title: Volatile Inhibitors of Phosphatidylinositol-3-Kinase (PI3K) Pathway: Anticancer Potential of Aroma Compounds of Plant Essential Oils.
abstract: Cancer is a grave health problem for the world as the global cancer burden rises to 14 million new cases with 8.2 million deaths every year which is expected to rise by 70% in the next 2 decades as reported by the WHO.These steady rises in death demand for rapid developments in anti-cancer agents. Essential oils, being natural and multi-component complex systems have recently attracted a lot of attention in this search for novel anti-cancer agents.
  
  
  
  The pharmaceutical attributes of essential oil components, specifically focusing on their affinity towards COX, 5-LOX, AKT, MDM2, PDK1 and mTOR which defines the phosphatidylinositol-3- kinase (PI3K) pathway, were assessed. 123 compounds present in essential oils of different plants were analyzed for their drug like attributes which were then allowed to dock with PI3K dependent receptors crucial for the development of cancer malignancies. Among them, 21 compounds were filtered possessing high druglikeness with favourable metabolism offered by major cytochromeP450 isoforms. Finally, the best docked compounds with highest binding affinities were employed for building a ligand based pharmacophore. Being inhibitors of P-glycoproteins, these molecules also exhibited good absorption profiles and noncarcinogenic properties. Further from these 21, six compounds were evaluated against A549 lung cancer cells.
  
  
  
  The pharmacophoric feature obtained can be applied for both designing and screening moieties for active inhibitors of the phosphatidylinositol-3-kinase pathway specifically from essential oil compounds and these final 21 compounds can be further promoted to studies for anti-cancer drug development. Among these, six compounds exhibited promising inhibitory results against A549 lung cancer cells. Furthermore, immunoblotting assay confirmed the efficacy of the compounds for inhibiting mTOR and AKT enzymes which are bandmasters for downstream signaling of thePI3K pathway.
  
  
  
  Methyl nonanoate, (R)-citronellol, cis-carveol (L-carveol), 3-methyl-Cyclohexanone, 4-carene and thujopsene were finally screened for PI3K targeted anti-cancer therapies which may find direct application as inhalers or sprays against lung cancer as these compounds are highly volatile.
authors.affiliation: Natural Products Chemistry Group, CSIR North East Institute of Science & Technology, Jorhat-785006, Assam, India.
authors.forename: Manobjyoti
authors.initials: M
authors.lastname: Bordoloi
authors.affiliation: Natural Products Chemistry Group, CSIR North East Institute of Science & Technology, Jorhat-785006, Assam, India.
authors.forename: Surovi
authors.initials: S
authors.lastname: Saikia
authors.affiliation: Natural Products Chemistry Group, CSIR North East Institute of Science & Technology, Jorhat-785006, Assam, India.
authors.forename: Bhaskor
authors.initials: B
authors.lastname: Kolita
authors.affiliation: Allied Health Sciences, Assam Down Town University, Panikhaiti, Guwahati 781026, Assam, India.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Sarmah
authors.affiliation: Natural Products Chemistry Group, CSIR North East Institute of Science & Technology, Jorhat-785006, Assam, India.
authors.forename: Sonali
authors.initials: S
authors.lastname: Roy
authors.affiliation: Natural Products Chemistry Group, CSIR North East Institute of Science & Technology, Jorhat-785006, Assam, India.
authors.forename: Bardwi
authors.initials: B
authors.lastname: Narzary
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009822:Oils, Volatile / Q000737:chemistry*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D009822:Oils, Volatile; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors
keywords: Essential oils; anti-cancer volatile molecules; docking; inhaling application against lung cancer.; pharmacophore; phosphatidylinositol-3-kinase pathway