title: Sesterterpenes as tubulin tyrosine ligase inhibitors. First insight of structure-activity relationships and discovery of new lead.
abstract: Twenty-four new sesterterpenes, compounds 1-24, were isolated from the aerial parts of Salvia dominica. Their structures were elucidated by 1D and 2D NMR experiments as well as ESIMS analysis and chemical methods. The evaluation of the biological activity of Salvia dominica sesterterpenes by means of a panel of chemical and biological approaches, including chemical proteomics, surface plasmon resonance (SPR) measurements, and biochemical assays were realized. Obtained results showed that 18 out of the 24 sesterterpene lactones isolated from Salvia dominica interact with tubulin-tyrosine ligase (TTL) an enzyme involved in the tyrosination cycle of the C-terminal of tubulin, and inhibit TTL activity in cancer cells. Besides, results of our studies provided an activity/structure relationship that can be used to design effective TTL inhibitors.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Universita di Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Dal Piaz
authors.forename: Antonio
authors.initials: A
authors.lastname: Vassallo
authors.forename: Laura
authors.initials: L
authors.lastname: Lepore
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tosco
authors.forename: Ammar
authors.initials: A
authors.lastname: Bader
authors.forename: Nunziatina
authors.initials: N
authors.lastname: De Tommasi
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D040901:Proteomics; D027544:Salvia / Q000737:chemistry; D054830:Sesterterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D054830:Sesterterpenes; D010453:Peptide Synthases; C023213:tyrosyltubulin ligase