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1.
J Med Chem ; 67(9): 7516-7538, 2024 May 09.
Article in English | MEDLINE | ID: mdl-38686671

ABSTRACT

The NLRP3 inflammasome has been recognized as a promising therapeutic target in drug discovery for inflammatory diseases. Our initial research identified a natural sesquiterpene isoalantolactone (IAL) as the active scaffold targeting NLRP3 inflammasome. To improve its activity and metabolic stability, a total of 64 IAL derivatives were designed and synthesized. Among them, compound 49 emerged as the optimal lead, displaying the most potent inhibitory efficacy on nigericin-induced IL-1ß release in THP-1 cells, with an IC50 value of 0.29 µM, approximately 27-fold more potent than that of IAL (IC50: 7.86 µM), and exhibiting higher metabolic stability. Importantly, 49 remarkably improved DSS-induced ulcerative colitis in vivo. Mechanistically, we demonstrated that 49 covalently bound to cysteine 279 in the NACHT domain of NLRP3, thereby inhibiting the assembly and activation of NLRP3 inflammasome. These results provided compelling evidence to further advance the development of more potent NLRP3 inhibitors based on this scaffold.


Subject(s)
Drug Design , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Sesquiterpenes , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Humans , Inflammasomes/metabolism , Inflammasomes/antagonists & inhibitors , Animals , Sesquiterpenes/pharmacology , Sesquiterpenes/chemical synthesis , Sesquiterpenes/chemistry , Mice , Structure-Activity Relationship , Interleukin-1beta/metabolism , THP-1 Cells , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/metabolism , Mice, Inbred C57BL
2.
Eur J Med Chem ; 209: 112922, 2021 Jan 01.
Article in English | MEDLINE | ID: mdl-33069436

ABSTRACT

Magnolol and honokiol are the two major active ingredients with similar structure and anticancer activity from traditional Chinese medicine Magnolia officinalis, and honokiol is now in a phase I clinical trial (CTR20170822) for advanced non-small cell lung cancer (NSCLC). In search of potent lead compounds with better activity, our previous study has demonstrated that magnolol derivative C2, 3-(4-aminopiperidin-1-yl)methyl magnolol, has better activity than honokiol. Here, based on the core of 3-(4-aminopiperidin-1-yl)methyl magnolol, we synthesized fifty-one magnolol derivatives. Among them, compound 30 exhibited the most potent antiproliferative activities on H460, HCC827, H1975 cell lines with the IC50 values of 0.63-0.93 µM, which were approximately 10- and 100-fold more potent than those of C2 and magnolol, respectively. Besides, oral administration of 30 and C2 on an H460 xenograft model also demonstrated that 30 has better activity than C2. Mechanism study revealed that 30 induced G0/G1 phase cell cycle arrest, apoptosis and autophagy in cancer cells. Moreover, blocking autophagy by the autophagic inhibitor enhanced the anticancer activity of 30in vitro and in vivo, suggesting autophagy played a cytoprotective role on 30-induced cancer cell death. Taken together, our study implied that compound 30 combined with autophagic inhibitor could be another choice for NSCLC treatment in further investigation.


Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Autophagy/drug effects , Biphenyl Compounds/chemistry , Carcinoma, Non-Small-Cell Lung/drug therapy , Lignans/chemistry , Lung Neoplasms/drug therapy , Magnolia/chemistry , Plant Extracts/chemistry , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Biphenyl Compounds/pharmacology , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor , Female , Humans , Lignans/pharmacology , Mice, Inbred BALB C , Solubility , Structure-Activity Relationship
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