Chemistry of Natural Products and Bioactive Synthetics

Synthesis of Drugs and Bioactive Compounds

The Synthesis of Drugs and Bioactive Compounds group, created in 2004, is dedicated to the development of new synthetic methodologies and their application to obtain compounds of pharmacological and agricultural interest (One Health).

These compounds include nucleoside analogues, peptides and peptidomimetics (e.g. antimicrobial peptides and quorum inhibitors), fluorescent drug and medical probe derivatives, nanodrugs and crop protection agents.

The Synthesis of Drugs and Bioactive Compounds group profile page on Digital.CSIC.

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Drug group
Presentation

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Procesos en cadena

Development of more efficient chemical processes with less environmental impact

Sequential processes are developed that link various ionic and radical reactions. Intermediates do not need to be isolated and materials, energy and time are saved, and the waste to be treated is reduced. These processes have been used to manufacture a wide variety of bioactive compounds, such...

Responsable:

Alicia Boto Castro

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Modificación selectiva de péptidos

Site-selective peptide modification to develop drugs and peptide catalysts

Selective peptide modification allows easy generation of varied peptide libraries from a few starting substrates, and saves time and resources in the process of drug and peptide catalyst discovery. Our group has introduced "modifiable units" that, once introduced in peptides, can be easily...

Responsable:

Alicia Boto Castro

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Antimicrobianos

Preparation of antimicrobial peptides and quorum sensing inhibitors

Our group is developing antimicrobial peptides for biomedicine, livestock and agriculture, and also compounds with potential quorum sensing inhibitory action. Several of the results have been patented and have led to international communications.

Responsable:

Alicia Boto Castro

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Tamoxifeno

Development of fluorescent drug derivatives and medical probes

In collaboration with ULL, fluorescent analogues of tamoxifen, an anti-tumour agent widely used to treat breast cancer, have been developed as medical probes and new drugs.

Responsable:

Alicia Boto Castro

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Nanofarmacos

Nanodrug development

In collaboration with several Biotechnology and Nanotechnology groups, we are preparing nano-drugs for use as antimicrobials and antitumor agents, from phototherapy to nanoparticles for selective transport of antitumor agents, antimicrobials or medical probes. The nanoparticles are decorated...

Responsable:

Alicia Boto Castro

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APOGEO

Development of protective agents for crops

In collaboration with two IPNA Agrobiology groups, we are developing crop protection compounds against phytopathogens and abiotic stresses such as drought and salinity.

Responsable:

Alicia Boto Castro

Nuevos métodos para convertir sustratos de bajo coste en compuestos de alto valor añadido, por su interés químico y farmacéutico

Esta tesis obtuvo la Mención Industrial y ha sido la primera tesis en la ULL del programa de Doctorados Industriales. Calificación: Sobresaliente cum laude.

Año:2019
Director del trabajo:

Directora: Alicia Boto (CSIC) 

Codirectores: Dácil Hernández (CSIC) y Gabriel García-Llanos (BIOSIGMA SL)

Estudiante:

Carmen Carro Sabina

Tipo:Tesis doctoral

Procesos secuenciales para la síntesis de aminas quirales a partir de amino ácidos y de péptidos

Calificación: Sobresaliente cum laude.

Año:2014
Director del trabajo:

Dra. Alicia Boto

Estudiante:

Iván Romero Estudillo

Tipo:Tesis doctoral

Síntesis estereoselectiva de análogos de alcaloides y de nucleósidos por medio de un proceso secuencial de fragmentación-adición de nucleófilos

Calificación: Apto (cum laude).

Año:2013
Director del trabajo:

Dra. Alicia Boto

Estudiante:

Javier Miguélez Ramos

Tipo:Tesis doctoral

Modificación de productos Bioactivos: Aproximación a la Síntesis de análogos simplificados de enzimas

Año:2013
Director del trabajo:

Dra. Alicia Boto (Coop: Dr. Pedro Martín Zarza)

Estudiante:

Alejandro Cabrera García

Tipo:Máster y TFG

Modificación de productos Bioactivos: Síntesis de derivados de aminoácidos, péptidos y fármacos antitumorales

Año:2013
Director del trabajo:

Dra. Alicia Boto y Dra. Dácil Hernández

Estudiante:

David Guzmán Ríos

Tipo:Máster y TFG

Procesos secuenciales de escisión radicalaria-oxidación-adición de nucleófilos: aplicación a la modificación selectiva de péptidos y a la síntesis de productos bioactivos

Calificación: Apto cum laude.

