Advances in the discovery of heterocyclic-based drugs against Alzheimer's disease.

INTRODUCTION: Alzheimer's disease is a multifactorial neurodegenerative disorder characterized by beta-amyloid accumulation and tau protein hyperphosphorylation. The disease involves interconnected mechanisms, which can be clustered into two target-packs based on the affected proteins. Pack-1 focuses on beta-amyloid accumulation, oxidative stress, and metal homeostasis dysfunction, and Pack-2 involves tau protein, calcium homeostasis, and neuroinflammation. Against this background heterocyclic system, there is a powerful source of pharmacophores to develop effective small drugs to treat multifactorial diseases like Alzheimer's. AREAS COVERED: This review highlights the most promising heterocyclic systems as potential hit candidates with multi-target capacity for the development of new drugs targeting Alzheimer's disease. The selection of these heterocyclic systems was based on two crucial factors: their synthetic versatility and their well-documented biological properties of therapeutic potential in neurodegenerative diseases. EXPERT OPINION: The synthesis of small drugs against Alzheimer's disease requires a multifactorial approach that targets the key pathological proteins. In this context, the utilization of heterocyclic systems, with well-established synthetic processes and facile functionalization, becomes a crucial element in the design phases. Furthermore, the selection of hit heterocyclic should be guided by a full understanding of their biological activities. Thus, the identification of promising heterocyclic scaffolds with known biological effects increases the potential to develop effective molecules against Alzheimer's disease.

Easy and Versatile Technique for the Preparation of Stable and Active Lipase-Based CLEA-like Copolymers by Using Two Homofunctional Cross-Linking Agents: Application to the Preparation of Enantiopure Ibuprofen.

An easy and versatile method was designed and applied successfully to obtain access to lipase-based cross-linked-enzyme aggregate-like copolymers (CLEA-LCs) using one-pot, consecutive cross-linking steps using two types of homobifunctional cross-linkers (glutaraldehyde and putrescine), mediated with amine activation through pH alteration (pH jump) as a key step in the process. Six lipases were utilised in order to assess the effectiveness of the technique, in terms of immobilization yields, hydrolytic activities, thermal stability and application in kinetic resolution. A good retention of catalytic properties was found for all cases, together with an important thermal and storage stability improvement. Particularly, the CLEA-LCs derived from Candida rugosa lipase showed an outstanding behaviour in terms of thermostability and capability for catalysing the enantioselective hydrolysis of racemic ibuprofen ethyl ester, furnishing the eutomer (S)-ibuprofen with very high conversion and enantioselectivity.

Biocatalysis for the asymmetric synthesis of Active Pharmaceutical Ingredients (APIs): this time is for real.

INTRODUCTION: Biocatalysis has emerged as a powerful and useful strategy for the synthesis of active pharmaceutical ingredients (APIs). The outstanding developments in molecular biology techniques allow nowadays the screening, large-scale production, and designing of biocatalysts, adapting them to desired reactions. Many enzymes can perform reactions both in aqueous and non-aqueous media, broadening even further the opportunities to integrate them in complex pharmaceutical multi-step syntheses. AREAS COVERED: This paper showcases several examples of biocatalysis in the pharmaceutical industry, covering examples of different enzymes, such as lipases, oxidoreductases, and transaminases, to deliver active drugs through complex synthetic routes. Examples are critically discussed in terms of reaction conditions, motivation for using an enzyme, and how biocatalysts can be integrated in multi-step syntheses. When possible, biocatalytic routes are benchmarked with chemical reactions. EXPERT OPINION: The reported enzymatic examples are performed with high substrate loadings (>100 g L-1) and with excellent selectivity, making them inspiring strategies for present and future industrial applications. The combination of powerful molecular biology techniques with the needs of the pharmaceutical industry can be aligned, creating promising platforms for synthesis under more sustainable conditions.

Analogues of cannabinoids as multitarget drugs in the treatment of Alzheimer's disease.

