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[PMID]:29274490
[Au] Autor:Ghawanmeh AA; Chong KF; Sarkar SM; Bakar MA; Othaman R; Khalid RM
[Ad] Endereço:Faculty of Industrial Sciences & Technology, University Malaysia Pahang, Gambang, 26300 Kuantan, Pahang, Malaysia. Electronic address: gh.just4chem@hotmail.com.
[Ti] Título:Colchicine prodrugs and codrugs: Chemistry and bioactivities.
[So] Source:Eur J Med Chem;144:229-242, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Antimitotic colchicine possesses low therapeutic index due to high toxicity effects in non-target cell. However, diverse colchicine analogs have been derivatized as intentions for toxicity reduction and structure-activity relationship (SAR) studying. Hybrid system of colchicine structure with nontoxic biofunctional compounds modified further affords a new entity in chemical structure with enhanced activity and selectivity. Moreover, nanocarrier formulation strategies have been used for colchicine delivery. This review paper focuses on colchicine nanoformulation, chemical synthesis of colchicine prodrugs and codrugs with different linkers, highlights linker chemical nature and biological activity of synthesized compounds. Additionally, classification of colchicine prodrugs based on type of conjugates is discussed, as biopolymers prodrugs, fluorescent prodrug, metal complexes prodrug, metal-labile prodrug and bioconjugate prodrug. Finally, we briefly summarized the biological importance of colchicine nanoformulation, colchicine prodrugs and codrugs.
[Mh] Termos MeSH primário: Colchicina/análogos & derivados
Colchicina/farmacologia
Pró-Fármacos/química
Pró-Fármacos/farmacologia
Moduladores de Tubulina/química
Moduladores de Tubulina/farmacologia
[Mh] Termos MeSH secundário: Animais
Desenho de Drogas
Seres Humanos
Mitose/efeitos dos fármacos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Prodrugs); 0 (Tubulin Modulators); SML2Y3J35T (Colchicine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171224
[St] Status:MEDLINE


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[PMID]:28456679
[Au] Autor:Khaliq NU; Oh KS; Sandra FC; Joo Y; Lee J; Byun Y; Kim IS; Kwon IC; Seo JH; Kim SY; Yuk SH
[Ad] Endereço:College of Pharmacy, Korea University, 2511 Sejongro, Sejong 30019, Republic of Korea.
[Ti] Título:Assembly of polymer micelles through the sol-gel transition for effective cancer therapy.
[So] Source:J Control Release;255:258-269, 2017 Jun 10.
[Is] ISSN:1873-4995
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Photo-induced apoptosis-targeted chemotherapy (PIATC) was designed and characterized to propose a new protocol for improved chemotherapy. Intratumoral injection was selected as the mode of administration of the anticancer drug, doxorubicin (DOX). To extend the retention time of DOX at the tumor parenchyma, in-situ gel formation was induced through the sol-gel transition of the Pluronic NPs containing a prodrug of DOX or a photosensitizer. The prodrug (DEVD-S-DOX) was designed to be inactive with a peptide moiety (Aspartic acid-Glutamic acid-Valine-Aspartic acid: DEVD) linked to DOX and to be cleaved into free DOX by caspase-3 expressed with apoptosis. For reactive oxygen species (ROS)-mediated apoptosis, photo-irradiation with methylene blue (MB, photosensitizer) was utilized. The sol-gel transition of the Pluronic NPs containing reactive species, DEVD-S-DOX or MB, was examined by measuring the cloud point and the gel strength in response to temperature change. ROS-mediated apoptosis was observed by measuring the ROS and membrane integrity with induced apoptosis. The in vivo antitumor efficacy of PIATC was measured with a cardiotoxicity assay in tumor-bearing mice.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Doxorrubicina/administração & dosagem
Azul de Metileno/administração & dosagem
Fotoquimioterapia
Fármacos Fotossensibilizantes/administração & dosagem
Poloxâmero/administração & dosagem
Pró-Fármacos/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacocinética
Antineoplásicos/uso terapêutico
Apoptose/efeitos dos fármacos
Caspase 3/metabolismo
Linhagem Celular Tumoral
Doxorrubicina/farmacocinética
Doxorrubicina/uso terapêutico
Liberação Controlada de Fármacos
Géis
Luz
Masculino
Azul de Metileno/uso terapêutico
Camundongos Endogâmicos C3H
Micelas
Neoplasias/tratamento farmacológico
Neoplasias/metabolismo
Fármacos Fotossensibilizantes/uso terapêutico
Poloxâmero/uso terapêutico
Pró-Fármacos/farmacocinética
Pró-Fármacos/uso terapêutico
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Gels); 0 (Micelles); 0 (Photosensitizing Agents); 0 (Prodrugs); 0 (Reactive Oxygen Species); 106392-12-5 (Poloxamer); 80168379AG (Doxorubicin); EC 3.4.22.- (Caspase 3); T42P99266K (Methylene Blue)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE


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[PMID]:29441997
[Au] Autor:Bhunchu S; Muangnoi C; Rojsitthisak P; Rojsitthisak P
[Ti] Título:Curcumin diethyl disuccinate encapsulated in chitosan/alginate nanoparticles for improvement of its cytotoxicity against MDA-MB-231 human breast cancer cells.
