No abstract

The continued drug discovery failures in complex neurodegenerative diseases, including Alzheimer's disease (AD), has raised questions about the classical paradigm "one-drug, one-target, one-disease." In parallel, the ever-increasing awareness of the multiplicity of the underlying pathways has led to the affirmation of polypharmacological approaches. Polypharmacology, which broadly embodies the use of pharmaceutical agents acting on multiple targets, seems to be the best way to restore the complex diseased network and to provide disease-modifying effects in AD. In this review, our aim is to provide a roadmap into a world that is still only partly explored and that should be seen as a continuum of pharmacological opportunities, from drug combinations to multitarget-directed ligands (both codrugs and hybrids). Each modality has unique features that can be effectively exploited by medicinal chemists. We argue that understanding their advantages and drawbacks is very helpful in choosing a proper approach and developing successful AD multitarget drug-discovery endeavors. We also briefly dwell on (co)target validation, an aspect that is quite often neglected, but critical for an efficient clinical translation. We substantiate our discussion with instructive examples taken from the recent literature. Our wish is that, in spite of the specter of the high attrition rates, best researchers preferring to enter, stay, and progress in the field would help grow the sector and develop AD polypharmacology to full potential.

Despite the applicability of histone deacetylase inhibitors (HDACis) for cancer treatment, several works in the literature have shown that these inhibitors can be used in several other diseases, such as neurodegenerative diseases (NDs). This review begins by discussing the signaling pathways of HDACs, focused on the context of NDs, presenting a discussion about the pharmacophoric features of HDACis and crystal structure analysis and discussing interesting case studies from the literature about the development of HDACis. Additionally, a discussion about the consequences of isoform-selective inhibition vs pan-HDACis on neurotoxic effects and clinical trial investigations of HDACis for NDs is also presented.

Targeting histone deacetylases (HDACs) and phosphatidylinositol 3‐kinases (PI3Ks) is a very promising approach for cancer treatment. This manuscript describes the design, synthesis, in vitro pharmacological profile, and molecular modeling of a novel class of N‐acylhydrazone (NAH) derivatives that act as HDAC6/8 and PI3Kα dual inhibitors. The surprising selectivity for PI3Kα may be related to differences in the conformation in the active site. Cellular studies showed that these compounds act in HDAC6 inhibition and the PI3/K/AKT/mTOR pathway. The compounds that are selective for inhibition of HDAC6/8 and inhibit PI3Kα show potential for the treatment of cancer.

During the early preclinical phase, from hit identification and optimization to a lead compound, several medicinal chemistry strategies can be used to improve potency and/or selectivity. The conformational restriction is one of these approaches. It consists of introducing some specific structural constraints in a lead candidate to reduce the overall number of possible conformations in order to favor the adoption of a bioactive conformation and, as a consequence, molecular recognition by the target receptor. In this work, we focused on the application of the conformational restriction strategy in the last five years for the optimization of hits and/or leads of several important classes of therapeutic targets in the drug discovery field. Thus, we recognize the importance of several kinase inhibitors to the current landscape of drug development for cancer therapy and the use of G-protein Coupled Receptor (GPCR) modulators. Several other targets are also highlighted, such as the class of epigenetic drugs. Therefore, the possibility of exploiting conformational restriction as a tool to increase the potency and selectivity and promote changes in the intrinsic activity of some ligands intended to act on many different targets makes this strategy of structural modification valuable for the discovery of novel drug candidates.

RESUMONeste trabalho descrevemos as malformações e co-morbidades observadas em pacientes com síndrome de Turner (ST). Foi realizado um estudo retrospectivo, avaliando os prontuários de 60 pacientes cujo diagnóstico de ST foi confirmado através do cariótipo, desde a fase pré-natal até a idade de 49 anos. As pacientes encontram-se com idades entre 1 e 50 anos e foram evoluídas num período de 4 meses a 29 anos. Trinta e uma apresentavam o cariótipo 45XO, 24 eram mosaico e 5 apresentavam o padrão 46Xi, (i,Xq). Todas tinham baixa estatura e algum tipo de estigma. Cinco (8,3%) não apresentavam outras malformações congênitas e eram saudáveis; 55 (91,6%) apresentavam doenças associadas, sendo que em 23 (38,3%) foram detectadas doenças endócrinas, em 16 (26,6%) otorrinolaringológicas, 15 (25%) cardiológicas, 14 (23,3%) nefrológicas e 6 (10%) gastrointestinais. Entre as doenças endócrinas mais comuns, observamos hipotireoidismo (36,6%), seguido de osteoporose (18,3%) e hiperlipemia (11,6%). As doenças otorrinolaringológicas mais comuns foram as infecções (otite média e amigdalite); das doenças cardiológicas, as valvulopatias (principalmente aorta bicúspi-de), das nefrológicas as duplicações do sistema coletor e rotações renais e das gastrointestinais foram observados dois casos de divertículo de Meckel. Encontramos maior prevalência de malformações cardía-cas nas pacientes com cariótipo 45XO, embora sem significância estatística quando considerados os demais cariótipos. Concluímos que, devido à alta ocorrência de doenças nesta síndrome, estas devem ser acompanhadas periodicamente em diferentes especialidades. ABSTRACTA retrospective study was held on data of 60 patients with Turner's Syndrome (TS), aiming to report the most prevalent diseases in this syndrome. Diagnosis was confirmed by kariotype from the prenatal period to the age of 49 years. At the time of the study the age of the patients ranged from 1 to 50 years, and they were observed during 4 months to 29 years. Thirty-one patients presented 45XO kariotype, 24 were mosaic and 5 were 46Xi, (i,Xq). All presented with low stature and some stigmas. Five (8.3%) did not present other diseases and are currently healthy. In 55 (91.6%) the following associate diseases were observed: 23 (38.3%) had endocrine, 16 (26.6%) ear, throat and nose, 15 (25%) cardiologic, 14 (23.3%) renal and 6 (10%) gastrointestinal diseases. The most common endocrine diseases were hypothyroidism (36.6%), osteoporosis (18.3%) and hyperlipidemia (11.6%). The most frequent ear, nose and throat diseases were infections (media otitis and tonsillitis). Congenital diseases of the aorta valve (bicuspid aorta valve) and double collecting systems with renal rotation were the most prevalent cardiac and renal diseases, respectively. Two patients had a diagnosis of Meckel's diverticulum. Although congenital diseases were more common in 45XO patients, no artigo original

PIK-75 is a phosphoinositide-3-kinase (PI3K) α-isoform-selective inhibitor with high potency. Although published structure-activity relationship data show the importance of the NO and the Br substituents in PIK-75, none of the published studies could correctly determine the underlying reason for their importance. In this publication, we report the first X-ray crystal structure of PIK-75 in complex with the kinase GSK-3β. The structure shows an unusual U-shaped conformation of PIK-75 within the active site of GSK-3β that is likely stabilized by an atypical intramolecular Br⋅⋅⋅NO halogen bond. NMR and MD simulations show that this conformation presumably also exists in solution and leads to a binding-competent preorganization of the PIK-75 molecule, thus explaining its high potency. We therefore suggest that the site-specific incorporation of halogen bonds could be generally used to design conformationally restricted bioactive substances with increased potencies.

Sigma-hole (σ-hole) bonds are interactions that are gaining special attention in medicinal chemistry.