Natural Products for drug development

The use of diterpenes with a latyran (ingols) or tiglian (phorbols and 12-deoxyphorbols) skeleton, which activate specific PKC isozymes, may lead to the development of pharmacological tools to regenerate brain damage through neuronal replacement therapies. It is well known that the side chain nature of phorbol esters can lead to modulation of its biological response. However, the determining factor of this response and its relationship with the ability of these products to induce proliferation or differentiation of neural stem cells is not well established, especially in the case of ingoles in which there are no studies in this regard. . For this reason, our group is especially interested in further studying the structure-activity relationship and clarifying the influence of the nature of these esters on the ability to activate specific PKC isozymes and its influence on the biological response of these compounds. To do this, we obtain the diterpenes from natural sources and subject them to chemical, enzymatic or microbiological transformations that allow diversifying and changing the nature of the ester chains in the different positions, to evaluate their biological activity, and we carry out structure-activity relationship studies.

On the other hand, in order to find more accessible and profitable sources of these products, we carry out studies of the metabolome of endophytic fungi of plants of the genus Euphorbia from which a compound of interest has previously been isolated. Additionally, we carry out studies to determine the products in the brain of treated mice by means of UPLC-MS.

• Rosario Hernández Galán:
• E-mail: rosario.hernandez@uca.es.
• ORCID: 0000-0003-1887-4796.
• Research ID: B-7697-2009.

• Natural Products with PKC modulating activity: Isolation, chemical transformations and synthesis of diterpenes from plants of the Euphorbia genus. Search for new sources through the study of endophytic microorganisms.
• Biosynthesis and Synthesis of Bioactive Natural Products: Studies of the biosynthesis of natural products from microorganisms through the use of stable isotopes. Generation and study of mutant strains to determine the involvement of genes in the biosynthesis of natural products. Search for new products through epigenetic techniques.

Natural products Diterpenes PKC Biotransformation Euphorbia

• Principal Investigators:
  • Rosario Hernández Galán (PI).
• Investigators:
  • Antonio José Macías Sánchez.
  • Rosa Durán Patrón.

• Ministerio de Ciencia e Innovación. Programa Retos de la Sociedad. Retos. RTI2018-099908-B-C22, PI: Rosario Hernández Galán. DITERPENOS COMO NUEVOS MODELOS DE FARMACOS EN TERAPIAS DE REGENERACION NEURONAL.
• Ministerio de Economía e Innovación. Programa Retos de la Sociedad MINECO. Retos. BFU2015-68652-R PI: Carmen Castro González (IP1), Rosario Hernández Galán (IP2). Regeneración de lesiones traumáticas en el sistema nervioso central mediante moduladores de la actividad de PKC.

1. Cristina Pinedo, Sandra A. I. Wright, Isidro G. Collado, Rebecca J. M. Goss, Raffaello Castoria, Patrizia Hrelia, Francesca Maffei*, Rosa Durán-Patrón*. Title: Isotopic Labeling Studies Reveal the Patulin Detoxification Pathway by the Biocontrol Yeast Rhodotorula kratochvilovae LS11. Ref. Journal/Book: Journal of Natural Products. Year, volume, first and last pages: 2018, 81 (12), 2692-2699. Impact factor:  4.257. Quartile/Decile in the year of publication: D1 (Plant Science), Q1 (Pharmacology & Pharmacy, Medicinal Chemistry).
2. IvonneSuárez, Gesiane da Silva Lima, Raphael Conti, Cristina Pinedo, Javier Moraga, Javier Barúa, Ana Ligia L.de Oliveira, Josefina Aleu, Rosa Durán-Patrón, Antonio J. Macías-Sánchez, James R. Hanson, MônicaTallarico Pupo, Rosario Hernández-Galán, Isidro G.Collado*. Title: Structural and biosynthetic studies on eremophilenols related to the phytoalexin capsidiol, produced by Botrytis cinerea. Ref. Journal/Book: Phytochemistry 2018, 154, 10-18. Impact Factor: 2,905. Quartile/Decile in the year of publication: Q1 (Plant Science).

