Epigenetic Modulators as Treatment Alternative to Diverse Types of Cancer.

DNA is packaged in an octamer of histones, forming chromatin, a complex of DNA and proteins. The structural matrix of a chromosome, chromatin and its changes are now regarded as important factors in controlling gene expression, which has sparked a lot of interest in understanding genetic pathways governing various diseases, including cancer. DNA methylation in the CpG dinucleotide as a transcriptional silencing mechanism, post-translational histone modifications such as acetylation, methylation, and others that affect chromatin structure, ATP-dependent chromatin remodelling, and miRNA-mediated gene silencing are all found to be important in various types of cancer. In this review, we analyze the main alterations in gene expression, epigenetic modification patterns in cancer cells, the main modulators and inhibitors of each epigenetic mechanism, and the molecular evolution of the most representative inhibitors, all of which point to a promising future for HAT, HDAC, non-glycoside DNMT inhibitors, and domain inhibitors.

Quorum Sensing Regulation as a Target for Antimicrobial Therapy.

Some bacterial species use a cell-to-cell communication mechanism called Quorum Sensing (QS). Bacteria release small diffusible molecules, usually termed signals which allow the activation of beneficial phenotypes that guarantee bacterial survival and the expression of a diversity of virulence genes in response to an increase in population density. The study of the molecular mechanisms that relate signal molecules with bacterial pathogenesis is an area of growing interest due to its use as a possible therapeutic alternative through the development of synthetic analogues of autoinducers as a strategy to regulate bacterial communication as well as the study of bacterial resistance phenomena, the study of these relationships is based on the structural diversity of natural or synthetic autoinducers and their ability to inhibit bacterial QS, which can be approached with a molecular perspective from the following topics: i) Molecular signals and their role in QS regulation; ii) Strategies in the modulation of Quorum Sensing; iii) Analysis of Bacterial QS circuit regulation strategies; iv) Structural evolution of natural and synthetic autoinducers as QS regulators. This mini-review allows a molecular view of the QS systems, showing a perspective on the importance of the molecular diversity of autoinducer analogs as a strategy for the design of new antimicrobial agents.

Recent synthetic efforts in the preparation of 2-(3,4)-alkenyl (aryl) quinoline molecules towards anti-kinetoplastid agents.

Leishmaniasis, Chagas disease and African sleeping sickness have been considered some of the most important tropical protozoan afflictions. As the number of drugs currently available to treat these human illnesses is severely limited and the majority has poor safety profiles and complicated administration schedules, actually there is an urgent need to develop new effective, safe and cost-effective drugs. Because quinoline alkaloids with antiprotozoal activity (quinine, chimanine, cryptolepine or huperzine groups) were historically and are still essential models for drug research to combat these parasitic infections, synthetic or semi-synthetic quinoline-based molecules are important for anti-kinetoplastid drug design approaches and synthetic methods of their preparation become a key task that is the central subject of this review. Its goal is to highlight the advances in the conventional and current syntheses of new 2-(3,4)-alkenyl (aryl) quinoline derivatives, which kill the most important kinetoplastid protozoa, - Leishmania and Trypanosoma and could be useful models for antileishmanial and antitrypanosomal research. An attempt has been made to present and discuss the more recent contributions in this field over the period 2015-2019, paying special attention to molecular design, synthetic efforts to new green reaction conditions for classical methods such as Skraup synthesis, Friedländer synthesis, Conrad-Limpach, Doebner-Miller, as well as contemporary methods like Gould-Jacobs, Meth-Cohn and Povarov reactions. This review includes brief general information on these neglected tropical diseases, their current chemotherapies, and primary natural models (quinoline alkaloids), suitable for development of anti-kinetoplastid quinoline-based agents. The main part of the review comprises critical discussion on the synthesis and chemistry of new quinolines diversely substituted by alkyl (alkenyl, aryl) fragments on the pyridine part of the quinoline skeleton, which could be considered interesting analogues of chimanine alkaloids. The methods described in this review were developed with the aim of overcoming the drawbacks of the traditional protocols using revolutionary precursors and strategies.

Photoreceptor stretching: An optical coherence tomography finding in a case of incomplete Vogt-Koyanagi-Harada disease.

