title: Rohitukine inhibits in vitro adipogenesis arresting mitotic clonal expansion and improves dyslipidemia in vivo.
abstract: We developed a common feature pharmacophore model using known antiadipogenic compounds (CFPMA). We identified rohitukine, a reported chromone anticancer alkaloid as a potential hit through in silico mapping of the in-house natural product library on CFPMA. Studies were designed to assess the antiadipogenic potential of rohitukine. Rohitukine was isolated from Dysoxylum binacteriferum Hook. to ⬧95% purity. As predicted by CFPMA, rohitukine was indeed found to be an antiadipogenic molecule. Rohitukine inhibited lipid accumulation and adipogenic differentiation in a concentration- and exposure-time-dependent manner in 3T3-L1 and C3H10T1/2 cells. Rohitukine downregulated expression of PPARγ, CCAAT/enhancer binding protein α, adipocyte protein 2 (aP2), FAS, and glucose transporter 4. It also suppressed mRNA expression of LPL, sterol-regulatory element binding protein (SREBP) 1c, FAS, and aP2, the downstream targets of PPARγ. Rohitukine arrests cells in S phase during mitotic clonal expansion. Rohitukine was bioavailable, and 25.7% of orally administered compound reached systemic circulation. We evaluated the effect of rohitukine on dyslipidemia induced by high-fat diet in the hamster model. Rohitukine increased hepatic expression of liver X receptor α and decreased expression of SREBP-2 and associated targets. Rohitukine decreased hepatic and gonadal lipid accumulation and ameliorated dyslipidemia significantly. In summary, our strategy to identify a novel antiadipogenic molecule using CFPMA successfully resulted in identification of rohitukine, which confirmed antiadipogenic activity and also exhibited in vivo antidyslipidemic activity.
authors.affiliation: Division of Pharmacology, Council of Scientific & Industrial Research-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow, Uttar Pradesh 226031, India.
authors.forename: Salil
authors.initials: S
authors.lastname: Varshney
authors.affiliation: Division of Pharmacology, Council of Scientific & Industrial Research-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow, Uttar Pradesh 226031, India.
authors.forename: Kripa
authors.initials: K
authors.lastname: Shankar
authors.affiliation: Division of Pharmacology, Council of Scientific & Industrial Research-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow, Uttar Pradesh 226031, India.
authors.forename: Muheeb
authors.initials: M
authors.lastname: Beg
authors.affiliation: Medicinal and Process Chemistry Division, Council of Scientific & Industrial Research-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow, Uttar Pradesh 226031, India.
authors.forename: Vishal M
authors.initials: VM
authors.lastname: Balaramnavar
authors.affiliation: Medicinal and Process Chemistry Division, Council of Scientific & Industrial Research-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow, Uttar Pradesh 226031, India.
authors.forename: Sunil Kumar
authors.initials: SK
authors.lastname: Mishra
authors.affiliation: Regulatory Toxicology Group, Council of Scientific & Industrial Research-Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh 226001, India.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Jagdale
authors.affiliation: Medicinal and Process Chemistry Division, Council of Scientific & Industrial Research-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow, Uttar Pradesh 226031, India.
authors.forename: Shishir
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Pharmacokinetics and Metabolism Division, Council of Scientific & Industrial Research-Central Drug Research Institute, 10/1, Sector 10, Jankipuram Extension, Lucknow, Uttar Pradesh 226031, India.
authors.forename: Yashpal S
authors.initials: YS
authors.lastname: Chhonker
authors.affiliation: Department of Biochemistry, King George's Medical University, Chowk Area, Lucknow, Uttar Pradesh 226003, India.
authors.forename: Vijai
authors.initials: V
authors.lastname: Lakshmi
authors.affiliation: Regulatory Toxicology Group, Council of Scientific & Industrial Research-Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh 226001, India.
authors.forename: Bhushan P
authors.initials: BP
authors.lastname: Chaudhari
authors.affiliation: Pharmacokinetics and Metabolism Division, Council of Scientific & Industrial Research-Central Drug Research Institute, 10/1, Sector 10, Jankipuram Extension, Lucknow, Uttar Pradesh 226031, India.
authors.forename: Rabi Shankar
authors.initials: RS
authors.lastname: Bhatta
authors.affiliation: Medicinal and Process Chemistry Division, Council of Scientific & Industrial Research-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow, Uttar Pradesh 226031, India.
authors.forename: Anil Kumar
authors.initials: AK
authors.lastname: Saxena
authors.affiliation: Division of Pharmacology, Council of Scientific & Industrial Research-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow, Uttar Pradesh 226031, India.
authors.forename: Anil Nilkanth
authors.initials: AN
authors.lastname: Gaikwad
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D002867:Chromones / Q000737:chemistry / Q000494:pharmacology*; D050171:Dyslipidemias / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008938:Mitosis / Q000187:drug effects*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects*
chemical_list: C573233:5,7-dihydroxy-2-methyl-8-(4-(3-hydroxy-1-methyl)-piperidinyl)-4H-1-benzopyran-4-one; D002867:Chromones; D010880:Piperidines
keywords: 3T3-L1; C3H10T1/2; Dysoxylum binacteriferum Hook. f.; S-phase arrest