In vitro and in vivo activity of a new small-molecule inhibitor of HDAC6 in mantle cell lymphoma

Cancer origin and development is associated not only with genetic alterations, but also with the disturbance of epigenetic profiles.1 In this regard, the tumoral epigenome is characterized by both specific and general shifts in the DNA methylation and histone-modification landscapes.1 However, in contrast to genetic disruption, the effect of epigenetic modifications or marks may potentially be reversed by the use of drugs that target enzymes involved in adding, removing or signaling DNA methylation and histone modifications.1 This basic knowledge has been adopted into clinical practice, and inhibitors of histone deacetylases and DNA demethylating agents have been approved for use in the therapy of hematologic malignancies, such as cutaneous T-cell lymphoma and myelodysplastic syndrome, respectively.2 Other promising epigenetic drugs include inhibitors of histone methyltransferases,2 histone demethylases,2 histone kinases,3 and bromodomain proteins that interfere with the 'reading' of acetylated histone residues

Synthetic conjugates of ursodeoxycholic acid inhibit cystogenesis in experimental models of polycystic liver disease

Background and aims: polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. Approach and results: here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. Conclusions: these UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs

A Critical Review of Biomarkers Used for Monitoring Human Exposure to Lead: Advantages, Limitations, and Future Needs

Lead concentration in whole blood (BPb) is the primary biomarker used to monitor exposure to this metallic element. The U.S. Centers for Disease Control and Prevention and the World Health Organization define a BPb of 10 μg/dL (0.48 μmol/L) as the threshold of concern in young children. However, recent studies have reported the possibility of adverse health effects, including intellectual impairment in young children, at BPb levels < 10 μg/dL, suggesting that there is no safe level of exposure. It appears impossible to differentiate between low-level chronic Pb exposure and a high-level short Pb exposure based on a single BPb measurement; therefore, serial BPb measurements offer a better estimation of possible health outcomes. The difficulty in assessing the exact nature of Pb exposure is dependent not so much on problems with current analytical methodologies, but rather on the complex toxicokinetics of Pb within various body compartments (i.e., cycling of Pb between bone, blood, and soft tissues). If we are to differentiate more effectively between Pb stored in the body for years and Pb from recent exposure, information on other biomarkers of exposure may be needed. None of the current biomarkers of internal Pb dose have yet been accepted by the scientific community as a reliable substitute for a BPb measurement. This review focuses on the limitations of biomarkers of Pb exposure and the need to improve the accuracy of their measurement. We present here only the traditional analytical protocols in current use, and we attempt to assess the influence of confounding variables on BPb levels. Finally, we discuss the interpretation of BPb data with respect to both external and endogenous Pb exposure, past or recent exposure, as well as the significance of Pb determinations in human specimens including hair, nails, saliva, bone, blood (plasma, whole blood), urine, feces, and exfoliated teeth

G6PD deficiency in Latin America: systematic review on prevalence and variants

Plasmodium vivax radical cure requires the use of primaquine (PQ), a drug that induces haemolysis in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals, which further hampers malaria control efforts. The aim of this work was to study the G6PDd prevalence and variants in Latin America (LA) and the Caribbean region. A systematic search of the published literature was undertaken in August 2013. Bibliographies of manuscripts were also searched and additional references were identified. Low prevalence rates of G6PDd were documented in Argentina, Bolivia, Mexico, Peru and Uruguay, but studies from Curaçao, Ecuador, Jamaica, Saint Lucia, Suriname and Trinidad, as well as some surveys carried out in areas of Brazil, Colombia and Cuba, have shown a high prevalence (> 10%) of G6PDd. The G6PD A-202A mutation was the variant most broadly distributed across LA and was identified in 81.1% of the deficient individuals surveyed. G6PDd is a frequent phenomenon in LA, although certain Amerindian populations may not be affected, suggesting that PQ could be safely used in these specific populations. Population-wide use of PQ as part of malaria elimination strategies in LA cannot be supported unless a rapid, accurate and field-deployable G6PDd diagnostic test is made available

Double Group Transfer Reactions: Role of Activation Strain and Aromaticity in Reaction Barriers

Double group transfer (DGT) reactions, such as the bimolecular automerization of ethane plus ethene, are known to have high reaction barriers despite the fact that their cyclic transition states have a pronounced in-plane aromatic character, as indicated by NMR spectroscopic parameters. To arrive at a way of understanding this somewhat paradoxical and incompletely understood phenomenon of high-energy aromatic transition states, we have explored six archetypal DGT reactions using density functional theory (DFT) at the OLYP/TZ2P level. The main trends in reactivity are rationalized using the activation strain model of chemical reactivity. In this model, the shape of the reaction profile ΔE(ζ) and the height of the overall reaction barrier ΔE≠=ΔE(ζ=ζTS) is interpreted in terms of the strain energy ΔEstrain(ζ) associated with deforming the reactants along the reaction coordinate ζ plus the interaction energy ΔEint(ζ) between these deformed reactants: ΔE(ζ)=ΔEstrain(ζ)+ΔEint(ζ). We also use an alternative fragmentation and a valence bond model for analyzing the character of the transition states