The aim of the study was to describe an optical coherence tomography finding in Vogt-Koyanagi-Harada (VKH) disease and discuss its physiopathology. A 34-year-old Hispanic male was referred to the retina clinic, with 2 weeks of "drowsiness," headache, photopsia, and blurred vision. He was diagnosed with incomplete VKH. Optical coherence tomography, among other studies, was obtained, and a focal separation of the photoreceptor outer segments (OSs) from the inner neuroepithelium was observed. Here, we report a rare finding associated with VKH disease, which we called photoreceptor stretching and hypothesize it results from the presence of a spot of strong adherence between the OS of the photoreceptors and the retinal pigment epithelium.

Subcostal transversus abdominis plane phenol injection for abdominal wall cancer pain.

A subcostal transversus abdominis plane (TAP) phenol injection was performed on a patient with refractory cancer pain due a metastatic involvement of the abdominal wall. A diagnostic block with local anesthetic was performed under ultrasound guidance (USG), resulting in a decrease of 80% and 100% in dynamic and static visual analog scale (VAS) for pain, respectively, for 20 hours. A phenol injection was then performed under USG. The patient reported 70% and 100% reduction in the dynamic and static VAS for pain and had a 50% decrease in the opioid requirement that was maintained for 2 months. TAP blocks offer an interesting tool for either diagnosis or therapeutic purpose in chronic pain management. USG provides an optimal approach to soft-tissue lesions where fluoroscopy techniques are not useful.

Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study.

BACKGROUND: Mild cognitive impairment (MCI) and pre-MCI have been proposed as stages preceding Alzheimer's disease (AD) dementia. We assessed descendants of individuals with a mutation in presenilin 1 (PSEN1) that causes familial AD, with the aim of identifying distinct stages of clinical progression to AD dementia. METHODS: We retrospectively studied a cohort of descendants of carriers of the PSEN1 E280A mutation. Pre-dementia cognitive impairment was defined by a score 2 SD away from normal values in objective cognitive tests, and was subdivided as follows: asymptomatic pre-MCI was defined by an absence of memory complaints and no effect on activities of daily living; symptomatic pre-MCI was defined by a score on the subjective memory complaints checklist higher than the mean and no effect on activities of daily living; and MCI was defined by a score on the subjective memory complaints checklist higher than the mean, with no effect on basic activities of daily living and little or no effect on complex daily activities. Dementia was defined according to the diagnostic and statistical manual of mental disorders, fourth edition. Reference mean scores were those of participants who did not carry the PSEN1 E280A mutation. We used the Turnbull survival analysis method to identify ages at onset of each stage of the disease. We measured the time from birth until onset of the three pre-dementia stages, dementia, and death, and assessed decline in cognitive domains for each stage. FINDINGS: Follow-up was from Jan 1, 1995, to Jan 27, 2010. 1784 patients were initially identified, 449 of whom were PSEN1 E280A carriers who had complete clinical follow-up. Median age at onset was 35 years (95% CI 30-36) for asymptomatic pre-MCI, 38 years (37-40) for symptomatic pre-MCI, 44 years (43-45) for MCI, and 49 years (49-50) for dementia. The median age at death was 59 years (95% CI 58-61). The median time of progression from asymptomatic to symptomatic pre-MCI was 4 years (95% CI 2-8), from symptomatic pre-MCI to MCI was 6 years (4-7), from MCI to dementia was 5 years (4-6), and from dementia to death was 10 years (9-12). The cognitive profile was predominantly amnestic and was associated with multiple domains. Affected domains showed variability in initial stages, with some transient recovery in symptomatic pre-MCI followed by continuous decline. INTERPRETATION: Clinical deterioration can be detected as measurable cognitive impairment around two decades before dementia onset in PSEN1 E280A carriers. Onset and progression of pre-dementia stages should be considered in the investigation and use of therapeutic interventions for familial AD. FUNDING: Departamento Administrativo de Ciencia, Tecnología e Innovación, COLCIENCIAS, Republic of Colombia.

