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1.
Nucleic Acids Res ; 50(5): 2719-2735, 2022 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-35234933

RESUMEN

Parasitic helminths infecting humans are highly prevalent infecting ∼2 billion people worldwide, causing inflammatory responses, malnutrition and anemia that are the primary cause of morbidity. In addition, helminth infections of cattle have a significant economic impact on livestock production, milk yield and fertility. The etiological agents of helminth infections are mainly Nematodes (roundworms) and Platyhelminths (flatworms). G-quadruplexes (G4) are unusual nucleic acid structures formed by G-rich sequences that can be recognized by specific G4 ligands. Here we used the G4Hunter Web Tool to identify and compare potential G4 sequences (PQS) in the nuclear and mitochondrial genomes of various helminths to identify G4 ligand targets. PQS are nonrandomly distributed in these genomes and often located in the proximity of genes. Unexpectedly, a Nematode, Ascaris lumbricoides, was found to be highly enriched in stable PQS. This species can tolerate high-stability G4 structures, which are not counter selected at all, in stark contrast to most other species. We experimentally confirmed G4 formation for sequences found in four different parasitic helminths. Small molecules able to selectively recognize G4 were found to bind to Schistosoma mansoni G4 motifs. Two of these ligands demonstrated potent activity both against larval and adult stages of this parasite.


Asunto(s)
G-Cuádruplex , Nematodos , Parásitos/genética , Platelmintos , Animales , Bovinos , Genoma , Helmintos/genética , Humanos , Ligandos , Nematodos/genética , Platelmintos/genética
2.
Nucleic Acids Res ; 49(13): 7695-7712, 2021 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-34232992

RESUMEN

The multidomain non-structural protein 3 (Nsp3) is the largest protein encoded by coronavirus (CoV) genomes and several regions of this protein are essential for viral replication. Of note, SARS-CoV Nsp3 contains a SARS-Unique Domain (SUD), which can bind Guanine-rich non-canonical nucleic acid structures called G-quadruplexes (G4) and is essential for SARS-CoV replication. We show herein that the SARS-CoV-2 Nsp3 protein also contains a SUD domain that interacts with G4s. Indeed, interactions between SUD proteins and both DNA and RNA G4s were evidenced by G4 pull-down, Surface Plasmon Resonance and Homogenous Time Resolved Fluorescence. These interactions can be disrupted by mutations that prevent oligonucleotides from folding into G4 structures and, interestingly, by molecules known as specific ligands of these G4s. Structural models for these interactions are proposed and reveal significant differences with the crystallographic and modeled 3D structures of the SARS-CoV SUD-NM/G4 interaction. Altogether, our results pave the way for further studies on the role of SUD/G4 interactions during SARS-CoV-2 replication and the use of inhibitors of these interactions as potential antiviral compounds.


Asunto(s)
COVID-19/virología , Proteasas Similares a la Papaína de Coronavirus/metabolismo , G-Cuádruplex , Dominios y Motivos de Interacción de Proteínas , SARS-CoV-2 , Secuencia de Aminoácidos , Proteasas Similares a la Papaína de Coronavirus/química , Humanos , Ligandos , Modelos Moleculares , Unión Proteica , Conformación Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Análisis Espectral , Relación Estructura-Actividad , Replicación Viral
3.
J Pharmacol Exp Ther ; 377(2): 293-304, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33602875

RESUMEN

In failing hearts, Na+/Ca2+ exchanger (NCX) overactivity contributes to Ca2+ depletion, leading to contractile dysfunction. Inhibition of NCX is expected to normalize Ca2+ mishandling, to limit afterdepolarization-related arrhythmias, and to improve cardiac function in heart failure (HF). SAR340835/SAR296968 is a selective NCX inhibitor for all NCX isoforms across species, including human, with no effect on the native voltage-dependent calcium and sodium currents in vitro. Additionally, it showed in vitro and in vivo antiarrhythmic properties in several models of early and delayed afterdepolarization-related arrhythmias. Its effect on cardiac function was studied under intravenous infusion at 250,750 or 1500 µg/kg per hour in dogs, which were either normal or submitted to chronic ventricular pacing at 240 bpm (HF dogs). HF dogs were infused with the reference inotrope dobutamine (10 µg/kg per minute, i.v.). In normal dogs, NCX inhibitor increased cardiac contractility (dP/dtmax) and stroke volume (SV) and tended to reduce heart rate (HR). In HF dogs, NCX inhibitor significantly and dose-dependently increased SV from the first dose (+28.5%, +48.8%, and +62% at 250, 750, and 1500 µg/kg per hour, respectively) while significantly increasing dP/dtmax only at 1500 (+33%). Furthermore, NCX inhibitor significantly restored sympathovagal balance and spontaneous baroreflex sensitivity (BRS) from the first dose and reduced HR at the highest dose. In HF dogs, dobutamine significantly increased dP/dtmax and SV (+68.8%) but did not change HR, sympathovagal balance, or BRS. Overall, SAR340835, a selective potent NCX inhibitor, displayed a unique therapeutic profile, combining antiarrhythmic properties, capacity to restore systolic function, sympathovagal balance, and BRS in HF dogs. NCX inhibitors may offer new therapeutic options for acute HF treatment. SIGNIFICANCE STATEMENT: HF is facing growing health and economic burden. Moreover, patients hospitalized for acute heart failure are at high risk of decompensation recurrence, and no current acute decompensated HF therapy definitively improved outcomes. A new potent, Na+/Ca2+ exchanger inhibitor SAR340835 with antiarrhythmic properties improved systolic function of failing hearts without creating hypotension, while reducing heart rate and restoring sympathovagal balance. SAR340835 may offer a unique and attractive pharmacological profile for patients with acute heart failure as compared with current inotrope, such as dobutamine.


Asunto(s)
Insuficiencia Cardíaca/tratamiento farmacológico , Moduladores del Transporte de Membrana/uso terapéutico , Intercambiador de Sodio-Calcio/antagonistas & inhibidores , Nervio Vago/efectos de los fármacos , Animales , Barorreflejo , Perros , Corazón/efectos de los fármacos , Frecuencia Cardíaca , Moduladores del Transporte de Membrana/administración & dosificación , Moduladores del Transporte de Membrana/farmacología , Contracción Miocárdica , Miocardio/metabolismo , Porcinos
4.
Arch Pharm (Weinheim) ; 354(8): e2000450, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33852185

RESUMEN

Current multiagent chemotherapy regimens have improved the cure rate in acute leukemia patients, but they are highly toxic and poorly efficient in relapsed patients. To improve the treatment approaches, new specific molecules are needed. The G-quadruplexes (G4s), which are noncanonical nucleic acid structures found in specific guanine-rich DNA or RNA, are involved in many cellular events, including control of gene expression. G4s are considered as targets for the development of anticancer agents. Heterocyclic molecules are well known to target and stabilize G4 structures. Thus, a new series of 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives (1a-i) was designed, synthesized, and evaluated against five human myeloid leukemia cell lines (K562, KU812, MV4-11, HL60, and U937). Their ability to stabilize various oncogene promoter G4 structures (c-MYC, BCL-2, and K-RAS) as well as the telomeric G4 was also determined through the fluorescence resonance energy transfer melting assay and native mass spectrometry. In addition, the more bioactive ligands 1g-i were tested for telomerase activity in HuT78 and MV4-11 protein extracts.


Asunto(s)
Antineoplásicos/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Fenantrolinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Diseño de Fármacos , Transferencia Resonante de Energía de Fluorescencia , G-Cuádruplex/efectos de los fármacos , Células HL-60 , Humanos , Células K562 , Leucemia Mieloide Aguda/patología , Ligandos , Fenantrolinas/síntesis química , Fenantrolinas/química , Relación Estructura-Actividad , Telomerasa/metabolismo , Células U937
5.
Molecules ; 26(4)2021 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-33562106

RESUMEN

Proviral integration site for Moloney murine leukemia virus (Pim)-1/2 kinase overexpression has been identified in a variety of hematologic (e.g., multiple myeloma or acute myeloid leukemia (AML)) and solid (e.g., colorectal carcinoma) tumors, playing a key role in cancer progression, metastasis, and drug resistance, and is linked to poor prognosis. These kinases are thus considered interesting targets in oncology. We report herein the design, synthesis, structure-activity relationships (SAR) and in vitro evaluations of new quinoxaline derivatives, acting as dual Pim1/2 inhibitors. Two lead compounds (5c and 5e) were then identified, as potent submicromolar Pim-1 and Pim-2 inhibitors. These molecules were also able to inhibit the growth of the two human cell lines, MV4-11 (AML) and HCT-116 (colorectal carcinoma), expressing high endogenous levels of Pim-1/2 kinases.


