antineoplásicos Límite: Female / Humans Idioma: En Revista: Bioorg Chem Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos