Structural characterization of tetranortriterpenes from Pseudrocedrela kotschyi and Trichilia emetica and study of their activity towards the chaperone Hsp90.
Investigation of roots extracts Pseudrocedrela kotschyi and Trichilia emetica led to identification of 5 limonoid derivatives, Kotschyins D-H, and 11 known compounds. Their structures were elucidated by extensive 1D and 2D NMR experiments in conjunction with mass spectrometry. A surface plasmon resonance (SPR) approach was adopted to screen their Hsp90 binding capability and kotschyin D showed a significant affinity for the chaperone. Therefore, the characterization of the biological activity of kotschyin D by means of a panel of chemical and biological approaches, including limited proteolysis, molecular docking and biochemical and cellular assays, was performed. Our result indicated this compound as a type of client selective Hsp90 inhibitor, directly binding to the middle domain of the protein and possibly preventing its interaction with the activator of Hsp90 ATPase 1 (Aha1).
Dipartimento di Scienze Farmaceutiche, Università di Salerno, Via Ponte Don Melillo, 84084 Fisciano, SA, Italy.
Fabrizio Dal
FD
Piaz
Nicola
N
Malafronte
Adriana
A
Romano
Dario
D
Gallotta
Maria Antonietta
MA
Belisario
Giuseppe
G
Bifulco
Maria Josefine
MJ
Gualtieri
Rokia
R
Sanogo
Nunziatina De
ND
Tommasi
Claudio
C
Pisano
D001665:Binding Sites / Q000187:drug effects; D019295:Computational Biology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029582:Meliaceae / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry; D019666:Rubiaceae / Q000737:chemistry*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
D018841:HSP90 Heat-Shock Proteins; D010936:Plant Extracts; D014315:Triterpenes