Año:2013
Director del trabajo:

Dra. Alicia Boto y Dr. Rosendo Hernández

Estudiante:

Carlos Javier Saavedra Fernández

Tipo:Tesis doctoral

Procesos Secuenciales estereoselectivos para la síntesis de precursores de productos bioactivos

Año:2010
Director del trabajo:

Dra. Alicia Boto

Estudiante:

Iván Romero Estudillo

Tipo:Máster y TFG

Síntesis en un paso de beta-amino ácidos a partir de alfa-amino ácidos. Preparación de alfa,beta-péptidos

Premio de la Facultad de Química

Año:2009
Director del trabajo:

Alicia Boto y Rosendo Hernández

Estudiante:

Carlos Saavedra Fernández

Tipo:Máster y TFG

Reactividad de Radicales Alcoxilo y Carboxilo. Abstracción Intramolecular de Hidrógeno y beta-Fragmentación: Aplicaciones Sintéticas

A esta tesis se le concedió uno de los Premios Extraordinarios de Doctorado 2009 de la Universidad de La Laguna, en la modalidad “Ciencias Experimentales y Técnicas”.

Año:2007
Director del trabajo:

Dr. Rosendo Hernández y Dra. Alicia Boto

Estudiante:

Dácil Hernández Mesa

Tipo:Tesis doctoral

Estudio del Mecanismo de Fragmentación de Radicales Alcoxilo Anoméricos y Radicales Carboxilo: Intermedios Radicalarios e Iónicos. Aplicaciones a la Síntesis de Carbociclos y Heterociclos Nitrogenados

Calificación: Sobresaliente (cum laude)

Año:2005
Director del trabajo:

Dr. Rosendo Hernández González y Dra. Alicia Boto Castro

Estudiante:

Yolanda María de León Rizo

Tipo:Tesis doctoral
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APOGEO

MAC-INTERREG APOGEO “Agricultura de Precisión para la Mejora de la Producción Vitícola en la Macaronesia”

El proyecto APOGEO está liderado por la ULPGC y en él participan universidades, entidades públicas y empresas de Canarias, Madeira y Azores. APOGEO trata de la monitorización inteligente de…

Investigador principal:

Coordinador: José Francisco López (ULPGC)

Estado:

En Ejecución

Proyecto de investigación

Preparación de péptidos antimicrobianos de uso en salud humana y agricultura

Estado:

Finalizado

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MINECO

Preparación de péptidos antimicrobianos de uso en salud humana y agricultura

Investigador principal:

Alicia Boto Castro

Estado:

Finalizado

Proyecto de investigación

Preparacion de peptidos antimicrobianos de uso en salud humana y agricultura (SAF2013-48399-R)

Estado:

Finalizado

Proyecto de investigación

Utilización de los desechos del cultivo del plátano de Canarias: Aplicabilidad frente a patologías de la piel

Investigador principal:

Raquel Marín (Universidad de La Laguna)

Estado:

Finalizado

Proyecto de investigación

Métodos prácticos, de alcance y bajo coste para despertar vocaciones científicas en épocas de crisis (FCT-14-8265)

Investigador principal:

Alicia Boto

Estado:

Finalizado

Proyecto de investigación

Drug discovery for the treatment of selected protozoa (Toxoplasma, Neospora and Acanthamoeba)

Investigador principal:

Hany Elsheikha (Universidad de Nottingham)

Estado:

Finalizado

Proyecto de investigación

Nuevas metodologías para la modificación selectiva de péptidos (bioactivos o catalíticos) y para obtener azanucleotidos (CTQ2009-07109)

Investigador principal:

Alicia Boto

Estado:

Finalizado

Proyecto de investigación

Síntesis estereoselectiva de análogos de alcaloides citotóxicos

Investigador principal:

Alicia Boto

Estado:

Finalizado

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Ministerio de Ciencia

Síntesis Estereoselectiva de Compuestos Nitrogenados con Posible Actividad Farmacológica: Amino ácidos, Azanucleósidos, Alcaloides y Análogos Sintéticos (CTQ2006-14260)

Investigador principal:

Alicia Boto

Estado:

Finalizado

Proyecto de investigación

Síntesis de Alcaloides Bioactivos y Análogos Sintéticos a partir de Amino Ácidos

Investigador principal:

Alicia Boto Castro

Estado:

Finalizado

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Ministerio de educación y ciencia

Síntesis de Alcaloides y Nucleósidos Acíclicos con Potencial Actividad Farmacológica a partir de Amino Ácidos y Carbohidratos

Investigador principal:

Rosendo Hernández González

Estado:

Finalizado

Proyecto de investigación

Nueva Metodología Sintética para la Obtención de Alcaloides con Actividad Biológica y Análogos Sintéticos a partir de Aminoácidos

Investigador principal:

Rosendo Hernández González

Estado:

Finalizado

Galería de imágenes y vídeos

Selected Publications

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Metal-Free, Site-Selective Peptide Modification

Metal-Free, Site-Selective Peptide Modification by Conversion of “Customizable” Units into β-Substituted Dehydroamino Acids

Our site-selective modification of serine or threonine units in peptides allows the generation of β-substituted dehydroamino acids, which increase peptide resistance to hydrolysis and may improve their biological properties. Both the terminal and internal positions can be modified, and different customizable units can be activated separately. Remarkably, high Z selectivity is achieved, even at internal positions. The conversion involves a one-pot oxidative radical scission/phosphorylation process by using the low-toxicity (diacetoxyiodo)benzene/iodine system as the scission reagent. The resulting α-amino phosphonates undergo a Horner-Wadsworth-Emmons reaction to produce the dehydroamino acid derivatives (in a Z/E ratio of usually >98:2) under mild and metal-free conditions.

Saavedra, Carlos Javier; Hernández, Dácil; Boto, Alicia

Chemistry-A European Journal 24(3): 599-607 (2018)
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Domino Process Achieves Site-Selective Peptide Modification

Domino Process Achieves Site-Selective Peptide Modification with High Optical Purity. Applications to Chain Diversification and Peptide Ligation

The development of peptide libraries by site-selective modification of a few parent peptides would save valuable time and materials in discovery processes but still is a difficult synthetic challenge. Herein, we introduce natural hydroxyproline as a convertible unit for the production of a variety of optically pure amino acids, including expensive N-alkyl amino acids, homoserine lactones, and Agl lactams, and to achieve the mild, efficient, and site-selective modification of peptides. A domino process is used to cleave the customizable Hyp unit under mild, metal-free conditions. Both terminal and internal positions can be modified, and similar customizable units can be differentiated. The resulting products possess two reactive chains which can be manipulated independently. The versatility and scope of this process is highlighted by its application to the ligation of two peptide chains, and the generation of peptides with several chains and peptides with conformational restrictions.

Romero Estudillo, Iván Omar; Boto, Alicia

Journal of Organic Chemistry 80(19): 9379-9391 (2015)
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Nucleoside analogues Synthesis and biological

Nucleoside analogues: Synthesis and biological properties of azanucleoside derivatives

The azanucleosides are nucleoside analogues where the furanose ring is replaced by a nitrogen‐containing ring or chain. Many azanucleosides are potent antiviral, anticancer and antimicrobial agents, or serve as valuable components of oligonucleotides with improved stability, binding or hybridization properties. Therefore, the development of new analogues is a very active area in medicinal and synthetic chemistry. Their synthesis and their interesting biological properties are discussed in this microreview.