Asunto(s)
Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Quinoxalinas/síntesis química , Quinoxalinas/farmacología , Técnicas de Química Sintética , Humanos , Simulación del Acoplamiento Molecular , Conformación Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-pim-1/química , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Quinoxalinas/química , Quinoxalinas/metabolismo
6.
J Pharmacol Exp Ther ; 374(1): 24-37, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32332113

RESUMEN

Chronic kidney disease (CKD) remains a common disorder, leading to growing health and economic burden without curative treatment. In diabetic patients, CKD may result from a combination of metabolic and nonmetabolic-related factors, with mortality mainly driven by cardiovascular events. The marked overactivity of the urotensinergic system in diabetic patients implicates this vasoactive peptide as a possible contributor to the pathogenesis of renal as well as heart failure. Previous preclinical studies with urotensin II (UII) antagonists in chronic kidney disease were based on simple end points that did not reflect the complex etiology of the disease. Given this, our studies revisited the therapeutic value of UII antagonism in CKD and extensively characterized 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino) cyclohexanecarboxylic acid hydrochloride (SAR101099), a potent, selective, and orally long-acting UII receptor competitive antagonist, inhibiting not only UII but also urotensin-related peptide activities. SR101099 treatment more than halved proteinurea and albumin/creatinine ratio in spontaneously hypertensive stroke-prone (SHR-SP) rats fed with salt/fat diet and Dahl-salt-sensitive rats, respectively, and it halved albuminuria in streptozotocin-induced diabetes rats. Importantly, these effects were accompanied by a decrease in mortality of 50% in SHR-SP and of 35% in the Dahl salt-sensitive rats. SAR101099 was also active on CKD-related cardiovascular pathologies and partly preserved contractile reserve in models of heart failure induced by myocardial infarction or ischemia/reperfusion in rats and pigs, respectively. SAR101099 exhibited a good safety/tolerability profile at all tested doses in clinical phase-I studies. Together, these data suggest that CKD patient selection considering comorbidities together with new stratification modalities should unveil the urotensin antagonists' therapeutic potential. SIGNIFICANCE STATEMENT: Chronic kidney disease (CKD) is a pathology with growing health and economic burden, without curative treatment. For years, the impact of urotensin II receptor (UT) antagonism to treat CKD may have been compromised by available tools or models to deeper characterize the urotensinergic system. New potent, selective, orally long-acting cross-species UT antagonist such as SAR101099 exerting reno- and cardioprotective effects could offer novel therapeutic opportunities. Its preclinical and clinical results suggest that UT antagonism remains an attractive target in CKD on top of current standard of care.


Asunto(s)
Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/epidemiología , Animales , Comorbilidad , Células HEK293 , Hemodinámica/efectos de los fármacos , Humanos , Ratas , Insuficiencia Renal Crónica/fisiopatología
7.
J Enzyme Inhib Med Chem ; 35(1): 432-459, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31899980

RESUMEN

A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives was designed, synthesised, and evaluated in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiprotozoal activity with IC50 values in the µM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The quinoline 1c was identified as the most potent antimalarial candidate with a ratio of cytotoxic to antiparasitic activities of 97 against the P. falciparum CQ-sensitive strain 3D7. The quinazoline 3h was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 43 on T. brucei brucei strain. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma are possible targets of this kind of nitrogen heterocyclic compounds, we have also investigated stabilisation of the Plasmodium and Trypanosoma telomeric G-quadruplexes by our best compounds through FRET melting assays.


Asunto(s)
Antiprotozoarios/química , Antiprotozoarios/farmacología , Diseño de Fármacos , Quinolinas/química , Quinolinas/farmacología , Antiprotozoarios/síntesis química , Células Hep G2 , Humanos , Leishmania donovani/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Quinolinas/síntesis química , Relación Estructura-Actividad , Trypanosoma brucei brucei/efectos de los fármacos
8.
Int J Toxicol ; 38(1): 23-32, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30567462