Given that neuronal degeneration in Alzheimer's disease (AD) is caused by the combination of multiple neurotoxic insults, current directions in the research of novel therapies to treat this disease attempts to design multitarget strategies that could be more effective than the simply use of acetylcholinesterase inhibitors; currently, the most used therapy for AD. One option, explored recently, is the synthesis of new analogues of cannabinoids that could competitively inhibit the acetylcholinesterase (AChE) enzyme and showing the classic neuroprotective profile of cannabinoid compounds. In this work, molecular docking has been used to design some cannabinoid analogues with such multitarget properties, based on the similarities of donepezil and Δ9-tetrahydrocannabinol. The analogues synthesized, compounds 1 and 2, demonstrated to have two interesting characteristics in different in vitro assays: competitive inhibition of AChE and competitive antagonism at the CB1/CB2 receptors. They are highly lipophilic, highlighting that they could easily reach the CNS, and apparently presented a low toxicity. These results open the door to the synthesis of new compounds for a more effective treatment of AD.

Developments with multi-target drugs for Alzheimer's disease: an overview of the current discovery approaches.

Introduction: Alzheimer's disease (AD), the most common type of dementia among older adults, is a chronic neurodegenerative pathology that causes a progressive loss of cognitive functioning with a decline of rational skills. It is well known that AD is multifactorial, so there are many different pharmacological targets that can be pursued. Areas covered: The authors highlight the strategic value of privileged scaffolds in a multi-target lead compound generation against AD, exploring the concept of multi-target design, with a special emphasis on hybrid compounds. Hence, the most promising building blocks for designing and synthesizing hybrid anti-AD drugs are shown, while also presenting the more advanced hybrid compounds. Expert opinion: The available therapeutic arsenal for AD, designed under the traditional paradigm of 'one-drug/one target/one-disease', is based on the inhibition of brain acetylcholinesterase (AChE) to increase acetylcholine (ACh) levels. However, this classical approach has not been sufficiently effective when used to treat any multifactor-depending pathology (cancer, diabetes or AD). The multi-target drug concept has been quickly adopted by medicinal chemists. The basic research developments reported in recent years are a solid foundation that will pave the way for the construction of future AD therapeutics.

Docking studies for melatonin receptors.

INTRODUCTION: Melatonin is a neurohormone that controls many relevant physiological processes beyond the control of circadian rhythms. Melatonin's actions are carried out by two main types of melatonin receptors; MT1 and MT2. These receptors are important, and not just because of the biological actions of its natural agonist; but also, because melatonin analogues can improve or antagonize their biological effect. Area covered: The following article describes the importance of melatonin as a biologically relevant molecule. It also defines the receptors for this substance, as well as the second messengers coupled to these receptors. Lastly, the article describes the amino acid residues involved in the docking process in both MT1 and MT2 melatonin receptors. Expert opinion: The biological actions of melatonin and their interpretations are becoming more relevant and therefore require the development of new pharmacological tools. Understanding the second messenger mechanisms involved in melatonin actions, as well as the characteristics of the docking of this molecule to MT1 and MT2 melatonin receptors, will permit the development of more selective agonists and antagonists which will help us to better understand this molecule as well to develop new therapeutic compounds.

Metodologías de modelado molecular en el diseño, sintesis y explicación racional de resultados / Molecular modeling methodologies in the design, synthesis and rational explanation of results

La Química computacional integra los conceptos básicos especializados de la Química, para la solución de problemas por medio de representaciones graficas que tratan de explicar los sucesos estudiados. El Modelado Molecular es una herramienta de gran utilidad, pues permite interpretar de manera racional por ejemplo el proceso de interacción entre una molécula y su diana, y proporciona datos fiables que permiten predecir el comportamiento del sistema. Por otra parte el auge experimentado por la Biología estructural así como la Resonancia Magnética Nuclear ha permitido incrementar en los últimos años el número de estructuras en 3D para su utilización en modelado. Sin duda, los grandes avances en el campo de la Bioinformática, asociados al empleo de medios computacionales cada vez más sofisticados, auguran la capacidad de extraer conclusiones racionales de los procesos químicos, por lo que esta área de investigación ha experimentado un considerable aumento reconocido en el año 2013 por la Real Academia Sueca de las Ciencias con la concesión del Premio Nobel de Química. En el presente trabajo revisamos algunos de los logros obtenidos en el campo de la modelización molecular realizados por nuestro grupo en el pasado, aplicados fundamentalmente a la Biocatálisis, así como los resultados obtenidos en el presente en el campo de liberación controlada de fármacos y postulamos modelos de predicción que pueden utilizarse en un futuro próximo en este campo de gran interés en Medicina