[So] Source:Pharmazie;71(12):691-700, 2016 Dec 01.
[Is] ISSN:0031-7144
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Curcumin diethyl disuccinate (CDD) is a succinate prodrug of curcuminoids that has better stability in human plasma and improved in vitro cytotoxicity compared to curcumin. Therefore, CDD has the potential for further development as an anticancer agent. In this study, we focused on optimization of the formulation of CDD-loaded chitosan/alginate nanoparticles using Box-Behnken statistical design to enhance the therapeutic efficacy of CDD. Oil-in-water emulsification followed by ionotropic gelification was used to prepare the CDD-loaded chitosan/ alginate nanoparticles. A formulation with a 0.05:1 chitosan/alginate mass ratio, 0.65% (w/v) Pluronic F127 and 1.5 mg/ml CDD was found to be optimal. FTIR, TGA and XRD confirmed the encapsulation of CDD molecules in the nanoparticles. In vitro cytotoxicity and cellular uptake studies showed that CDD-loaded chitosan/alginate nanoparticles had significantly higher cytotoxicity and cellular uptake in human breast adenocarcinoma MDA-MB-231 cells, compared to free CDD. Physical and chemical stability studies indicated that the optimally formulated CDD-loaded chitosan/alginate nanoparticles were stable at 4 °C for 3 months.
[Mh] Termos MeSH primário: Alginatos/química
Antineoplásicos Fitogênicos/administração & dosagem
Antineoplásicos Fitogênicos/farmacologia
Neoplasias da Mama/tratamento farmacológico
Quitosana/química
Curcumina/análogos & derivados
Excipientes/química
Nanopartículas
Succinatos/administração & dosagem
Succinatos/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos Fitogênicos/farmacocinética
Neoplasias da Mama/metabolismo
Linhagem Celular Tumoral
Curcumina/administração & dosagem
Curcumina/farmacocinética
Curcumina/farmacologia
Composição de Medicamentos
Estabilidade de Medicamentos
Emulsões
Feminino
Seres Humanos
Poloxâmero
Pró-Fármacos
Succinatos/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Alginates); 0 (Antineoplastic Agents, Phytogenic); 0 (Emulsions); 0 (Excipients); 0 (Prodrugs); 0 (Succinates); 0 (curcumin diethyl disuccinate); 106392-12-5 (Poloxamer); 9012-76-4 (Chitosan); IT942ZTH98 (Curcumin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180215
[St] Status:MEDLINE
[do] DOI:10.1691/ph.2016.6105


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[PMID]:29324339
[Au] Autor:Azzouz R; Peauger L; Gembus V; Tîntas ML; Sopková-de Oliveira Santos J; Papamicaël C; Levacher V
[Ad] Endereço:VFP Therapies, 15 rue François Couperin, 76000 Rouen, France.
[Ti] Título:Novel donepezil-like N-benzylpyridinium salt derivatives as AChE inhibitors and their corresponding dihydropyridine "bio-oxidizable" prodrugs: Synthesis, biological evaluation and structure-activity relationship.
