Podophyllotoxin: Recent Advances in the Development of Hybridization Strategies to Enhance Its Antitumoral Profile.

Podophyllotoxin is a naturally occurring cyclolignan isolated from rhizomes of Podophyllum sp. In the clinic, it is used mainly as an antiviral; however, its antitumor activity is even more interesting. While podophyllotoxin possesses severe side effects that limit its development as an anticancer agent, nevertheless, it has become a good lead compound for the synthesis of derivatives with fewer side effects and better selectivity. Several examples, such as etoposide, highlight the potential of this natural product for chemomodulation in the search for new antitumor agents. This review focuses on the recent chemical modifications (2017-mid-2023) of the podophyllotoxin skeleton performed mainly at the C-ring (but also at the lactone D-ring and at the trimethoxyphenyl E-ring) together with their biological properties. Special emphasis is placed on hybrids or conjugates with other natural products (either primary or secondary metabolites) and other molecules (heterocycles, benzoheterocycles, synthetic drugs, and other moieties) that contribute to improved podophyllotoxin bioactivity. In fact, hybridization has been a good strategy to design podophyllotoxin derivatives with enhanced bioactivity. The way in which the two components are joined (directly or through spacers) was also considered for the organization of this review. This comprehensive perspective is presented with the aim of guiding the medicinal chemistry community in the design of new podophyllotoxin-based drugs with improved anticancer properties.

1,3-Cyclohexadien-1-Als: Synthesis, Reactivity and Bioactivities.

In synthetic organic chemistry, there are very useful basic compounds known as building blocks. One of the main reactions wherein they are applied for the synthesis of complex molecules is the Diels-Alder cycloaddition. This reaction is between a diene and a dienophile. Among the most important dienes are the cyclic dienes, as they facilitate the reaction. This review considers the synthesis and reactivity of one of these dienes with special characteristics-it is cyclic and has an electron withdrawing group. This building block has been used for the synthesis of biologically active compounds and is present in natural compounds with interesting properties.

Zr-MOF-808 as Catalyst for Amide Esterification.

In this work, zirconium-based metal-organic framework Zr-MOF-808-P has been found to be an efficient and versatile catalyst for amide esterification. Comparing with previously reported homogeneous and heterogeneous catalysts, Zr-MOF-808-P can promote the reaction for a wide range of primary, secondary and tertiary amides with n-butanol as nucleophilic agent. Different alcohols have been employed in amide esterification with quantitative yields. Moreover, the catalyst acts as a heterogeneous catalyst and could be reused for at least five consecutive cycles. The amide esterification mechanism has been studied on the Zr-MOF-808 at molecular level by in situ FTIR spectroscopic technique and kinetic study.

Tianeptine, an atypical pharmacological approach to depression. / Tianeptina, un abordaje farmacológico atípico de la depresión.

The introduction of the first antidepressants in the 50s of the 20th century radically changed the treatment of depression, while providing information on pathophysiological aspects of this disease. New antidepressants drugs (agomelatine, tianeptine, vortioxetine) are providing data that give rise to pathophysiological hypotheses of depression that differ from the classic monoaminergic theory. In this sense, tianeptina, an atypical drug by its mechanism of differential action, contributes to clarify that in depression there is more than monoamines. Thus, tianeptine does not modify the rate of extracellular serotonin, so it does not increase or decrease the reuptake of serotonin. Chronic administration of tianeptine does not alter the density or affinity of more than a hundred classical receptors related to depression. Recently, a weak action of tianeptine on Mu opioid receptors has been described that could explain the release of dopamine in the limbic system and its participation in the modulation of glutamatergic mechanisms. These mechanisms support the hypothesis of the possible mechanism of action of this antidepressant. Tianeptine is an antidepressant, with anxiolytic properties, that can improve somatic symptoms. Tianeptine as a glutamatergic modulator, among other mechanisms, allows us to approach depression from a different point of view than other antidepressants.