Simple preparation of new N-(6-methyl-2-nitrophenyl-1, 2, 3, 4-tetrahydroquinolin-4-yl) pyrrolidin-2-ones and their spectroscopic analysis / Preparação simples de novas N-(6-metil-2-nitrofenil-1, 2, 3, 4-tetrahydroquinoline-4-il) pirrolidin-2-onas e sua análise espectroscópica / Preparación simple de nuevas N-(6-metil-2-nitrofenil-1, 2, 3, 4-tetrahidroquinolin-4-il) pirrolidin-2-onas y su análisis espectroscópico

Preparación simple de nuevas N-(6-metil-2-nitrofenil-1,2,3,4-tetrahidroquinolin-4-il) pirrolidin-2-onas y su análisis espectroscópico. Objetivos. Preparar nuevas moléculas N-(1,2,3,4-tetrahidroquinolin-4-il) 2-oxopirrolidínicas y caracterizarlas por métodos espectroscópicos. Materiales y métodos. Todos los reactivos usados son de Aldrich, grado comercial. La pureza de los productos y la composición de las mezclas de reacción fueron monitoreadas por cromatografía en capa fina sobre cromatoplacas de Silufol UV254 (0.25 mm). El aislamiento y purificación se realizó usando cromatografía en columna (SiO2), usando acetato de etilo. Resultados. La preparación de las nuevas N-(tetrahidroquinolin-4-il) pirrolidin-2-onas 4-nitrofenil (ó 2-nitrofenil) sustituidas en C-2 del anillo tetrahidroquinolínico, se realizóvía síntesis one-pot basada en la reacción de cicloadición imino Diels-Alder catalizada por BiCl3 entre toluidina, N-vinilpirrolidin-2-ona y 4-nitrobenzaldehído (3-nitrobenzaldehído). La estructura de los derivados pirrolidónicos fue confirmada por 1H RMN y 13C RMN, además de experimentos 2D RMN y difracción de rayos X de monocristal. Conclusiones. Una ruta eficiente, económica y rápida (reacción imino Diels-Alder multi-componente) fue empleada para la construcción de nuevas moléculas N-(tetrahidroquinolin-4-il) 2-oxopirrolidínicas, esqueleto muy atractivo y usado con estereoquímica bien definida...

Objectives. To prepare new N-(1,2,3,4-tetrahydroquinolin-4-yl) pyrrolidin-2-one molecules and to characterize them by spectroscopic methods. Materials and methods. All reagents were purchased from Aldrich, commercial grade. The purity of the products and the composition of the reaction mixtures were monitored by thin layer chromatography over Silufol UV254 chromatoplates (0.25 mm). Product isolation and purification were performed by column chromatography (SiO2) using ethyl acetate. Results. Preparation of new N-(2-nitrophenyl-1,2,3,4-tetrahydroquinolin-4-yl) pyrrolidin-2-ones has been achieved via the one-pot synthesis, based on a BiCl3-catalyzedimino Diels-Alder cycloaddition reaction of toluidine, N-vinylpyrrolidin-2-one and 4-nitro- or 3-nitrobenzaldehydes. The structure of the pyrrolidine derivatives was confirmed by 1H nmr and 13C nmr studies, in addition to inverse-detected 2D NMR experiments and monocrystal X-ray diffraction. Conclusions. An efficient, economic, and fast synthetic route (multi-component imino Diels-Alder reaction) was employed in the construction of several new tetrahydroquinoline derivatives, useful and attractive rigid skeleton with well-defined stereochemistry...

Preparação simples de novas N-(6-metil-2-nitrofenil-1,2,3,4-tetrahydroquinoline-4-il) pirrolidin-2-onas e sua análise espectroscópica. Objetivos. Preparar novas moléculas N-(1,2,3,4-tetrahydroquinoline-4-il) 2-oxopirrolidínicas e sua caracterização por espectroscopia. Materiais e métodos. Todos os reagentes utilizados são de Aldrich, de grau comercial. A pureza dos produtos e a composição das misturas de reação foram monitoradas por cromatografia em camada fina sobre cromatoplacas de Silufol UV254 (0,25 mm). O isolamento e purificação foi realizado utilizando cromatografia em coluna (SiO2), utilizando acetato de etila. Resultados. Preparação de novas N-(tetrahydroquinoline-4-il) pirrolidin-2-onas 4-nitrofenil (ou 2-nitrofenil) substituídas em C-2 do anel tetrahydroquinoline foi realizada através da síntese “one pot” baseada na reação de cicloadição imino Diels-Alder catalisada por BiCl3 entre toluidina, N-vinilpirrolidin-2-ona e 4 nitrobenzaldehyde (3 nitrobenzaldehyde). A estrutura dos derivados pirrolidónicos foi confirmada por 1H RMN y 13C RMN, experimentos 2D RMN, assim como difração de raios X e monocristais. Conclusões. Uma rota eficiente, econômica e rápida (reação imino Diels-Alder multi-componente) foi utilizada para a construção de novas moléculas N-(tetrahydroquinoline-4-il) 2-oxopirrolidínicas esqueleto muito atraente e usado com estereoquímica bem definida...