[So] Source:Eur J Med Chem;145:165-190, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:As an extension of our previous work on donepezil-based "bio-oxidizable" prodrug approach, two new classes of N-benzylpyridinium donepezil analogues in tetralone B2 and acetophenone B3 series and a new set of indanone derivatives B1 were investigated along with the corresponding dihydropyridine prodrugs A1-3. A total of fifty one N-benzylpyridinium quaternary donepezil analogues B1-3 and twenty two prodrugs A1-3 were synthesized and evaluated for their inhibitory activities against hAChE and eqBuChE. While most prodrugs A1-3 were demonstrated to be inactive against AChE (IC > 10 µM), a large number of the corresponding N-benzylpyridinium salt B1-3 exhibited appealing three-to-one-digit nanomolar hAChE inhibitory activities and even reaching subnanomolar activity (IC = 0.36 nM). In addition, in silico docking studies were conducted for several compounds to explain the more relevant in vitro results. Lastly, the influence of the two stereogenic centers in prodrugs A was also evaluated, highlighting not only marked differences in residual AChE inhibitory activity of the four separated isomers of prodrug 23h (IC ranging from 173 nM to 10 µM) but also significant variations of the oxidation rate between two separated diastereoisomers of prodrug 24a. This work provides useful information in the search of a preclinical candidate to conduct further development of this attractive "bio-oxidizable" prodrug strategy.
[Mh] Termos MeSH primário: Acetilcolinesterase/metabolismo
Inibidores da Colinesterase/farmacologia
Di-Hidropiridinas/farmacologia
Pró-Fármacos/farmacologia
Compostos de Piridínio/farmacologia
[Mh] Termos MeSH secundário: Animais
Butirilcolinesterase/metabolismo
Inibidores da Colinesterase/síntese química
Inibidores da Colinesterase/química
Di-Hidropiridinas/química
Relação Dose-Resposta a Droga
Electrophorus
Cavalos
Simulação de Acoplamento Molecular
Estrutura Molecular
Pró-Fármacos/síntese química
Pró-Fármacos/química
Compostos de Piridínio/síntese química
Compostos de Piridínio/química
Sais/síntese química
Sais/química
Sais/farmacologia
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Dihydropyridines); 0 (Prodrugs); 0 (Pyridinium Compounds); 0 (Salts); 7M8K3P6I89 (1,4-dihydropyridine); EC 3.1.1.7 (Acetylcholinesterase); EC 3.1.1.8 (Butyrylcholinesterase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE


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[PMID]:29231931
[Au] Autor:Imani Nejad M; Yang D; Shen B; Gates KS
[Ad] Endereço:Department of Chemistry, University of Missouri, 125 Chemistry Bldg, Columbia, MO 65211, USA. gatesk@missouri.edu.
[Ti] Título:Oxidative activation of leinamycin E1 triggers alkylation of guanine residues in double-stranded DNA.
[So] Source:Chem Commun (Camb);54(3):256-259, 2018 Jan 02.
[Is] ISSN:1364-548X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:It may be useful to develop prodrugs that are selectively activated by oxidative stress in cancer cells to release cell-killing reactive intermediates. However, relatively few chemical strategies exist for the activation of prodrugs under conditions of oxidative stress. Here we provide evidence for a novel process in which oxidation of a thiol residue in the natural product leinamycin E1 by H O and other byproducts of cellular oxidative stress initiates generation of an episulfonium ion that selectively alkylates guanine residues in duplex DNA.
[Mh] Termos MeSH primário: Antineoplásicos Alquilantes/química
DNA/química
Guanina/química
Lactamas Macrocíclicas/química
Pró-Fármacos/química
[Mh] Termos MeSH secundário: Alquilação
Antineoplásicos Alquilantes/síntese química
Dano ao DNA
Compostos Férricos/química
Peróxido de Hidrogênio/química
Lactamas Macrocíclicas/síntese química
Oxirredução
Pró-Fármacos/síntese química
Xantina/química
Xantina Oxidase/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Alkylating); 0 (Ferric Compounds); 0 (Lactams, Macrocyclic); 0 (Prodrugs); 0 (leinamycin E1); 1AVZ07U9S7 (Xanthine); 5Z93L87A1R (Guanine); 9007-49-2 (DNA); BBX060AN9V (Hydrogen Peroxide); EC 1.17.3.2 (Xanthine Oxidase); LUX2X1H1IC (ammonium ferric sulfate)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171213
[St] Status:MEDLINE
[do] DOI:10.1039/c7cc08482j


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[PMID]:29258368
[Au] Autor:Ward K; Citrome L
[Ad] Endereço:a University of Michigan College of Pharmacy , Ann Arbor , MI , USA.
[Ti] Título:Lisdexamfetamine: chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy, safety, and tolerability in the treatment of binge eating disorder.