RESUMEN

INTRODUCTION: Based on the ICH S7B and E14 guidance documents, QT interval (QTc) is used as the primary in vivo biomarker to assess the risk of drug-induced torsades de pointes (TdP). Clinical and nonclinical data suggest that drugs that prolong the corrected QTc with balanced multiple ion channel inhibition (most importantly the l-type calcium, Cav1.2, and persistent or late inward sodium current, Nav1.5, in addition to human Ether-à-go-go-Related Gene [hERG] IKr or Kv11.1) may have limited proarrhythmic liability. The heart rate-corrected J to T-peak (JTpc) measurement in particular may be considered to discriminate selective hERG blockers from multi-ion channel blockers. METHODS: Telemetry data from Beagle dogs given dofetilide (0.3 mg/kg), sotalol (32 mg/kg), and verapamil (30 mg/kg) orally and Cynomolgus monkeys given medetomidine (0.4 mg/kg) orally were retrospectively analyzed for effects on QTca, JTpca, and T-peak to T-end covariate adjusted (Tpeca) interval using individual rate correction and super intervals (calculated from 0-6, 6-12, 12-18, and 18-24 hours postdose). RESULTS: Dofetilide and cisapride (IKr or Kv11.1 blockers) were associated with significant increases in QTca and JTpca, while sotalol was associated with significant increases in QTca, JTpca, and Tpeca. Verapamil (a Kv11.1 and Cav1.2 blocker) resulted in a reduction in QTca and JTpca, however, and increased Tpeca. Medetomidine was associated with a reduction in Tpeca and increase in JTpca. DISCUSSION: Results from this limited retrospective electrocardiogram analysis suggest that JTpca and Tpeca may discriminate selective IKr blockers and multichannel blockers and could be considered in the context of an integrated comprehensive proarrhythmic risk assessment.


Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Electrocardiografía/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Animales , Biomarcadores , Cisaprida/farmacología , Perros , Evaluación Preclínica de Medicamentos , Síndrome de QT Prolongado/inducido químicamente , Macaca fascicularis , Masculino , Medetomidina/farmacología , Fenetilaminas/farmacología , Sotalol/farmacología , Sulfonamidas/farmacología , Telemetría , Verapamilo/farmacología
9.
Molecules ; 24(2)2019 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-30669445

RESUMEN

Peptides of natural and synthetic sources are compounds operating in a wide range of biological interactions. They play a key role in biotechnological applications as both therapeutic and diagnostic tools. They are easily synthesized thanks to solid-phase peptide devices where the amino acid sequence can be exactly selected at molecular levels, by tuning the basic units. Recently, peptides achieved resounding success in drug delivery and in nanomedicine smart applications. These applications are the most significant challenge of recent decades: they can selectively deliver drugs to only pathological tissues whilst saving the other districts of the body. This specific feature allows a reduction in the drug side effects and increases the drug efficacy. In this context, peptide-based aggregates present many advantages, including biocompatibility, high drug loading capacities, chemical diversity, specific targeting, and stimuli responsive drug delivery. A dual behavior is observed: on the one hand they can fulfill a structural and bioactive role. In this review, we focus on the design and the characterization of drug delivery systems using peptide-based carriers; moreover, we will also highlight the peptide ability to self-assemble and to actively address nanosystems toward specific targets.


Asunto(s)
Sistemas de Liberación de Medicamentos/tendencias , Nanoestructuras/química , Péptidos/química , Aminoácidos/química , Transporte Biológico , Dipéptidos , Liberación de Fármacos , Humanos , Terapia Molecular Dirigida , Nanomedicina , Fenilalanina/análogos & derivados , Fenilalanina/química , Multimerización de Proteína
10.
J Therm Biol ; 73: 32-40, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29549989

RESUMEN

The sexual phenotype of the gonad is dependent on incubation temperature in many turtles, all crocodilians, and some lepidosaurians. At hatching, identification of sexual phenotype is impossible without sacrificing the neonates. For this reason, a general method to infer sexual phenotype from incubation temperatures is needed. Temperature influences sex determination during a specific period of the embryonic development, starting when the gonad begins to form. At constant incubation temperatures, this thermosensitive period for sex determination (TSP) is located at the middle third of incubation duration (MTID). When temperature fluctuates, the position of the thermosensitive period for sex determination can be shifted from the MTID because embryo growth is affected by temperature. A method is proposed to locate the thermosensitive period for sex determination based on modelling the embryo growth, allowing its precise identification from a natural regime of temperatures. Results from natural nests and simulations show that the approximation of the thermosensitive period for sex determination to the middle third of incubation duration may create a quasi-systematic bias to lower temperatures when computing the average incubation temperature during this period and thus a male-bias for sex ratio estimate.