Computational Chemistry integrates basic concepts of chemistry to solve problems through graphical representations that attempt to explain the events studied. Molecular modeling is a useful tool because it allows rationally interpret for example the process of interaction between a molecule and its target, and provides reliable data that can predict system behavior. Moreover, the boom experienced by Structural Biology and Nuclear Magnetic Resonance has allowed in recent years to increase the number of 3D structures for use in modeling. Undoubtedly, the great advances in the field of bioinformatics, associated with the use of increasingly sophisticated computational means, portend the ability to draw sound conclusions from chemical processes, so this research area has experienced considerable recognized increase in 2013 by the Royal Swedish Academy of Sciences awarding the Nobel Prize in Chemistry. In this paper we review some of the achievements in the field of molecular modeling by our group in the past, mainly applied to Biocatalysis, and the results obtained in the present in the field of controlled drug release and posit models prediction that can be used in the near future in the field of great interest in medicine

Análogos de cannabinoides en el tratamiento del dolor / Cannabinoid analogs in the treatment of pain

El uso terapéutico de los cannabinoides en el tratamiento del dolor es tan lejano como el conocimiento que se tiene de la planta Cannabis sativa y a pesar de ello sigue aún vigente. La principal vía de actuación de los cannabinoides, naturales o sintéticos, es la activación de receptores CB-1 ó CB-2, generalmente acoplados a proteínas G. La transmisión del estímulo doloroso depende inicialmente, de la liberación de glutamato en el asta posterior de la médula espinal y en la que también se implican otros neurotransmisores o mediadores como la sustancia P, el ATP, diferentes interleuquinas o TNF entre otros. Estas sustancias, que son liberadas por neuronas son responsables de la cronificación del dolor y juegan un papel fundamental en el desarrollo del dolor con componente neuropático. Los cannabinoides son buenos analgésicos, especialmente para el dolor crónico. Esto es consecuencia de la presencia de receptores CB1 en las regiones que participan en el control de la nocicepción, tanto a nivel espinal como a nivel supraespinal. En el caso de la esclerosis lateral amiotrófica (ELA), se ha observado un incremento del nivel de endocannabinoides y de la expresión del receptor cannabinoide CB2. El uso de agonistas selectivos para CB2 y la depleción del receptor CB1 así como de enzimas de degradación del SCE, mejoran los síntomas de la enfermedad e incrementan la supervivencia en ensayos realizados con ratones transgénicos Los fármacos derivados del cannabis deben considerarse como una opción de tratamiento más, pero existen otras familias de fármacos que, dependiendo del caso y el paciente, pueden ser más o menos adecuadas. La modificacion estructural en la molécula de THC y CBN aplicando cálculos de mecánica molecular, orbitales moleculares y Docking molecular servirá para saber que compuestos podrán atravesar la barrera hematoencefálica y cuales no, así como los valores de energía obtenidos mediante Docking molecular. Estos resultados nos darán un criterio para evaluar los posibles candidatos a inhibir la acetilcolinesterasa y de esta forma ser posibles candidatos anti-Alzheimer así como su evaluación para el tratamiento del dolor crónico

