title: Oleanolic acid analogs as NO, TNF-α and IL-1β inhibitors: synthesis, biological evaluation and docking studies.
abstract: A series of oleanolic acid analogs, characterized by structural modifications at position C-3 and C-28 of oleanane skeleton were synthesized and assessed for antiinflammatory potential towards lipopolysaccharide (LPS) induced nitric oxide (NO) production in macrophages. Results revealed that all the synthesized analogs of oleanolic acid inhibit NO production with an IC50 of 2.66-41.7 μM as compared to the specific nitric oxide synthase (NOS) inhibitor, L-NAME (IC50=69.21 and 73.18 μM on RAW 264.7 and J774A.1 cells, respectively) without affecting the cell viability when tested at their half maximal concentration. The most potent NO inhibitors (2, 8, 9 and 10) at a concentration of 20 μg/mL also demonstrated mild inhibition (27.9-51.9%) of LPS-induced tumor necrosis factor alpha (TNF-α) and weak inhibition (11.1-37.5%) towards interleukin 1-beta (IL-1β) production in both the cells. The present study paves a direction that analogs of oleanolic acid can be employed as a lead in the development of potent NO inhibitors. Molecular docking studies also showed that 10 (with top Goldscore docking pose 19.05) showed similar interaction as that of co-crystallized inhibitor and, thereby, helps to design the potent inhibitors of TNF-α.
authors.affiliation: Department of Natural Products, National Institute of Pharmaceutical and Education Research, Sector 67, S.A.S. Nagar, Mohali, Punjab 160 062, India.
authors.forename: Pamita
authors.initials: P
authors.lastname: Bhandari
authors.affiliation: Department of Natural Products, National Institute of Pharmaceutical and Education Research, Sector 67, S.A.S. Nagar, Mohali, Punjab 160 062, India.
authors.forename: Neeraj Kumar
authors.initials: NK
authors.lastname: Patel
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical and Education Research, Sector 67, S.A.S. Nagar, Mohali, Punjab 160 062, India.
authors.forename: Rahul P
authors.initials: RP
authors.lastname: Gangwal
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical and Education Research, Sector 67, S.A.S. Nagar, Mohali, Punjab 160 062, India.
authors.forename: Abhay T
authors.initials: AT
authors.lastname: Sangamwar
authors.affiliation: Department of Natural Products, National Institute of Pharmaceutical and Education Research, Sector 67, S.A.S. Nagar, Mohali, Punjab 160 062, India. Electronic address: kkbhutani@niper.ac.in.
authors.forename: Kamlesh Kumar
authors.initials: KK
authors.lastname: Bhutani
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors*; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D009828:Oleanolic Acid
keywords: Antiinflammatory activity; Indole-fused derivatives; Interleukin 1-β; Nitric oxide; Oleanolic acid; Tumor necrosis factor-α