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1. Amide-controlled, one-pot synthesis of tri-substituted purines generates structural diversity and analogues with trypanocidal activity

Author

José A. García-Salcedo, María José Pineda de las Infantas Villatoro, Miguel Ángel Gallo Mezo, Rafael Contreras-Montoya, Juan D. Unciti-Broceta, Juan J. Díaz-Mochón, Asier Unciti-Broceta, [Pineda de las Infantas y Villatoro,MJ, Gallo Mezo,MA, Diaz-Mochon,JJ] Departamento de Química Farmacéutica y Orgánica. University of Granada, Granada, Spain. [Unciti-Broceta,JD, Contreras-Montoya,R, Garcia-Salcedo,JA, Diaz-Mochon,JJ] Pfizer - Universidad de Granada - Junta de Andalucía Centre for Genomics and Oncological Research (GENYO),Granada, Spain. [Garcia-Salcedo,JA] Unidad de Enfermedades Infecciosas y Microbiología, Complejo Hospitalario de Granada. Instituto de Investigación Biosanitaria de Granada, Granada, Spain. [ Unciti-Broceta,A] Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., and This work was partially supported by Grant SAF2011-30528.

Subjects
Annulation, Stereochemistry, Reaction mechanisms, One-pot synthesis, Trypanosoma brucei brucei, Purine analogue, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Purines [Medical Subject Headings], Chemistry Techniques, Synthetic, Trypanosoma brucei, Organisms::Eukaryota::Euglenozoa::Kinetoplastida::Trypanosomatina::Trypanosoma::Trypanosoma brucei brucei [Medical Subject Headings], Tripanocidas, Article, chemistry.chemical_compound, Amidas, Técnicas de químicas sintética, Amide, Purine metabolism, Trypanocidal activity, Phenomena and Processes::Chemical Phenomena::Organic Chemistry Phenomena::Organic Chemistry Processes::Chemistry Techniques, Synthetic [Medical Subject Headings], Multidisciplinary, Schiff base, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiparasitic Agents::Antiprotozoal Agents::Trypanocidal Agents [Medical Subject Headings], Chemicals and Drugs::Organic Chemicals::Amides [Medical Subject Headings], biology, biology.organism_classification, Amides, Trypanocidal Agents, Parasite biology, chemistry, Biochemistry, Purines, Alkoxide, Purinas
Abstract

Anovel one-pot synthesis of tri-substituted purines and the discovery of purine analogues with trypanocidal activity are reported. The reaction is initiated by a metal-free oxidative coupling of primary alkoxides and diaminopyrimidines with Schiff base formation and subsequent annulation in the presence of large N,N-dimethylamides (e.g.N,N-dimethylpropanamide or larger). This synthetic route is in competition with a reaction previously-reported by our group1, allowing the generation of a combinatorial library of tri-substituted purines by the simple modification of the amide and the alkoxide employed. Among the variety of structures generated, two purine analogues displayed trypanocidal activity against the protozoan parasite Trypanosoma brucei with IC50 , 5 mM, being each of those compounds obtained through each of the synthetic pathways., J.J.D.M. thanks Spanish Ministerio de Economı´a y Competitividad for a Ramon y Cajal Fellowship. A.U.B. thanks MRC IGMM for an academic fellowship. This work was partially supported by Grant SAF2011-30528 to J.A.G.S..

Published
2015
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2. Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation

Author

Ignacio Puche-Sanz, Pedro J. Real, Pablo Lupiañez, Sonia Perales, Iris Simon, Clara Alaminos, José A. Lorente, Alba Rodríguez-Martínez, Laura Casado-Medina, Juan J. Díaz-Mochón, María José Serrano, María del Carmen Garrido-Navas, [Simon,I, Perales,S, Casado-Medina,L, Lupiañez,P, Real,PJ] GENyO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Gene Regulation, Stem Cells & Development Lab, PTS Granada, Granada, Spain. [Simon,I, Real,PJ] Faculty of Science, Department of Biochemistry and Molecular Biology I, University of Granada, Granada, Spain. [Rodríguez-Martínez,A, Garrido-Navas,MDC, Lorente,JA, Serrano,MJ] GENyO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Liquid Biopsy and Cancer Interception Group, PTS Granada, Granada, Spain. [Rodríguez-Martínez,A, Lorente,JA] Faculty of Medicine, Legal Medicine and Toxicology Department, University of Granada, Laboratory of Genetic Identification, Spain. [Garrido-Navas,MDC] Universidad Internacional de la Rioja, Logroño, Spain. [Puche-Sanz,I] Department of Urology, Bio-Health Research Institute (Instituto de Investigación Biosanitaria ibs.GRANADA), Hospital Universitario Virgen de las Nieves, University of Granada, Granada, Spain. [Diaz-Mochon, JJ] GENyO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Nanochembio Lab, PTS Granada, Granada, Spain. [Diaz-Mochon,JJ] Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Campus de Cartuja, University of Granada, Granada, Spain. [Alaminos,C] Department of Urology, University Hospital of Jaen, Jaen, Spain. [Serrano,MJ] Comprehensive Oncology Division, Clinical University Hospital, Virgen de las Nieves-IBS, Granada, Spain. [Serrano,MJ] Department of Pathological Anatomy, Faculty of Medicine, University of Granada, Granada, Spain. [Real, PJ] Bio-Health Research Institute (Instituto de Investigación Biosanitaria ibs.GRANADA), Personalized Oncology Group, Granada, Spain, This study was supported by the Institute of Health Carlos III, Spain (PI17/00989) to M.J.S. and cofunded by the European Regional Development Fund 'A way to build Europe' and the Ramon y Cajal (RYC-2015-18382) to P.J.R., funded by the Ministry of Economy and Competitiveness. A.R.-M. was supported by the predoctoral-University Teacher Training Program from the Ministry of Education, Culture and Sport (FPU14/05461), I.S. was supported by the Young Researcher program from University of Granada (Joven Personal Investigador-Fondo Social Europeo, and Universidad de Granada (2018-19)) and a donation from Rolucan Association (Rota Lucha contra el Cancer).

Subjects
0301 basic medicine, Cancer Research, Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], castration resistant prostate cancer, Cell, Andrógenos, urologic and male genital diseases, Diseases::Male Urogenital Diseases::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms::Prostatic Neoplasms, Castration-Resistant [Medical Subject Headings], Androgen deprivation therapy, chemistry.chemical_compound, Prostate cancer, 0302 clinical medicine, Castration Resistance, Anatomy::Cells::Cells, Cultured::Cell Line [Medical Subject Headings], androgen receptor, abiraterone, transcriptional regulation, Abiraterone, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Cytophotometry::Flow Cytometry [Medical Subject Headings], medicine.diagnostic_test, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Protein Isoforms [Medical Subject Headings], enzalutamide, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Androgen receptor, medicine.anatomical_structure, Elementos reguladores de la transcripción, Oncology, Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormone Antagonists::Androgen Antagonists [Medical Subject Headings], 030220 oncology & carcinogenesis, Castration resistant prostate cancer, cross-resistance, Check Tags::Male [Medical Subject Headings], lcsh:RC254-282, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::RNA Processing, Post-Transcriptional::RNA Splicing::Alternative Splicing [Medical Subject Headings], Article, Flow cytometry, 03 medical and health sciences, Transcriptional regulation, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Motivation::Goals [Medical Subject Headings], Acetato de abiraterona, medicine, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Androgens [Medical Subject Headings], Enzalutamide, Cross-resistance, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell Proliferation [Medical Subject Headings], Cell growth, business.industry, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Surgical Procedures, Operative::Urogenital Surgical Procedures::Castration [Medical Subject Headings], Neoplasias de la próstata resistentes a la castración, medicine.disease, 030104 developmental biology, chemistry, Novel hormonal agents, Cancer research, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Receptors, Cytoplasmic and Nuclear::Receptors, Steroid::Receptors, Androgen [Medical Subject Headings], business, AR-V7, AR-V9
Abstract

Androgen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment. Although ADT is initially effective, a subsequent castration resistance status (CRPC) is commonly developed. The expression of androgen receptor (AR) alternative splicing isoforms (AR-V7 and AR-V9) has been associated to CRPC. However, resistance mechanisms to novel NHAs are not yet well understood. Androgen-dependent PCa cell lines were used to generate resistant models to ADT only or in combination with Abiraterone and/or Enzalutamide (concomitant models). Functional and genetic analyses were performed for each resistance model by real-time cell monitoring assays, flow cytometry and RT-qPCR. In androgen-dependent PCa cells, the administration of Abiraterone and/or Enzalutamide as first-line treatment involved a critical inhibition of AR activity associated with a significant cell growth inhibition. Genetic analyses on ADT-resistant PCa cell lines showed that the CRPC phenotype was accompanied by overexpression of AR full-length and AR target genes, but not necessarily AR-V7 and/or AR-V9 isoforms. These ADT resistant cell lines showed higher proliferation rates, migration and invasion abilities. Importantly, ADT resistance induced cross-resistance to Abiraterone and/or Enzalutamide. Similarly, concomitant models possessed an elevated expression of AR full-length and proliferation rates and acquired cross-resistance to its alternative NHA as second-line treatment., Instituto de Salud Carlos III PI17/00989, European Regional Development Fund "A way to build Europe", Ramon y Cajal - Ministry of Economy and Competitiveness RYC-2015-18382, Ministry of Education, Culture and Sport FPU14/05461, University of Granada