The therapeutic use of cannabinoids in the treatment of pain is as far as the knowledge we have of the plant Cannabis sativa and yet is still in force. The main way of action of cannabinoids, natural or synthetic, is the activation of CB-1 or CB-2 receptors, G-protein coupled usually transmission of painful stimuli initially dependent glutamate release in the dorsal horn of the spinal cord and in which other neurotransmitters and mediators such as substance P, ATP, various interleukins and TNF, among others are also involved. These substances, which are released by neurons are responsible for the chronicity of pain and play a key role in the development of neuropathic pain component. Cannabinoids are good analgesics, especially for chronic pain. This results from the presence of CB1 receptors in the regions involved in the control of nociception, both cord level and at the supraspinal level. In the case of amyotrophic lateral sclerosis (ALS), there has been an increased level of endocannabinoids and of cannabinoid receptor expression CB2. The use of selective agonists for CB2 and CB1 receptor depletion and degradation of enzymes SCE, improve the symptoms of the disease and increase survival in studies with transgenic mice cannabis drugs should be considered as a treatment option more, but other classes of drugs which, depending on the case and the patient, may be more or less suitable. The modificacionestructuralen molecule THC and CBN calculations using molecular orbital molecular mechanics and molecular docking serve to know that compounds can cross the blood brain barrier and what not, and the energy values obtained by molecular docking. These results give us a criterion for evaluating potential candidates to inhibit acetylcholinesterase and thus be potential anti-Alzheimer candidates and their evaluation for the treatment of chronic pain

Biotecnología: presente y futuro / No disponible

No disponible

Utilización de hidrolasas en la preparación de fármacos e intermedios homoquirales / Hydrolases use in the preparation of drugs and homochiral intermediates

La exquisita regio y estereoselectividad que presentan los biocatalizadores,amén de la buena sostenibilidad inherente a su empleo,permiten la realización de protocolos sintéticos difícilmente alcanzablespor las metodologías clásicas, a menos que se lleven a cabocostosos procesos de protección y desprotección. En este trabajo serevisan algunos ejemplos en los cuales las hidrolasas (las enzimas másempleadas dentro del ámbito de las Biotransformaciones) están implicadascomo biocatalizadores para la obtención del eutómero (esteroisómeroactivo, que presenta la actividad terapéutica deseada) biende diferentes fármacos quirales, o bien de precursores a través de loscuales se puedan sintetizar. Así, se comentarán distintos tipos de biotransformacionespara la obtención de compuestos con diferentesactividades: antivirales, anticancerosos, antihipertensivos, antiinflamatorios,etc, haciendo hincapié en la versatilidad y comodidad delempleo de los biocatalizadores en los pasos sintéticos descritos(AU)

The excellent regio and steroselectivity of biocatalysts, combinedwith their environmental friendly behaviour, make possible to carryout under biocatalytical conditions many processes which, conductedon strictly classical methodologies, would demand expensive andtedious protection and de-protection steps. In this work we reviewsome examples in which hydrolases (the most useful enzymes in theBiotransformations field) catalyse different reactions for synthesizingonly the therapeutically essential stereoisomer of differenthomochiral building blocks for drugs. Thus, processes leading toantiviral, anticancer, antihypertensive or antiinflammatory drugs,along with many others, are described, remarking the versatility andutility of the biocatalysts in the above-mentioned processes(AU)

Biocatálisis aplicada a la Química Farmacéutica / Enzymes and microorganisms as catalysts in the synthesis of products of pharmaceutical interest

La Industria Farmacéutica se enfrenta en la actualidad, forzada por la normativade la UE a reducir la producción de residuos (200 Kg) por kilogramo deproducto. Ello implica el desarrollo de procesos de síntesis más eficaces y selectivos,utilizando mejores catalizadores. Por ello la Biocatálisis y las Biotransformaciones,como aplicación de la misma a la Síntesis Orgánica, están adquiriendo unpapel importante en el diseño de las nuevas síntesis de fármacos. En la presenterevisión se comentan algunas de las metodologías desarrolladas por el Grupo deBiotransformaciones de la UCM en este campo. Se abordan las metodologías desarrolladaspara la mejora de los biocatalizadores: nuevas técnicas de inmovilización o de modificación química, control de la actividad de agua etc. Se describenalgunos procesos de interés desarrollados en el grupo como la resolución de racémicosy su aplicación a la obtención de ácidos S-2-arilpropiónicos o de β-bloqueantesadrenérgicos; la reducción estereoselectiva de cetonas proquirales, la síntesisen un paso de nucleósidos con actividad farmacológica etc. En todos los casos secomentan las ventajas de las nuevas metodologías de síntesis en sintonía con lanueva normativa de obligado cumplimiento de la UE sobre eliminación de disolventescontaminantes (CH2Cl2, TCE), inflamables (hexano, isooctano), compuestosorgánicos volátiles (COV) etc, y de reactivos contaminantes v.g.: catalizadoresórgano metálicos