[So] Source:Expert Opin Drug Metab Toxicol;14(2):229-238, 2018 Feb.
[Is] ISSN:1744-7607
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: The indications for lisdexamfetamine (LDX), a central nervous system stimulant, were recently expanded to include treatment of moderate to severe binge eating disorder (BED). Areas covered: This review aims to describe the chemistry and pharmacology of LDX, as well as the clinical trials investigating the efficacy and safety of this medication for the management of BED. Expert opinion: LDX is the first medication with United States Food and Drug Administration approval for the treatment of BED. It is an inactive prodrug of d-amphetamine that extends the half-life of d-amphetamine to allow for once daily dosing. D-amphetamine acts primarily to increase the concentrations of synaptic dopamine and norepinephrine. Metabolism of LDX to d-amphetamine occurs when peptidases in red blood cells cleave the covalent bond between d-amphetamine and l-lysine. D-amphetamine is then further metabolized by CYP2D6. Excretion is primarily through renal mechanisms. In clinical trials, LDX demonstrated statistical and clinical superiority over placebo in reducing binge eating days per week at doses of 50 and 70 mg daily. Commonly reported side effects of LDX include dry mouth, insomnia, weight loss, and headache, and its use should be avoided in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia or coronary artery disease. As with all CNS stimulants, risk of abuse needs to be assessed prior to prescribing.
[Mh] Termos MeSH primário: Transtorno da Compulsão Alimentar/tratamento farmacológico
Estimulantes do Sistema Nervoso Central/administração & dosagem
Dimesilato de Lisdexanfetamina/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Transtorno da Compulsão Alimentar/fisiopatologia
Estimulantes do Sistema Nervoso Central/efeitos adversos
Estimulantes do Sistema Nervoso Central/farmacocinética
Esquema de Medicação
Meia-Vida
Seres Humanos
Dimesilato de Lisdexanfetamina/efeitos adversos
Dimesilato de Lisdexanfetamina/farmacocinética
Metildopa/metabolismo
Norepinefrina/metabolismo
Pró-Fármacos
Índice de Gravidade de Doença
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Central Nervous System Stimulants); 0 (Prodrugs); 56LH93261Y (Methyldopa); SJT761GEGS (Lisdexamfetamine Dimesylate); X4W3ENH1CV (Norepinephrine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE
[do] DOI:10.1080/17425255.2018.1420163


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[PMID]:29210311
[Au] Autor:Currò D
[Ad] Endereço:a Istituto di Farmacologia , Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli , Roma , Italia.
[Ti] Título:The role of gut microbiota in the modulation of drug action: a focus on some clinically significant issues.
[So] Source:Expert Rev Clin Pharmacol;11(2):171-183, 2018 Feb.
[Is] ISSN:1751-2441
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: A healthy gut microbiota is necessary for the normal operation of several body functions, including gastrointestinal sensitivity and motility, lipid and glucid metabolism, immune surveillance, and host behavior. In addition, intestinal bacteria contribute to determining the pharmacological properties of several drugs by producing different drug metabolizing enzymes. Areas covered: Four enzymatic processes are discussed: prodrug activation; drug inactivation; drug deconjugation; and hydrolysis of natural glycosides with further metabolism of released aglycones. For each of these processes, a literature search has been undertaken on certain paradigmatic examples that have significant clinical implications: aminosalicylates and anthranoid laxatives; digoxin; irinotecan and non-steroidal anti-inflammatory drugs (NSAIDs); rutin, diosmin, and baicalin. Expert commentary: The modulation of certain reactions catalyzed by gut bacterial enzymes may offer new opportunities to improve the clinical efficacy of drugs such as aminosalicylates, and natural glycosides by increasing their metabolic transformation, and of digoxin by reducing its inactivation, or to decrease the lower intestinal toxicity of irinotecan, and NSAIDs by inhibiting the hydrolytic cleavage of their conjugates. Randomized clinical trials are awaited to clarify whether new intervention strategies may modulate these processes and provide clinical benefits such as improved therapeutic outcomes and drug safety profiles.