Búsqueda de nuevos agentes antiprotozoarios selectivos / In search of new selective antiprotozoal agents

Se da la información general sobre los fármacos antiprotozoarios que están usándose en clínica, se discuten nuevas dianas de los parásitos protozoarios útiles en la búsqueda de nuevos agentes antiprotozoarios, enfocando la atención al rol biológico de las proteasas de los parásitos protozoarios. Esta información importante será útil para los estudiantes e investigadores que se interesen a los problemas de química medicinal (un área naciente en Colombia) cuál aporta mucho al desarrollo de ciencias médicas. [Kouznetsov V, Meléndez C. Búsqueda de nueveos agentes antiprotozoarios selectivos. MedUNAB 2009; 12:33-45].

The information is given on the antiprotozoal drugs used in clinic, new useful targets of the parasites protozoa in the search of new antiprotozoal agents are discussed, focusing the attention to the biological role of proteasas of the parasites protozoa. This important information will be useful for students and researchers, which are interested in the problems of medicinal chemistry (an appearing area in Colombia) that gives much to the development of medicine sciences. [Kouznetsov V, Meléndez C. In search of new selective antiprotozoal agents. MedUNAB 2009; 12:33-45].

Asociación entre hiperhomocisteinemia y preeclampsia / Association between hyperhomocysteinemia and preeclampsia

Objetivo: Explorar la asociación entre el nivel sérico posprandial de hemocisteína y la preeclampsia y describir las complicaciones en gestaciones menores de 35 semanas. Metodología: Estudio descriptivo de corte transversal en 109 gestantes: grupo I, 55 preeclámpticas (90,9 por ciento clasificadas como severas) y grupo II, 54 sin preeclampsia con menos de 35 semanas de edad gestacional, de los hospitales Universitario San Vicente de Paúl y General de Medellín, entre 1º de septiembre de 1999 y 1º de septiembre de 2000. Resultados: Cuando se compararon las características generales de las pacientes no se encontró diferencia. No se demostró correlación entre los niveles de homocisteína y la edad de la paciente, la edad gestacional, ni con el número de partos previos (rho de Spearmman - 0,057, -0,074 y - 0,17 respectivamente). Hubo diferencia entre las medianas de las concentraciones de homocisteinemia: 11,8 µmol/L y 8,8 µmol/L para G I y G II respectivamente (p < de 0,01). Las pacientes con homocisteinemia en el último cuartil (concentración mayor de 11,2 µmol/L por inmunoensayo de fluorescencia polarizada) presentan un riesgo de tener preeclampsia 9,67 veces mayor que las del primer cuartil (concentración menor de 7,1) (IC subíndice 95 por ciento 2-04 - 52.17, p = 0.001). El percentil 95 para homocisteinemia en embarazadas normotensas fue de 13,025 µmol/L. Se estableció este valor como el punto de corte para diagnósticar hiperhomocisteinemia en la gestante. Veinticinco (47.5 por ciento) de las gestantes del grupo I y 2 (3.7 por ciento) del grupo II fueron clasificadas con hiperhomocisteinemia, razón de disparidad (RD) 21,67 (IC subíndice 95 por ciento entre 4,48 y 142,66). Catorce pacientes del grupo I tuvieron complicaciones atribuibles a preeclampsia, 6 presentaron hiperhocisteinemia frente a 19 con hiperhomocisteinemia de 41 pacientes no complicadas en este grupo (p=0,397). Veinticinco pacientes del grupo I tuvieron hijos con RCIU. Trece resultaron de madres con hipermocisteinemia frente a 12 de las 30 restantes cuyos hijos nacieron con peso adecuado para la edad gestacional (PAEG) (p=0,37). Seis neonatos, hijos de 26 mujeres no hiperhomocisteinémicas del grupo II que terminaron su gestación en los hospitales donde se realizó el estudio, presentaron bajo peso para la edad gestacional. Conclusión: Se definió hiperhomocisteinemia en la gestante si el nivel sérico posprandial de homocisteína resultó...