Asunto(s)
Modelos Biológicos , Procesos de Determinación del Sexo , Razón de Masculinidad , Temperatura , Tortugas/embriología , Animales , Simulación por Computador , Embrión no Mamífero/fisiología , Femenino , Masculino
11.
J Enzyme Inhib Med Chem ; 32(1): 547-563, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28114821

RESUMEN

Novel series of bis- and tris-pyrrolo[1,2-a]quinoxaline derivatives 1 were synthesized and tested for in vitro activity upon the intraerythrocytic stage of W2 and 3D7 Plasmodium falciparum strains. Biological results showed good antimalarial activity with IC50 in the µM range. In attempting to investigate the large broad-spectrum antiprotozoal activities of these new derivatives, their properties toward Leishmania donovani were also investigated and revealed their selective antiplasmodial profile. In parallel, the in vitro cytotoxicity of these molecules was assessed on the human HepG2 cell line. Structure-activity relationships of these new synthetic compounds are discussed here. The bis-pyrrolo[1,2-a]quinoxalines 1n and 1p were identified as the most potent antimalarial candidates with selectivity index (SI) of 40.6 on W2 strain, and 39.25 on 3D7 strain, respectively. As the telomeres of the parasite could constitute an attractive target, we investigated the possibility of targeting Plasmodium telomeres by stabilizing the Plasmodium telomeric G-quadruplexes through a FRET melting assay by our new compounds.


Asunto(s)
Antiprotozoarios/farmacología , Diseño de Fármacos , Leishmania donovani/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Propilaminas/farmacología , Quinoxalinas/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Estructura Molecular , Propilaminas/síntesis química , Propilaminas/química , Quinoxalinas/síntesis química , Quinoxalinas/química , Relación Estructura-Actividad
12.
Adv Physiol Educ ; 41(4): 528-538, 2017 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-29066603

RESUMEN

This article reminisces about the life and key scientific achievements of Jan Evangelista Purkinje (1787-1869), a versatile 19th century Czech pioneer of modern experimental physiology. In 1804, after completing senior high school, Purkinje joined the Piarist monk order, but, after a 3-yr novitiate, he gave up the religious calling "to deal more freely with science." In 1818, he earned a Medical Doctor degree from Prague University by defending a dissertation on intraocular phenomena observed in oneself. In 1823, Purkinje became a Physiology and Pathology professor at the Prussian Medical University in Breslau, where he innovated the traditional teaching methods of physiology. Purkinje's contributions to physiology were manifold: accurate descriptions of various visual phenomena (e.g., Purkinje-Sanson images, Purkinje phenomenon), discovery of the terminal network of the cardiac conduction system (Purkinje fibers), identification of cerebellar neuronal bodies (Purkinje cells), formulation of the vertigo law (Purkinje's law), discovery of criteria to classify human fingerprints, etc. In 1850, Purkinje accepted and held until his death the Physiology chair at Prague Medical Faculty. During this period, he succeeded in introducing the Czech idiom (in addition to long-established German and Latin) as a Medical Faculty teaching language. Additionally, as a zealous Czech patriot, he actively contributed to the naissance and consolidation of a national Czech identity conscience. Purkinje was a trend-setting scientist who, throughout his career, worked to pave the way for the renovation of physiology from a speculative discipline, ancilla of anatomy, into a factual, autonomous science committed to the discovery of mechanisms governing in-life functions.


Asunto(s)
Investigación Biomédica/historia , Médicos/historia , Fisiología/historia , Células de Purkinje , Historia del Siglo XVIII , Historia del Siglo XIX , Humanos
13.
Molecules ; 23(1)2017 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-29301210

RESUMEN

G-quadruplexes (G4) are stacked non-canonical nucleic acid structures found in specific G-rich DNA or RNA sequences in the human genome. G4 structures are liable for various biological functions; transcription, translation, cell aging as well as diseases such as cancer. These structures are therefore considered as important targets for the development of anticancer agents. Small organic heterocyclic molecules are well known to target and stabilize G4 structures. In this article, we have designed and synthesized 2,6-di-(4-carbamoyl-2-quinolyl)pyridine derivatives and their ability to stabilize G4-structures have been determined through the FRET melting assay. It has been established that these ligands are selective for G4 over duplexes and show a preference for the parallel conformation. Next, telomerase inhibition ability has been assessed using three cell lines (K562, MyLa and MV-4-11) and telomerase activity is no longer detected at 0.1 µM concentration for the most potent ligand 1c. The most promising G4 ligands were also tested for antiproliferative activity against the two human myeloid leukaemia cell lines, HL60 and K562.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , G-Cuádruplex , Piridinas/síntesis química , Piridinas/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Células HL-60 , Humanos , Células K562 , Ligandos , Unión Proteica , Relación Estructura-Actividad , Telomerasa/antagonistas & inhibidores
14.
Biopolymers ; 106(3): 368-75, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26832831