[Mh] Termos MeSH primário: Microbioma Gastrointestinal
Trato Gastrointestinal/metabolismo
Preparações Farmacêuticas/metabolismo
[Mh] Termos MeSH secundário: Animais
Trato Gastrointestinal/microbiologia
Glicosídeos/metabolismo
Seres Humanos
Preparações Farmacêuticas/administração & dosagem
Pró-Fármacos
Ensaios Clínicos Controlados Aleatórios como Assunto
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Glycosides); 0 (Pharmaceutical Preparations); 0 (Prodrugs)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171207
[St] Status:MEDLINE
[do] DOI:10.1080/17512433.2018.1414598


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[PMID]:28454912
[Au] Autor:Pertusati F; Serafini S; Albadry N; Snoeck R; Andrei G
[Ad] Endereço:School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, CF10 3NB, Cardiff, Wales, United Kingdom. Electronic address: pertusatif1@cardiff.ac.uk.
[Ti] Título:Phosphonoamidate prodrugs of C5-substituted pyrimidine acyclic nucleosides for antiviral therapy.
[So] Source:Antiviral Res;143:262-268, 2017 07.
[Is] ISSN:1872-9096
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Acyclic nucleoside phosphonates (ANPs) are nowadays one of the key drugs in the treatment of DNA virus and retrovirus infections. In this work, we report the synthesis and antiviral evaluation of phosphonoamidate and diamidates prodrugs of C5-pyrimidine acyclic nucleosides derivatives functionalized with but-2-enyl- chain. In the phosphonoamidate series, the most active compound 15, showed sub-micromolar activity against varicella zoster virus (VZV) (EC = 0.09-0.5 µM) and µM activity against human cytomegalovirus (HCMV) and herpes simplex virus (HSV). Separation of single diastereoisomers for compound 14, showed that 14b had better anti-herpesvirus activity and no cytotoxicity compared to the diastereoisomeric mixture 14. Very interestingly, phosphonodiamidate 21 showed anti-herpesvirus activity with excellent activity against wild type and thymidine kinase-deficient (TK ) VZV strains (EC = 0.47 and 0.2 µM, respectively) and HCMV (EC = 3.5-7.2 µM) without any cytotoxicity (CC > 100).
[Mh] Termos MeSH primário: Pró-Fármacos/síntese química
Pró-Fármacos/farmacologia
Nucleosídeos de Pirimidina/síntese química
Nucleosídeos de Pirimidina/farmacologia
[Mh] Termos MeSH secundário: Antivirais/síntese química
Antivirais/farmacologia
Linhagem Celular
Citomegalovirus/efeitos dos fármacos
Herpesvirus Humano 3/efeitos dos fármacos
Seres Humanos
Simplexvirus/efeitos dos fármacos
Timidina Quinase
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Prodrugs); 0 (Pyrimidine Nucleosides); EC 2.7.1.21 (Thymidine Kinase)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


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[PMID]:28456517
[Au] Autor:Klein-Szanto AJ; Bassi DE
[Ad] Endereço:Fox Chase Cancer Center, 333 Cotman Ave, Philadelphia 19111, USA.
[Ti] Título:Proprotein convertase inhibition: Paralyzing the cell's master switches.
[So] Source:Biochem Pharmacol;140:8-15, 2017 09 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Proprotein convertases are serine proteases responsible for the cleavage and subsequent activation of protein substrates, many of them relevant for the development of an ample variety of diseases. Seven of the PCs, including furin and PACE4, recognize and hydrolyze the C-terminal end of the general sequence RXRR/KXR, whereas PCSK-9 recognizes a series of non-basic amino acids. In some systems, PC-mediated substrate activation results in the development of pathological processes, such as cancer, endocrinopathies, and cardiovascular and infectious diseases. After establishing PCs as relevant contributors to disease processes, research efforts were directed towards the development of inhibition strategies, including small and large molecules, anti-sense therapies, and antibody-based therapies. Most of these inhibitors mimic the consensus sequence of PCs, blocking the active site in a competitive manner. The most promising inhibitors were designed as bioengineered proteins; however, some non-protein and peptidomimetic agents have also proved to be effective. These efforts led to the design of pre-clinical studies and clinical trials utilizing inhibitors to PCs. Although the initial studies were performed using non-selective PCs inhibitors, such as CMK, the search for more specific, and compartmentalized selective inhibitors resulted in specific activities ascribed to some, but not all of the PCs. For instance, PACE4 inhibitors were effective in decreasing prostate cancer cell proliferation, and neovascularization. Decreased metastatic ovarian cancer utilizing furin inhibitors represents one of the major endeavors, currently in a phase II trial stage. Antibodies targeting PCSK-9 decreased significantly the levels of HDL-cholesterol, in a phase III trial. The study of Proprotein convertases has reached a stage of maturity. New strategies based on the alteration of their activity at the cellular and clinical level represent a promising experimental pharmacology field. The development of allosteric inhibitors, or specific agents directed against individual PCs is one of the challenges to be unraveled in the future.