title: Facile and Divergent Synthesis of Lamellarins and Lactam-Containing Derivatives with Improved Drug Likeness and Biological Activities.
abstract: With the goal to improve the aqueous solubility of lamellarins, the lactone ring in their skeleton was replaced with a lactam moiety in azalamellarins. However, the reported synthetic route produced such derivatives in very low yields. Hence, this study focused on developing an efficient simplified total synthetic scheme that could furnish both azalamellarins and the parent lamellarins from the same pyrrole ester intermediates. Subsequent comparative profiling revealed that the introduced lactone-to-lactam replacement rendered these molecules less lipophilic, whereas their cancer cytotoxicity remained equipotent to that of the parent compounds. Interestingly, their inhibitory activity was significantly enhanced towards the multifaceted GSK-3β enzyme. Our results clearly demonstrate the therapeutic potential of this promising class of marine-derived natural products and justify their further development, especially into anticancer agents.
authors.affiliation: Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Laksi, Bangkok, 10210, Thailand.|Chemical Biology Program, Chulabhorn Graduate Institute and Center of Excellence on Environmental, Health and Toxicology, Laksi, Bangkok, 10210, Thailand.
authors.forename: Atiruj
authors.initials: A
authors.lastname: Theppawong
authors.affiliation: Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Laksi, Bangkok, 10210, Thailand.|Chemical Biology Program, Chulabhorn Graduate Institute and Center of Excellence on Environmental, Health and Toxicology, Laksi, Bangkok, 10210, Thailand.
authors.forename: Poonsakdi
authors.initials: P
authors.lastname: Ploypradith
authors.affiliation: Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science and Special Research Unit for Advanced Magnetic, Resonance (AMR), Kasetsart University, Bangkok, 10900, Thailand.
authors.forename: Pitak
authors.initials: P
authors.lastname: Chuawong
authors.affiliation: Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Laksi, Bangkok, 10210, Thailand.|Chemical Biology Program, Chulabhorn Graduate Institute and Center of Excellence on Environmental, Health and Toxicology, Laksi, Bangkok, 10210, Thailand.
authors.forename: Somsak
authors.initials: S
authors.lastname: Ruchirawat
authors.affiliation: Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Laksi, Bangkok, 10210, Thailand. montakarn@cri.or.th.|Chemical Biology Program, Chulabhorn Graduate Institute and Center of Excellence on Environmental, Health and Toxicology, Laksi, Bangkok, 10210, Thailand. montakarn@cri.or.th.
authors.forename: Montakarn
authors.identifier: http://orcid.org/0000-0002-8043-8859
authors.initials: M
authors.lastname: Chittchang
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001372:Aza Compounds / Q000737:chemistry; D001665:Binding Sites; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000737:chemistry*; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D011758:Pyrroles / Q000737:chemistry
chemical_list: D000470:Alkaloids; D001372:Aza Compounds; D001688:Biological Products; D007769:Lactams; D011758:Pyrroles; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: cytotoxicity; drug likeness; inhibitors; lamellarins; total synthesis