RESUMEN

The design and synthesis of novel peptides that inhibit angiogenesis is an important area for anti-angiogenic drug development. Cyclic and small peptides present several advantages for therapeutic application, including stability, solubility, increased bio-availability and lack of immune response in the host cell. We describe here the synthesis and biological evaluations of a new cyclic peptide analog of CBO-P11: cyclo(RIKPHE), designated herein as CBO-P23M, a hexamer peptide encompassing residues 82 to 86 of VEGF which are involved in the interaction with VEGF receptor-2. CBO-P23M was prepared using in solution cyclization, therefore reducing the peptide cyclodimerization occurred during solid-phase cyclization. The cyclic dimer of CBO-P23M, which was obtained as the main side product during synthesis of the corresponding monomer, was also isolated and investigated. Both peptides markedly reduce VEGF-A-induced phosphorylation of VEGFR-2 and Erk1/2. Moreover, they exhibit anti-angiogenic activity in an in vitro morphogenesis study. Therefore CBO-P23M and CBO-P23M dimer appear as attractive candidates for the development of novel angiogenesis inhibitors for the treatment of cancer and other angiogenesis-related diseases. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 368-375, 2016.


Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Péptidos Cíclicos/síntesis química , Soluciones/química , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/farmacología , Ciclización , Dimerización , Regulación de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana , Humanos , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Modelos Biológicos , Neovascularización Fisiológica/efectos de los fármacos , Péptidos Cíclicos/farmacología , Fosforilación/efectos de los fármacos , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo
15.
J Theor Biol ; 370: 184-96, 2015 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-25637766

RESUMEN

Metapopulations may consist of patches of different quality, and are often disturbed by extrinsic processes causing variation of patch quality. The persistence of such metapopulations then depends on the species' dispersal strategy. In a temporally constant environment, the evolution of dispersal rates follows the resource matching rule, i.e. at the evolutionarily stable dispersal strategy the number of competitors in each patch matches the resource availability in each patch. Here, we investigate how the distribution of individuals resulting from convergence stable dispersal strategies would match the distribution of resources in an environment which is temporally variable due to extrinsic disturbance. We develop an analytically tractable asexual model with two qualities of patches. We show that convergence stable dispersal rates are such that resource matching is predicted in expectation before habitat quality variation, and that the distribution of individuals undermatches resources after habitat quality variation. The overall flow of individuals between patches matches the overall flow of resources between patches resulting from environmental variation. We show that these conclusions can be generalized to organisms with sexual reproduction, and to a metapopulation with three qualities of patches when there is no mutational correlation between dispersal rates.


Asunto(s)
Distribución Animal , Evolución Biológica , Ambiente , Animales , Modelos Biológicos , Factores de Tiempo
16.
Int J Mol Sci ; 16(6): 12159-73, 2015 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-26030674

RESUMEN

This work reports on the design and the synthesis of two short linear peptides both containing a few amino acids with disorder propensity and an allylic ester group at the C-terminal end. Their structural properties were firstly analyzed by means of experimental techniques in solution such as CD and NMR methods that highlighted peptide flexibility. These results were further confirmed by MD simulations that demonstrated the ability of the peptides to assume conformational ensembles. They revealed a network of transient and dynamic H-bonds and interactions with water molecules. Binding assays with a well-known drug-target, i.e., the CXCR4 receptor, were also carried out in an attempt to verify their biological function and the possibility to use the assays to develop new specific targets for CXCR4. Moreover, our data indicate that these peptides represent useful tools for molecular recognition processes in which a flexible conformation is required in order to obtain an interaction with a specific target.