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Desenho de Drogas
Drogas em Investigação/uso terapêutico
Inibidores Enzimáticos/uso terapêutico
Terapia de Alvo Molecular
Neoplasias/tratamento farmacológico
Pró-Proteína Convertases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Ativação Metabólica
Animais
Antineoplásicos/química
Antineoplásicos/farmacocinética
Antineoplásicos/farmacologia
Sítios de Ligação
Ligação Competitiva
Domínio Catalítico
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Drogas em Investigação/química
Drogas em Investigação/farmacocinética
Drogas em Investigação/farmacologia
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacocinética
Inibidores Enzimáticos/farmacologia
Seres Humanos
Isoenzimas/antagonistas & inibidores
Isoenzimas/química
Isoenzimas/metabolismo
Proteínas de Neoplasias/antagonistas & inibidores
Proteínas de Neoplasias/química
Proteínas de Neoplasias/metabolismo
Neoplasias/enzimologia
Neoplasias/patologia
Pró-Fármacos/química
Pró-Fármacos/farmacocinética
Pró-Fármacos/farmacologia
Pró-Fármacos/uso terapêutico
Pró-Proteína Convertases/química
Pró-Proteína Convertases/metabolismo
Carga Tumoral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Drugs, Investigational); 0 (Enzyme Inhibitors); 0 (Isoenzymes); 0 (Neoplasm Proteins); 0 (Prodrugs); EC 3.4.21.- (Proprotein Convertases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180201
[Lr] Data última revisão:
180201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE


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[PMID]:29211454
[Au] Autor:Vlahov IR; Qi L; Kleindl PJ; Santhapuram HK; Felten A; Parham GL; Wang K; You F; Vaughn JF; Hahn SJ; Klein HF; Vetzel M; Reddy JA; Nelson M; Nicoson J; Leamon CP
[Ad] Endereço:Endocyte Inc. , 3000 Kent Avenue, West Lafayette, Indiana 47906, United States.
[Ti] Título:Latent Warheads for Targeted Cancer Therapy: Design and Synthesis of pro-Pyrrolobenzodiazepines and Conjugates.
[So] Source:Bioconjug Chem;28(12):2921-2931, 2017 Dec 20.
[Is] ISSN:1520-4812
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds, and are currently under development as novel payloads in antibody-drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed diazepine-ring-opened conjugated prodrugs lacking the imine moiety. Once the prodrug (pro-PBD) conjugate enters a targeted cell, cleavage of the linker system triggers the generation of a reactive intermediate possessing an aldehyde and aromatic amine. An intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine and, as a result, the diazepine ring. In our pro-PBDs, we mask the aldehyde as a hydrolytically sensitive oxazolidine moiety which in turn is a part of a reductively labile self-immolative linker system. To prove the range of applications for this new class of latent DNA-alkylators, we designed and synthesized several novel latent warheads: pro-PBD dimers and hybrids of pro-PBD with other sequence-selective DNA minor groove binders. Preliminary preclinical pharmacology studies showed excellent biological activity and specificity.
[Mh] Termos MeSH primário: Benzodiazepinas/química
Benzodiazepinas/metabolismo
Desenho de Drogas
Terapia de Alvo Molecular
Neoplasias/tratamento farmacológico
Pró-Fármacos/síntese química
Pró-Fármacos/metabolismo
Pirróis/química
Pirróis/metabolismo
[Mh] Termos MeSH secundário: Antineoplásicos/química
Antineoplásicos/metabolismo
Antineoplásicos/farmacologia
Antineoplásicos/uso terapêutico
Benzodiazepinas/farmacologia
Benzodiazepinas/uso terapêutico
Técnicas de Química Sintética
Seres Humanos
Células KB
Neoplasias/patologia
Pró-Fármacos/química
Pirróis/farmacologia
Pirróis/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Prodrugs); 0 (Pyrroles); 0 (pyrrolo(2,1-c)(1,4)benzodiazepine); 12794-10-4 (Benzodiazepines)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171207
[St] Status:MEDLINE
[do] DOI:10.1021/acs.bioconjchem.7b00476



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