Pharmaceutical industries are nowadays facing the challenge of lowering theratio (kg of residues/kg of product) to levels below 200, as required by the Europeanlegislation. This fact is demanding the implementation of more selective andefficient synthetic procedures, so that new and better catalysts are needed. For thispurpose, Applied Biocatalysis, and more specifically Biotransformation (the use ofthe former in Organic Synthesis), are becoming more prominent in the design ofnew strategies for drugs synthesis. In this review, some of the methodologiesapplied inside the Biotransformations Group of the Complutense University arepresented; thus, the employ of different methodologies (such as immobilizationand/or modification of biocatalysts, or the control of water activity of the reactionmedia) for improving the biocatalyst performance are described. The biocatalyzedresolution of racemates for obtaining enantiopure S-2-aryl propionic acids (profens)or cardiotonic β-blockers, the estereoselective carbonyl reduction of prochiralketones, or the one-step semi-synthesis of therapeutically significant nucleosideswill be discussed. In all cases, a special emphasis is set on the environmentaladvantages of the biocatalyzed processes, as demanded by EU legislation on substitutionof contaminant solvents (CH2Cl2, TCE) or reagents (organo metallic catalysts),as well as highly flammable compounds (n-hexane, isooctane), or promotingVOCs release

Biotecnología blanca e industria farmacéutica / White biotechnology and pharmaceutical industry

La Biotecnología blanca está relacionada con la utilización de sistemas biológicos para la fabricación, transformación o degradación de moléculas gracias a procesos enzimáticos y fermentativos. Esta definición encuadra los procesos biocatalíticos y las biotransformaciones dentro de este conjunto de disciplinas y ciencias más amplio que se ha definido como Biotecnología. La estabilización de enzimas y células para hacerlas más resistentes a los disolventes orgánicos mediante técnicas de inmovilización y modificación así como posteriormente por ingeniería genética ha supuesto el impulso significativo para este campo. Por otra parte, el conocimiento del medio de reacción así como el control de las variables que intervienen en el proceso ha supuesto una verdadera transformación tecnológica. La Biotecnología Industrial puede ser de una gran ayuda para la obtención de medicamentos (y otros bioproductos) que son difícil o imposibles de obtener mediante métodos químicos tradicionales. En la actualidad más de 325 millones de personas en el mundo consumen medicamentos de origen biotecnológico, de lo que se deduce que la aplicación de la Biotecnología y Biocatálisis en particular ha atravesado la frontera académica encontrando un amplio campo de acción en la Industria Farmacéutica. Los procesos biotecnológicos, por su elevada eficiencia y especificidad, cuentan entre sus propiedades más características el que generan unos menores niveles de residuos que los procesos químicos convencionales y, además, esos residuos son comparativamente mucho menos peligrosos

White Biotechnology is related to the utilization of biological systems for the manufacture, transformation or degradation of molecules using enzymatic and fermentative processes. This definition fits the biocatalytic processes and the biotransformations in the huge set of disciplines and sciences that have been defined as Biotechnology. The stabilization of enzymes and cells for increasing their resistance towards the organic solvents by immobilization and modification techniques, as well as using genetic engineering, has supposed a significant impulse. On the other hand, the knowledge of the reaction media and the control of the variables affecting the process has supposed a real technological transformation. Industrial Biotechnology has become an important tool for obtaining drugs (and other bioproducts) which are difficult or impossible to obtain by chemical traditional methods. At the present, more than 325 million people in the world use drugs with a biotechnological origin, so it can be deduced that the application of the Biotechnology (and specially Biocatalysis) has crossed the academic border finding a wide range of utilities in the pharmaceutical Industry. The biotechnological processes, due to their high efficiency and specificity, generate reduced levels of residues when compared to chemical conventional processes which on the other hand, are comparatively more dangerous