title: Semi-synthesis and antiproliferative evaluation of PEGylated pentacyclic triterpenes.
abstract: Several PEGylated derivatives of oleanolic and maslinic acids have been semi-synthesized, attaching one acid-PEG reagent to the hydroxyl group/s at C-2 or C-2/C-3 of the A rings of these natural triterpenes, and also to their corresponding C-28 benzyl derivatives. Several monomeric and dimeric PEGylated compounds have also been produced by linking one diamine-PEG reagent to the carboxyl group at C-28 of the same natural triterpenes and also to their corresponding C-2 or C-2/C-3 acetylated derivatives. The cytotoxic effects of 12 triterpenic PEGylated derivatives in three cancer-cell lines (B16F10, HT29, and Hep G2) have been assayed. The best results have been achieved by the PEGylated-amine derivative of oleanolic acid, with IC50 concentrations between 0.22 and 3.78 μM, being between 28- and 963-fold more effective than its natural precursor. The percentages of apoptosis induction have also been determined for the five PEGylated derivatives with the lowest cytotoxicity data. All five compounds showed apoptotic effects on the treated cells, with a total apoptosis rate of 99% in the B16F10 cells, 80% in the Hep G2 cells, and 51% in the HT29 cells. We have also studied the changes in the mitochondrial membrane potential (MMP) to elucidate the possible mechanism involved in the apoptotic responses (intrinsic or extrinsic). Finally, to verify the results found in the cytometry assays, we have used fluorescence microscopy techniques to determine changes in the cell morphology. These PEGylated derivatives of natural triterpenoids, which can induce apoptosis at very low concentrations in different tumour lines, may represent new effective therapeutic drugs against these diseases.
authors.affiliation: Departamento de Quimica Organica, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Medina-O'Donnell
authors.affiliation: Departamento de Quimica Organica, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain. Electronic address: frivas@ugr.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Rivas
authors.affiliation: Departamento de Bioquimica y Biologia Molecular I, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Reyes-Zurita
authors.affiliation: Departamento de Quimica Organica, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Martinez
authors.affiliation: Departamento de Quimica Organica, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
authors.forename: Samuel
authors.initials: S
authors.lastname: Martin-Fonseca
authors.affiliation: Departamento de Quimica Organica, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
authors.forename: Andres
authors.initials: A
authors.lastname: Garcia-Granados
authors.affiliation: Departamento de Biología Celular, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Ferrer-Martín
authors.affiliation: Departamento de Bioquimica y Biologia Molecular I, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain. Electronic address: jlcara@ugr.es.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Lupiañez
authors.affiliation: Departamento de Quimica Organica, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain. Electronic address: aparra@ugr.es.
authors.forename: Andres
authors.initials: A
authors.lastname: Parra
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D019073:HT29 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D053978:Pentacyclic Triterpenes / Q000737:chemistry* / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D053978:Pentacyclic Triterpenes; D011092:Polyethylene Glycols
keywords: Apoptosis; Maslinic acid; Oleanolic acid; PEGylation; Triterpene