Asunto(s)
Proteínas Intrínsecamente Desordenadas/química , Péptidos/síntesis química , Péptidos/metabolismo , Receptores CXCR4/metabolismo , Dicroismo Circular , Humanos , Enlace de Hidrógeno , Simulación de Dinámica Molecular , Péptidos/química , Unión Proteica , Conformación Proteica , Pliegue de Proteína , Espectroscopía de Protones por Resonancia Magnética
17.
Invest New Drugs ; 32(1): 60-7, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23761053

RESUMEN

We recently synthesized from aconitine a series of drugs with in vitro and in vivo antitumor properties, among which bis[O-(14-benzoylaconine-8-yl)]suberate (BBAS) was the most active (Eur J Med Chem 2012; 54: 343). In the present work, we used the NCI panel of 60 human tumor cell lines to identify the most sensitive cell lines and drugs with comparable cytotoxicity profiles. GI50 values of BBAS ranged between 0.12 and 6.5 µM. Activity was higher than average for leukemia and melanoma cell lines, especially SK-MEL-5 and SK-MEL-28, for the COLO-205 and HT-29 (colorectal) and MDA-MB-468 (breast) cancer cell lines. We evaluated the correlation between the GI50 of BBAS and those of 125 antiproliferative compounds with various mechanisms of action, using Bonferroni correction for multiple testing, and we observed a highly significant correlation with the GI50s of nitrosoureas. Interestingly, BBAS cytotoxicity was inversely correlated with the expression levels of MGMT (p = 0.009), an enzyme involved in the repair of nitrosourea-induced DNA damage. However, no correlation was found with the expression of 102 other genes involved in DNA repair. Antitumor activity was tested on immunodeficient mice with subcutaneously xenografted COLO-205, HT-29, MDA-MB-468, SK-MEL-5 and SK-MEL-28 cell lines. At 10 mg/kg, there was a significant reduction in tumor size with T/C values of 41 % and 43 % for COLO-205 and SK-MEL-28 cell lines, respectively. The drug was less active on HT-29 and SK-MEL-5 and inactive on MDA-MB-468 xenografts. Cell cycle studies showed an accumulation of BBAS-treated cells in G2/M phase after treatment at 20 µM. Together, our results allowed the identification of a potentially new class of anticancer agent displaying a mechanism of action related to that of nitrosoureas.


Asunto(s)
Aconitum/química , Alcaloides/farmacología , Antineoplásicos Fitogénicos/farmacología , Aconitina/análogos & derivados , Aconitina/química , Aconitina/farmacología , Alcaloides/química , Animales , Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones
18.
Toxicol Appl Pharmacol ; 273(2): 229-41, 2013 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-23732082

RESUMEN

Safety pharmacology (SP) is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials. SP studies are described in the International Conference on Harmonisation (ICH) S7A and S7B guidelines. The core battery and supplemental SP studies evaluate effects of a new chemical entity (NCE) at both anticipated therapeutic and supra-therapeutic exposures on major organ systems, including cardiovascular, central nervous, respiratory, renal and gastrointestinal. This review outlines the current practices and emerging concepts in SP studies including frontloading, parallel assessment of core battery studies, use of non-standard species, biomarkers, and combining toxicology and SP assessments. Integration of the newer approaches to routine SP studies may significantly enhance the scope of SP by refining and providing mechanistic insight to potential adverse effects associated with test compounds.


Asunto(s)
Descubrimiento de Drogas/normas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/metabolismo , Preparaciones Farmacéuticas/normas , Animales , Descubrimiento de Drogas/métodos , Descubrimiento de Drogas/tendencias , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/normas , Evaluación Preclínica de Medicamentos/tendencias , Interacciones Farmacológicas/fisiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Humanos , Preparaciones Farmacéuticas/metabolismo
19.
Magn Reson Chem ; 51(12): 837-41, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24123338

RESUMEN

The complete (1)H and (13)C assignments of eight bioactive indeno[1,2-b]indole-10-one derivatives were accomplished by the combined use of one-dimensional and two-dimensional NMR experiments.


Asunto(s)
Indenos/química , Indoles/química , Isótopos de Carbono , Espectroscopía de Resonancia Magnética/normas , Estructura Molecular , Protones , Estándares de Referencia
20.
Artículo en Inglés | MEDLINE | ID: mdl-24098219

RESUMEN

In the crystal structure of the title compound, C16H24N4O4, mol-ecules are linked by N-H⋯O hydrogen bonds between the carbonyl groups of the carbamoyl and amido functional groups and the amino groups, and by N-H⋯N hydrogen bonds between the amino group and the pyridine ring, forming two-dimensional networks parallel to the ab plane.

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