Hernández, Dácil; Boto, Alicia

European Journal of Organic Chemistry 2014(11): 2201-2220 (2014)
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Unique SERM-like properties of the novel fluorescent tamoxifen

Unique SERM-like properties of the novel fluorescent tamoxifen derivative FLTX1

Tamoxifen is a selective estrogen receptor modulator extensively used on estrogen receptor-positive breast cancer treatment. However, clinical evidences demonstrate the increased incidence of undesirable side effects during chronic therapies, the most life threatening being uterine cancers. Some of these effects are related to tissue-dependent estrogenic actions of tamoxifen, but the exact mechanisms remain poorly understood. We have designed and synthesized a novel fluorescent tamoxifen derivative, FLTX1, and characterized its biological and pharmacological activities. Using confocal microscopy, we demonstrate that FLTX1 colocalizes with estrogen receptor α (ERα). Competition studies showed that FLTX1 binding was totally displaced by unlabeled tamoxifen and partially by estradiol, indicating the existence of non-ER-related triphenylethylene-binding sites. Ligand binding assays showed that FLTX1 exhibits similar affinity for ER than tamoxifen. FLTX1 exhibited antiestrogenic activity comparable to tamoxifen in MCF7 and T47D cells transfected with 3xERE-luciferase reporter. Interestingly, FLTX1 lacked the strong agonistic effect of tamoxifen on ERα-dependent transcriptional activity. Additionally, in vivo assays in mice revealed that unlike tamoxifen, FLTX1 was devoid of estrogenic uterotrophic effects, lacked of hyperplasic and hypertrophic effects, and failed to alter basal proliferating cell nuclear antigen immunoreactivity. In the rat uterine model of estrogenicity/antiestrogenicity, FLTX1 displayed antagonistic activity comparable to tamoxifen at lower doses, and only estrogenic uterotrophy at the highest dose. We conclude that the fluorescent derivative FLTX1 is not only a suitable probe for studies on the molecular pharmacology of tamoxifen, but also a potential therapeutic substitute to tamoxifen, endowed with potent antiestrogenic properties but devoid of uterine estrogenicity.

Marrero-Alonso, Jorge; Morales, Araceli; García Marrero, B.; Boto, Alicia; Marín, Raquel; Cury, Débora; Gómez, Tomás; Fernández-Pérez, Leandro; Lahoz Zamarro, Fernando; Díaz, Mario

European Journal of Pharmaceutics and Biopharmaceutics 85(3): 898-910 (2013)
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Conformation and Chiral Effects

Conformation and Chiral Effects in α,β,α-Tripeptides

Short α,β,α-tripeptides comprising a central chiral trisubstituted β2,2,3*-amino acid residue form unusual γ-turns and δ-turns in CDCl3 and DMSO-d6 solutions but do not form β-turns. Thermal coefficients of backbone amide protons, 2D-NMR spectra, and molecular modeling revealed that these motifs were strongly dependent on the configuration (chiral effect) of the central β-amino acid residue within the triad. Accordingly, SSS tripeptides adopted an intraresidual γ-turn like (C6) arrangement in the central β-amino acid, whereas SRS diastereomers preferred an extended δ-turn (C9) conformation. A different SRS-stabilizing bias was observed in the crystal structures of the same compounds, which shared the extended δ-turn (C9) found in solution, but incorporated an additional extended β-turn (C11) to form an overlapped double turn motif.

Saavedra, Carlos J.; Boto, Alicia; Hernández, Rosendo; Miranda, José Ignacio; Aizpurua, Jesus M.

J. Org. Chem. 77(14): 5907-5913 ( 2012)
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Synthesis of α,γ-Peptide Hybrids by Selective

Synthesis of α,γ-peptide hybrids by selective conversion of glutamic acid units

The site-selective modification of small peptides at a glutamate residue allows the ready preparation of α,γ-hybrids. In this way, a single peptide can be transformed into a variety of hybrid derivatives. The process takes place under very mild conditions, and good global yields are obtained.

Saavedra, Carlos J.; Boto, Alicia; Hernández, Rosendo

Organic Letters 14(13): 3542-3545 (2012)

Collaborations

Carlos Javier Saavedra Fernández

Universidad de La Laguna

E-mail: csaavedr [at] ull.edu.es


Fernando Lobo Palacios 

Universidad de La Laguna

Other research groups

Química de Productos Naturales y Sintéticos Bioactivos

Chemistry of Natural Products and Bioactive Synthetics