Structural Optimization of Marine Natural Product Pretrichodermamide B for the Treatment of Colon Cancer by Targeting the JAK/STAT3 Signaling Pathway.

Autor: Zhou Y; Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China.; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China., He N; Key Laboratory of Marine Drugs of Ministry of Education & Qingdao Marine Biomedical Research Institute, Ocean University of China, Qingdao 266003, China., Liu Q; Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China.; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China., Li R; Key Laboratory of Marine Drugs of Ministry of Education & Qingdao Marine Biomedical Research Institute, Ocean University of China, Qingdao 266003, China., Yang L; Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China.; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China., Kang W; Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China.; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China., Zhang X; Key Laboratory of Marine Drugs of Ministry of Education & Qingdao Marine Biomedical Research Institute, Ocean University of China, Qingdao 266003, China., Xu X; Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China., Yao G; Fujian Key Laboratory on Conservation and Sustainable Utilization of Marine Biodiversity, Institute of Oceanography, Minjiang University, Fuzhou 350108, China., Wang P; Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China.; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China., Wang CY; Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China.; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China., Yang J; Key Laboratory of Marine Drugs of Ministry of Education & Qingdao Marine Biomedical Research Institute, Ocean University of China, Qingdao 266003, China., Liu Z; Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China.; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2024 Jul 11; Vol. 67 (13), pp. 10783-10794. Date of Electronic Publication: 2024 Jun 18.
DOI: 10.1021/acs.jmedchem.4c00278
Abstrakt: Marine natural product (MNP) pretrichodermamide B (Pre B, 9 ) was identified as a novel STAT3 inhibitor in our previous work, while its metabolic instability hindered its further development. To address this drawback, ligand structure-based drug design was adopted leading to a series of Pre B derivatives. Among them, MNP trichodermamide B (tri B, 24 ) obtained by skeletal rearrangement exhibited more potent antiproliferative activity with an IC 50 value of 0.12 μM against HCT116. Notably, 24 stood out with improved metabolic stability ( T 1/2 = 31 min) and more favorable oral bioavailability ( F = 37.5%). Further studies indicated that 24 blocked JAK/STAT3 signaling in dose- and time-dependent manner. In vivo , 24 suppressed tumor growth (TGI = 65%) at a dose of 20 mg/kg in a HCT116-derived xenograft mouse model. Overall, 24 might be a promising lead compound for colon cancer and is worthy of further investigation.
Databáze: MEDLINE