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Tesi etd-02272013-175756


Thesis type
Tesi di dottorato di ricerca
Author
FAIELLA, LAURA
URN
etd-02272013-175756
Title
Isolation and structural characterization of diterpenoidic compounds and identification of their molecular targets
Settore scientifico disciplinare
BIO/15
Corso di studi
FISIOPATOLOGIA CLINICA E SCIENZE DEL FARMACO
Supervisors
tutor Prof. Braca, Alessandra
Parole chiave
  • Podocarpus
  • phytochemical studies
  • diterpenes
  • Cle
Data inizio appello
27/03/2013;
Consultabilità
Completa
Riassunto analitico
As part of an ongoing research program on plants biosynthesizing diterpenes, it was performed a project aimed to create a diterpenes library from different plant’s species. The attention was paid on plants known to be rich on diterpenes, since they are a class of natural terpenoids with a great structural variability and a wide spectrum of biological activities.
Podocarpus elongatus (Aiton) L’Hèr. ex Pers, Podocarpus gracilior Pilger (Podocarpaceae), Clerodendrum splendens G. Don. (Verbenaceae), and Sideritis pullulans Vent. (Lamiaceae) were selected.
The new diterpenes nagilactone C 7-O-alpha-L-arabinopyranosyl-(1-4)-beta-D-xylopyranoside, nagilactone C 7-O-beta-D-glucopyranosyl-(1-4)-beta-D-xylopyranoside, nagilactone C 7-O-beta-D-xylopyranoside, nagilactone A 7-O-alpha-L-arabinopyranosyl-(1-4)-beta-D-xylopyranoside, 2beta,15S,16,17,19-pentahydroxy-isopimar-8(14)-ene 17-O-beta-D-glucopyranoside, 2beta,15R,16,17,19-pentahydroxy-isopimar-8(14)-ene 17-O-beta-D-glucopyranoside, and the known diterpenes 4-carboxy-19-nor-totarol, nagilactone B, and nagilactone C were isolated from P. elongatus leaves.
The new diterpenes 2alpha,16-dihydroxy-4beta-carboxy-O-beta-D-glucopyranosyl-19-nor-totarol, nagilactone K together with the known nagilactone B, nagilactone C, nagilactone D, and podolactone B were isolated from P. gracilior leaves.
The new diterpenoidic compounds 2alpha-acetoxy-3beta-(2’,3’-diacetoxy-2’-methyl)-butanoyloxy-14-hydro-15-hydroxyclerodin, 3,15-dihydroxy-14-hydro-clerodin, 2alpha,15-dihydroxy-3beta-(2’-hydroxy-3’-acetoxy-2’-methyl)-butanoyloxy-6alpha,18-diacetoxy-4alpha,17-epoxy-clerodan-11,16-lactone, 3beta,14S,15-trihydroxy-6alpha,18-diacetoxy-4alpha,17-epoxy-clerodan-11,16-lactone, and the only known 14,15-dihydroxy-3-epicarioptin were found in C. splendens leaves.
The new diterpenes, ent-1α,3α,7β,18-tetrahydroxykaur-16-ene, ent-3α,11α,18-trihydroxy-17-norkauran-16-ene, ent-3α,7β,18-trihydroxy-17-norkauran-16-one, ent-3α,7β-dihydroxy-18-acetyloxy-17-norkauran-16-one, ent-3α,7β,16α,17-tetrahydroxy-18-acetyloxy-kaurane, ent-7β,16α,17,18-tetrahydroxykaurane, and the known foliol, linearol, ent-3α,7β,17-trihydroxy-18-acetyloxy-15α,16α-epoxykaurane were isolated from S. pullulans leaves.
Finally, some diterpenes of our library were subjected to a chemical proteomics study as a strategy for the molecular target identification of natural bioactive compounds, setting up a method for the research of their molecular targets.
A fishing for partners study reveals Hsp70 and PPARγ as potential proteic target of 15-ketoatractyligenin methyl ester, a semi-synthetic ent-kaurane, while studies based on limited proteolysis-mass spectrometry strategy, free cell assays, and pro-apoptotic activity of hardwiickik acid in human monocytes allowed to validate Hsp27 as target for the clerodane diterpene.

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