Catalytic Transfer Hydrogenation of Biomass-Derived Carbonyls over Hafnium-Based Metal-Organic Frameworks.

A series of highly crystalline, porous, hafnium-based metal-organic frameworks (Hf-MOFs) have been shown to catalyze the transfer hydrogenation reaction of levulinic ester to produce γ-valerolactone by using isopropanol as a hydrogen donor. The results are compared with their zirconium-based counterparts. The role of the metal center in Hf-MOFs has been identified and reaction parameters optimized. NMR studies using isotopically labeled isopropanol provide evidence that the transfer hydrogenation occurs through a direct intermolecular hydrogen transfer route. The catalyst, Hf-MOF-808, can be recycled several times with only a minor decrease in catalytic activity. The generality of the procedure has been demonstrated by accomplishing the transformation with aldehydes, ketones, and α,ß-unsaturated carbonyl compounds. The combination of Hf-MOF-808 with the Brønsted-acidic Al-Beta zeolite gives the four-step one-pot transformation of furfural to γ-valerolactone in good yield of 75 %.

Organic-inorganic supramolecular solid catalyst boosts organic reactions in water.

Coordination polymers and metal-organic frameworks are appealing as synthetic hosts for mediating chemical reactions. Here we report the preparation of a mesoscopic metal-organic structure based on single-layer assembly of aluminium chains and organic alkylaryl spacers. The material markedly accelerates condensation reactions in water in the absence of acid or base catalyst, as well as organocatalytic Michael-type reactions that also show superior enantioselectivity when comparing with the host-free transformation. The mesoscopic phase of the solid allows for easy diffusion of products and the catalytic solid is recycled and reused. Saturation transfer difference and two-dimensional (1)H nuclear Overhauser effect NOESY NMR spectroscopy show that non-covalent interactions are operative in these host-guest systems that account for substrate activation. The mesoscopic character of the host, its hydrophobicity and chemical stability in water, launch this material as a highly attractive supramolecular catalyst to facilitate (asymmetric) transformations under more environmentally friendly conditions.

Psychiatric Comorbidity at the Time of Diagnosis in Adults With ADHD: The CAT Study.

OBJECTIVE: The CAT (Comorbilidad en Adultos con TDAH) study aimed to quantify and characterize the psychiatric comorbidity at the time of diagnosis of ADHD in adult outpatients. METHOD: Cross-sectional, multicenter, observational register of adults with ADHD diagnosed for the first time. RESULTS: In this large sample of adult ADHD (n = 367), psychiatric comorbidities were present in 66.2% of the sample, and were more prevalent in males and in the hyperactive-impulsive and combined subtypes. The most common comorbidities were substance use disorders (39.2%), anxiety disorders (23%), and mood disorders (18.1%). In all, 88.8% patients were prescribed pharmacological treatment for ADHD (in 93.4% of cases, modified release methylphenidate capsules 50:50). CONCLUSION: A high proportion of psychiatric comorbidity was observed when adult outpatients received a first-time diagnosis of ADHD. The systematic registering of patients and comorbidities in clinical practice may help to better understand and manage the prognostic determinants in adult ADHD.

Quo Vadis Clozapine? A Bibliometric Study of 45 Years of Research in International Context.

We have carried out a bibliometric study about the international scientific publications on clozapine. We have used the EMBASE and MEDLINE databases, and we applied bibliometric indicators of production, as Price's Law on the increase of scientific literature. We also calculated the participation index (PI) of the different countries. The bibliometric data have also been correlated with some social and health data from the 12 most productive countries in biomedicine and health sciences. In addition, 5607 original documents dealing with clozapine, published between 1970 and 2013, were downloaded. Our results state non-fulfilment of Price's Law, with scientific production on clozapine showing linear growth (r=0.8691, vs. r=0.8478 after exponential adjustment). Seven of the 12 journals with the highest numbers of publications on clozapine have an Impact Factor>2. Among the countries generating clozapine research, the most prominent is the USA (PI=24.32), followed by the UK (PI=6.27) and Germany (PI=5.40). The differences among countries on clozapine research are significantly related to economic variables linked to research. The scientific interest in clozapine remains remarkable, although after the application of bibliometric indicators of production, a saturation point is evident in the growth of scientific literature on this topic.