1. Authors: Flores-Giubi, Eugenia; Durán-Peña, Maria; Botubol-Ares, José; Escobar-Montaño, Felipe; Zorrilla, David; Macías-Sánchez, Antonio J.; Hernández-Galán, Rosario. Title: Gaditanon: Diterpenoid Based on an Unprecedented Carbon Skeleton Isolated from Euphorbia gaditana”. Journal: Journal of Natural Products. Year, volume, first and last pages: 2017, 80 (7), 2161–2165. Impact factor: 3.885. Quartile/Decile in the year of publication: Q1 (Pharmacology & Pharmacy, Plant sciences, Chemistril Medicinal).
2. Authors: Maribel Murillo-Carretero, Noelia Geribaldi-Doldán, Eugenia Flores-Giubi, Francisco García-Bernal, Elkin A. Navarro, Antonio J. Macías-Sánchez, Pilar Herero Foncubierta, Jesús Domínguez-Riscart, Antonio Delgado-Ariza, Cristina Verástegui, Mourad Daoubi, Rosario Hernández-Galán and Carmen Castro. Title: ELAC (3,12-di-O-acetyl-8-O-tigloilingol), a plant-derived lathyrane diterpene induces subventricular zone neural progenitor cell proliferation through protein kinase C beta activation. Journal: British Journal of Pharmacology. Year, volume, first and last pages: 2017, 174 (14), 2373-2392. Impact factor: 6,810. Quartile/Decile in the year of publication: D1 (Pharmacology & Pharmacy).

1. Authors: Noelia Geribaldi-Doldán, Eugenia Flores-Giubi, Maribel Murillo-Carretero, Francisco García-Bernal, Manuel Carrasco, Antonio J. Macías-Sánchez, Jesús Domínguez-Riscart, Cristina Verástegui, Rosario Hernández-Galán and Carmen Castro. Title: 12-Deoxyphorbols promote adult neurogenesis by inducing neural progenitor cell proliferation via PKC activation". Journal: The International Journal of Neuropsychopharmacology. Year, volume, first and last pages: 2016, 19 (1), 1-14; Impact factor: 4,333. Quartile/Decile in the year of publication: Q1 (Pharmacology & Pharmacy, Clinical Neurology).
2. Authors: Javier Moraga, Bérengère Dalmais, Inmaculada Izquierdo-Bueno, Josefina Aleu, James R. Hanson, Rosario Hernández-Galán, Muriel Viaud, and Isidro G. Collado. Title: Genetic and molecular basis of botrydial biosynthesis. Connecting cytochrome P450-encoding genes to biosynthetic intermediates. Journal: ACS Chem. Biol. Year, volume, first and last pages: 2016, 11 (10), pp 2838–2846. Impact factor: 4,995. Quartile/Decile in the year of publication: Q1 (Biochemistry & Molecular Biology).
3. Authors: Maria Jesús Durán, José Manuel Botubol, J.R. Hanson, Rosario Hernández-Galán, Isidro G. Collado. Title: Eficient O-Acylation of alcohols and phenols by using Cp2TiCl. Journal: European Journal of Organic Chemistry. Year, volume, first and last pages: 2016, 3584-91. Synfacts 2016; 12 (09), 0958. Impact factor: 2.834. Quartile/Decile in the year of publication: Q2 (Chemistry Organic).
4. Authors: Cristina Pinedo, Javier Moraga, Javier Barua, Victoria E. González-Rodríguez, Josefina Aleu, Rosa Durán-Patrón, Antonio J. Macías-Sánchez, James R. Hanson, Muriel Viaud, Rosario Hernández-Galán, Carlos Garrido, and Isidro G. Collado. Title: Chemically Induced Cryptic Sesquiterpenoids and Expression of Sesquiterpene Cyclases in Botrytis cinerea Revealed New Sporogenic (+)-4-Epieremophil-9-en-11-ols. Journal: ACS Chem. Biol. Year, volume, first and last pages: 2016, 11 (5), pp 1391–1400. Impact factor: 5,090. Quartile/Decile in the year of publication: Q1 (Biochemistry & Molecular Biology).
5. Authors: María Jesús Durán, José Manuel Botubol, Antonio J. Macías-Sánchez, Rosario Hernández-Galán, Isidro G. Collado. Title: Chemoselective and stereoselective lithium carbenoid mediated cyclopropanation of acyclic allylic alcohols. Journal: Organic and Biomolecular Chemistry. Year, volume, first and last pages: 2016, 14, 2731-2741. Impact factor: 3.564. Quartile/Decile in the year of publication: Q1 (Chemistry Organic).