Published
2021

3. Characterization and Therapeutic Effect of a pH Stimuli Responsive Polymeric Nanoformulation for Controlled Drug Release

Author

Maria Victoria Cano-Cortes, Rosario M. Sánchez-Martín, Jose Antonio Laz-Ruiz, Juan J. Díaz-Mochón, [Cano-Cortes,MV, Laz-Ruiz,JA, Diaz-Mochon,JJ, Sanchez-Martin,RM] GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain. [Cano-Cortes,MV, Sanchez-Martin,RM] Department of Medicinal & Organic Chemistry, Excellence Research Unit of 'Chemistry Applied to Biomedicine and the Environment', Faculty of Pharmacy, University of Granada, Granada, Spain. [Cano-Cortes,MV, Sanchez-Martin,RM] Biosanitary Research Institute of Granada (ibs. GRANADA), University Hospital, Granada, Spain., and This research was funded by the Spanish Ministry of Economy and Competitiveness (MINECO), grant number BIO2016-80519 and the Health Institute Carlos III (ISCIII), grant number DTS18/00121 and the Andalusian Regional Government, grant number PAIDI-TC-PVT-PSETC-2.0.

Subjects
Drug, Polymers and Plastics, Cancer therapy, Concentración de iones de hidrógeno, media_common.quotation_subject, Covalent drug conjugation, Therapeutic nanodevice, 02 engineering and technology, Pharmacology, 01 natural sciences, Article, Polymeric nanoparticles, lcsh:QD241-441, Therapeutic index, lcsh:Organic chemistry, Anatomy::Cells::Cells, Cultured::Cell Line [Medical Subject Headings], Controlled drug deliver, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Toxicity Tests::Inhibitory Concentration 50 [Medical Subject Headings], Nanodevice, IC50, Phenomena and Processes::Chemical Phenomena::Hydrogen-Ion Concentration [Medical Subject Headings], covalent drug conjugation, Technology and Food and Beverages::Technology, Industry, and Agriculture::Manufactured Materials::Nanostructures::Nanoparticles [Medical Subject Headings], media_common, therapeutic nanodevice, Controlled drug delivery, Phenomena and Processes::Genetic Phenomena::Genetic Processes::DNA Damage [Medical Subject Headings], 010405 organic chemistry, Chemistry, Therapeutic effect, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [Medical Subject Headings], Nanopartículas, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Drug Therapy::Drug Delivery Systems::Delayed-Action Preparations [Medical Subject Headings], General Chemistry, 021001 nanoscience & nanotechnology, Controlled release, controlled drug delivery, In vitro, 0104 chemical sciences, polymeric nanoparticles, Cancer cell, Concentración 50 Inhibidora, cancer therapy, Chemicals and Drugs::Organic Chemicals::Alcohols::Glycols::Ethylene Glycols::Polyethylene Glycols [Medical Subject Headings], 0210 nano-technology
Abstract

Despite the large number of polymeric nanodelivery systems that have been recently developed, there is still room for improvement in terms of therapeutic efficiency. Most reported nanodevices for controlled release are based on drug encapsulation, which can lead to undesired drug leakage with a consequent reduction in efficacy and an increase in systemic toxicity. Herein, we present a strategy for covalent drug conjugation to the nanodevice to overcome this drawback. In particular, we characterize and evaluate an effective therapeutic polymeric PEGylated nanosystem for controlled pH-sensitive drug release on a breast cancer (MDA-MB-231) and two lung cancer (A549 and H520) cell lines. A significant reduction in the required drug dose to reach its half maximal inhibitory concentration (IC50 value) was achieved by conjugation of the drug to the nanoparticles, which leads to an improvement in the therapeutic index by increasing the efficiency. The genotoxic effect of this nanodevice in cancer cells was confirmed by nucleus histone H2AX specific immunostaining. In summary, we successfully characterized and validated a pH responsive therapeutic polymeric nanodevice in vitro for controlled anticancer drug release., Spanish Ministry of Economy and Competitiveness (MINECO) BIO2016-80519, Health Institute Carlos III (ISCIII) DTS18/00121, Andalusian Regional Government PAIDI-TC-PVT-PSETC-2.0

Published
2020

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