Risk-benefit analysis of antidepressant drug treatment in the elderly.

Depression in the elderly is a significant health issue that has the potential to seriously affect physical and emotional well-being. Therefore, the treatment of geriatric depression is necessary. Antidepressant treatment in older depressed patients is efficacious, but differences in the effectiveness of different classes of antidepressants have not been demonstrated. However, differences in tolerability profile are most recognizable in the elderly. With ageing, a series of changes occur in the elderly that modify both the pharmacokinetics and pharmacodynamics of antidepressants and may influence the efficacy, tolerability and safety of treatment in the elderly. Comorbidities require the use of other drugs, which increases the possibility of drug-drug interactions. Given these aspects, individualized therapy for each elderly patient is needed to achieve acceptable risk-benefit ratio. Effective treatment of depression in the elderly, which may require combined pharmacological with psychosocial treatment, can decrease both morbidity and mortality; it also may lead to reduced demands on family members and on health-care and social services.

Multisite organic-inorganic hybrid catalysts for the direct sustainable synthesis of GABAergic drugs.

Multisite organic-inorganic hybrid catalysts have been prepared and applied in a new general, practical, and sustainable synthetic procedure toward industrially relevant GABA derivatives. The domino sequence is composed of seven chemical transformations which are performed in two one-pot reactions. The method produces both enantiomeric forms of the product in high enantiopurity as well as the racemate in good yields after a single column purification step. This protocol highlights major process intensification, catalyst recyclability, and low waste generation.

The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder.

The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients, caregivers, and society and accounts for the largest part of the morbidity-mortality of the illness. Lurasidone is an atypical antipsychotic with a potent binding affinity as antagonist for D2, 5-HT2A, 5-HT7, and partial agonist at 5-HT1A receptors. Affinity for other receptors as H1 and muscarinic were negligible. Lurasidone was approved in 2010 for the treatment of schizophrenia and recently, 2013, for bipolar depression in monotherapy and an adjunct to lithium or valproate. Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose, lipids, or the QT interval. Additional studies are desirable to know the clinical profile of lurasidone in long-term treatment, in patients with bipolar II disorders, and versus other antipsychotic agents.

Mapping the scientific research on atypical antipsychotic drugs in Spain: a bibliometric assessment.

OBJECTIVES: We carried out a bibliometric study on the scientific publications in relation to atypical antipsychotic drugs (AADs) in Spain. METHODS: We used the EMBASE and MEDLINE databases and we applied some bibliometric indicators of paper production and dispersion (Price's law and Bradford's law, respectively). We also calculated the participation index of the different countries and correlated the bibliometric data with some social and health data (total per capita expenditure on health and gross domestic expenditure on research and development). RESULTS: We collected 656 original papers published between 1988 and 2011. Our study results fulfilled Price's law with scientific production on AADs showing exponential growth (correlation coefficient r = 0.9693, vs. r = 0.9177 after linear adjustment). The most widely studied drugs were risperidone (181 papers), olanzapine (143), clozapine (94), and quetiapine (74). Division into Bradford zones yielded a nucleus occupied by the European Psychiatry and European Neuropsychopharmacology (70 articles). Totally 194 different journals were published, with 5 of the first 10 used journals having an impact factor being greater than 4. CONCLUSION: The publications on AADs in Spain have undergone exponential growth over the studied period, without evidence of reaching a saturation point.

Domino elimination/nucleophilic addition in the synthesis of chiral pyrrolidines.

Polyhydroxylated pyrrolidines have been synthesized in a one-pot procedure by the addition of an organometallic reagent to isoxazolidines obtained by a 1,3-dipolar cycloaddition between nitrones and vinylsulfones. This method highlights sulfone reactivity and provides an easy approach for the preparation of chiral pyrrolidines using cyclic imines as key intermediates.

