title: Design and synthesis of lupeol analogues and their glucose uptake stimulatory effect in L6 skeletal muscle cells.
abstract: Structure modifications of lupeol at the isopropylene moiety have been described via allylic oxidation using selenium dioxide. The antidiabetic efficacy of lupeol analogues were evaluated in vitro as glucose uptake stimulatory effect in L6 skeletal muscle cells. From all tested compounds, 2, 3, 4b and 6b showed significant stimulation of glucose uptake with respective percent stimulation of 173.1 (p <0.001), 114.1 (p <0.001), 98.3 (p <0.001) and 107.3 (p <0.001) at 10μM concentration. Stimulation of glucose uptake by these compounds is associated with enhanced translocation of glucose transporter 4 (GLUT4) and activation of IRS-1/PI3-K/AKT-dependent signaling pathway in L6 cells. Structure-activity relationship analysis of these analogues demonstrated that the integrity of α,β-unsaturated carbonyl and acetyl moieties were important in the retention of glucose uptake stimulatory effect. It is therefore proposed that naturally occurring lupeol and their analogues might reduce blood glucose, at least in part, through stimulating glucose utilization by skeletal muscles.
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Mohammad Faheem
authors.initials: MF
authors.lastname: Khan
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Chandan Kumar
authors.initials: CK
authors.lastname: Maurya
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi 110001, India.
authors.forename: Kapil
authors.initials: K
authors.lastname: Dev
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi 110001, India.
authors.forename: Deepti
authors.initials: D
authors.lastname: Arha
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Rai
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi 110001, India.
authors.forename: Akhilesh Kumar
authors.initials: AK
authors.lastname: Tamrakar
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi 110001, India. Electronic address: mauryarakesh@rediffmail.com.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Maurya
mesh_terms: D001692:Biological Transport; D050260:Carbohydrate Metabolism / Q000235:genetics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D018482:Muscle, Skeletal / Q000187:drug effects*; D053978:Pentacyclic Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000094042:Lupanes
chemical_list: D005947:Glucose; D007004:Hypoglycemic Agents; D053978:Pentacyclic Triterpenes; C010480:lupeol; D000094042:Lupanes
keywords: Glucose uptake stimulation; Isopropylene moiety; Lupeol; Type 2 diabetes mellitus