1. Authors: María Jesús Durán-Peña, José Manuel Botubol-Ares, James R. Hanson, Rosario Hernández-Galán and Isidro G. Collado. Title: Unexpected Mild Protection of Alcohols as 2-O-THF and 2-O-THP Ethers Catalysed by Cp2TiCl Reveal an Intriguing Role of the Solvent in the Single-Electron Transfer Reaction. Journal: European Journal of Organic Chemistry. Year, volume, first and last pages: 2015, 6333–6340. Impact factor: 3,068. Quartile/Decile in the year of publication: Q2 (Chemistry Organic).
2. Authors: M. J. Durán-Peña, J. M. Botubol-Ares, J. R. Hanson, R. Hernández-Galán and I. G. Collado. Title: Titanium carbenoid-mediated cyclopropanation of allylic alcohols: selectivity and mechanism. Journal: Organic and Biomolecular Chemistry. Year, volume, first and last pages: 2015, 13, 6325-6332. Impact index: 3,559; 11/58. Quartile/Decile in the year of publication: Q1 (Chemistry Organic).
3. Authors: Duran-Peña, M. Jesús; Botubol Ares, José Manuel; Hanson, J.R.; Collado, Isidro G; Hernández-Galán, Rosario. Title: Biological Activity of Natural Sesquiterpenoids containing a gem-Dimethylcyclopropane Unit. Journal: Nat. Prod. Rep. Year, volume, first and last pages: 2015, 32(8), 1236-1248. Impact index: 10.107. Quartile/Decile in the year of publication: D1 (Chemistry Medicinal); D1 (Chemistry, Organic).
4. Authors: Botubol Ares, José Manuel, Duran-Peña, M. Jesús; Macías-Sánchez, Antonio J; Hanson, J.R.; Collado, Isidro G; Hernández-Galán, Rosario. Title: The synthesis of 3-hydroxy-2,4,8-trimethyldec-8-enolides and an approach to 3,4-dihydroxy-2,4,6,8-tetramethyldec-8-enolide. Journal: Organic and Biomolecular Chemistry. Year, volume, first and last pages: 2015, 13, 465-476. Impact index: 3,559. Quartile/Decile in the year of publication: Q1 (Chemistry Organic).
5. Authors: Botubol-Ares, José Manuel; Duran-Peña, M. J.; Hernandez-Galan, Rosario; Collado, Isidro G.; Harwood, L. M.; Macias-Sanchez, Antonio J. Title: nor-Mevaldic acid surrogates as selective antifungal agent leads against Botrytis cinerea. Enantioselective preparation of 4-hydroxy-6-(1-phenylethoxy)tetrahydro-2H-pyran-2-one. Journal: Bioorganic and Medicinal Chemistry. Year, volume, first and last pages: 2015, 23, 3379-3387. Impact index: 2,923. Quartile/Decile in the year of publication: Q1 (Chemistry Organic).
6. Authors: Botubol-Ares, Jose Manuel; Duran-Peña, M. J.; Hernandez-Galan, Rosario; Collado, Isidro G.; Harwood, L. M.; Macias-Sanchez, Antonio J. Title: Diastereoselective and enantioselective preparation of nor-mevaldic acid surrogates through desymmetrisation methodology. Enantioselective synthesis of (+) and (-) nor-mevalonic lactones. Journal: Tetrahedron. Year, volume, first and last pages: 2015, 71, 7531-7538. Impact index: 2,641. Quartile/Decile in the year of publication: Q2 (Chemistry Organic).

1. Authors: Botubol Ares, José Manuel, Duran-Peña, M. Jesús; Macías- Sánchez, Antonio J; Hanson, J.R.; Collado, Isidro G; Hernández-Galán, Rosario. Title: The Asymmetric Total Synthesis of Cinbotolide: A Revision of the Original Structure. Journal: Journal of Organic Chemistry. Year, volume, first and last pages: 2014, 79 (23), 11349-11358. Impact index: 4,721. Quartile/Decile in the year of publication: Q1 (Chemistry Organic).
2. Authors: Botubol Ares, José Manuel, Duran-Peña, M. Jesús; Macías- Sánchez, Antonio J; Hanson, J.R.; Collado, Isidro G; Hernández-Galán, Rosario. Title: Exploring mutasynthesis to increase structural diversity in the synthesis of highly oxygenated polyketides lactones. Journal- Organic and Biomolecular Chemistry. Year, volume, first and last pages: 2014, 12, 5304-5310. Impact index: 3,562. Quartile/Decile in the year of publication: Q1 (Chemistry Organic).
3. Authors: Duran-Peña, M. Jesús; Botubol Ares, José Manuel; Hernández-Galán, Rosario; Collado, Isidro G. Title: Biologically active diterpenes containing a gem-dimethylcyclopropane subunit: An intriguing source of PKC modulators. Journal: Nat. Prod. Rep. Year, volume, first and last pages: 2014, 31(7), 940-952. Impact index: 10.715. Quartile/Decile in the year of publication: D1 (Chemistry Medicinal), 2/58 D1 (Chemistry, Organic).