Asymmetric counteranion-directed catalytic Hosomi-Sakurai reaction.

Counteranion control enables the enantioselective, organo Lewis acid catalyzed Hosomi-Sakurai reaction of (hetero)aromatic aldehydes and allylsilanes using an easily handled disulfonimide precatalyst (see scheme). The key to the success of this system is to turn the usually undesired silylium ion catalysis into the desired catalytic regime and pair the cation with an enantiopure disulfonimide anion, thereby applying the concept of asymmetric counteranion-directed catalysis.

The discovery of chlordiazepoxide and the clinical introduction of benzodiazepines: half a century of anxiolytic drugs.

The clinical introduction of chlordiazepoxide half a century ago was one of the major breakthroughs in the history of psychopharmacology, as it opened the door for the benzodiazepine saga, the pharmacological family par excellence in the treatment of anxiety disorders. This review analyses the discovery of this drug, which was filled with chance events, and numerous chemical and clinical errors of approach. Chlordiazepoxide, initially called methaminodiazepoxide, was patented in 1958 and introduced in clinical treatment in 1960 under the brand name Librium®. The benzodiazepines became the most widely prescribed drugs worldwide, provided truly effective treatment for "minor forms" (neuroses) of mental disorders for the first time, increased the quality of scientific methodology in clinical research, and enabled the development of new etiopathogenic theories for anxiety disorders, especially after the discovery in 1977 of their high-affinity receptor complex.

High-speed living polymerization of polar vinyl monomers by self-healing silylium catalysts.

This contribution describes the development and demonstration of the ambient-temperature, high-speed living polymerization of polar vinyl monomers (M) with a low silylium catalyst loading (≤ 0.05 mol % relative to M). The catalyst is generated in situ by protonation of a trialkylsilyl ketene acetal ((R)SKA) initiator (I) with a strong Brønsted acid. The living character of the polymerization system has been demonstrated by several key lines of evidence, including the observed linear growth of the chain length as a function of monomer conversion at a given [M]/[I] ratio, near-precise polymer number-average molecular weight (M(n), controlled by the [M]/[I] ratio) with narrow molecular weight distributions (MWD), absence of an induction period and chain-termination reactions (as revealed by kinetics), readily achievable chain extension, and the successful synthesis of well-defined block copolymers. Fundamental steps of activation, initiation, propagation, and catalyst "self-repair" involved in this living polymerization system have been elucidated, chiefly featuring a propagation "catalysis" cycle consisting of a rate-limiting C--C bond formation step and fast release of the silylium catalyst to the incoming monomer. Effects of acid activator, catalyst and monomer structure, and reaction temperature on polymerization characteristics have also been examined. Among the three strong acids incorporating a weakly coordinating borate or a chiral disulfonimide anion, the oxonium acid [H(Et(2)O)(2)](+)[B(C(6)F(5))(4)](-) is the most effective activator, which spontaneously delivers the most active R(3)Si(+), reaching a high catalyst turn-over frequency (TOF) of 6.0×10(3) h(-1) for methyl methacrylate polymerization by Me(3)Si(+) or an exceptionally high TOF of 2.4×10(5) h(-1) for n-butyl acrylate polymerization by iBu(3)Si(+), in addition to its high (>90 %) to quantitative efficiencies and a high degree of control over M(n) and MWD (1.07-1.12). An intriguing catalyst "self-repair" feature has also been demonstrated for the current living polymerization system.

A powerful chiral counteranion motif for asymmetric catalysis.

Room to swing a cat: A chiral disulfonimide has been designed as a powerful new motif for asymmetric catalysis. As a first illustration, a highly efficient and enantioselective Mukaiyama aldol reaction has been developed (see scheme). The actual catalyst is proposed to be an N-silyl imide which is generated in situ.