Periselectivity in electrocyclic processes: [2+2] vs. [4+2] selectivity in the cycloaddition reaction between ketenes and a, b - unsaturated imines

El objetivo de este trabajo es el estudio computacional del comportamiento de diversas cetenas y 1-azadienos para desarrollar un modelo general que pueda explicar las variables que determinan la formación de [2+2] y [4+2] cicloaductos. Puesto que el paso electrocíclico determina los productos de la reacción, se concentra en los estados de transición compatibles con el proceso electrocíclico. El efecto del disolvente se ha tomado en cuenta mediante el modelo OnsagerZetenak eta 1-azadienoen arteko erreakzioa konputazionalki aztertu egiten da. Helburua, [2 + 2] edota [4 + 2] zikloaduktoen formazioa esplikatzeko eredu orokor bat aurkitzea da. Prozesu elektroziklazioan ematen den urratsa erreakzioaren produktuak determinatzen duena denez gero, elektroziklazioan gerta daitezkeen bi trantsizio egoeratara bideratuko dugu geure analisia. Disolbatzearen eragina kontutan hartuko da ere, Onsager-en teoria erabiliz.L'objectif de cE travail est l'étude computational du comportement de plusieurescetènes et l-azadiènes pour développer un modèle général qui puisse expliquer les variables qui déterminent la formation des cycloadductes (2+2) et (4+ 2). Etant donné que l'étape électrocyclique détermine les produits de la réaction, on se concentre aux états de transition compatibles avec le procès élcctrociclique. On a tenu en compte l'effet du solvant en utilisant le modéle d'Onsager.The aim of the present work is to explore computationally the behaviour of several model ketenes and 1-azadienes in order to develop a general model which could eventually explain the variables governing the formation of [2+2] an [4+2] cycloadducts. Since the electrocyclic step determines the outcome of the reaction, we well focus on the transition states compatible with the electrocyclic process. Solvent effect has been taken into account using the Onsager model

Synthesis of radiolabelled aryl azides from diazonium salts: experimental and computational results permit the identification of the preferred mechanism

Experimental and computational studies on the formation of aryl azides from the corresponding diazonium salts support a stepwise mechanism via acyclic zwitterionic intermediates. The low energy barriers associated with both transition structures are compatible with very fast and efficient processes, thus making this method suitable for the chemical synthesis of radiolabelled aryl azides.Funding Agencies|RADIOMI project (EU FP7-PEOPLE-ITN-RADIOMI); Ministerio de Economia y Competitividad (MINECO) of Spain; FEDER [CTQ2013-45415-P]; University of the Basque Country (UPV/EHU) [UFI11/22 QOSYC]; Basque Government (GV/EJ) [IT-324-07]</p

Lacking Immunotherapy Biomarkers for Biliary Tract Cancer: A Comprehensive Systematic Literature Review and Meta-Analysis

Background: Immunotherapy has recently been incorporated into the spectrum of biliary tract cancer (BTC) treatment. The identification of predictive response biomarkers is essential in order to identify those patients who may benefit most from this novel treatment option. Here, we propose a systematic literature review and a meta-analysis of PD-1, PD-L1, and other immune-related biomarker expression levels in patients with BTC. Methods: Prisma guidelines were followed for this systematic review and meta-analysis. Eligible studies were searched on PubMed. Studies published between 2017 and 2022, reporting data on PD-1/PD-L1 expression and other immune-related biomarkers in patients with BTC, were considered eligible. Results: A total of 61 eligible studies were identified. Despite the great heterogeneity between 39 studies reporting data on PD-L1 expression, we found a mean PD-L1 expression percentage (by choosing the lowest cut-off per study) of 25.6% (95% CI 21.0 to 30.3) in BTCs. The mean expression percentages of PD-L1 were 27.3%, 21.3%, and 27.4% in intrahepatic cholangiocarcinomas (iCCAs—15 studies), perihilar–distal CCAs (p/dCCAs—7 studies), and gallbladder cancer (GBC—5 studies), respectively. Furthermore, 4.6% (95% CI 2.38 to 6.97) and 2.5% (95% CI 1.75 to 3.34) of BTCs could be classified as TMB-H and MSI/MMRd tumors, respectively. Conclusion: From our analysis, PD-L1 expression was found to occur approximately in 26% of BTC patients, with minimal differences based on anatomical location. TMB-H and MSI molecular phenotypes occurred less frequently. We still lack a reliable biomarker, especially in patients with mismatch-proficient tumors, and we must need to make an effort to conceive new prospective biomarker discovery studies

Microwave-Assisted 1,3-Dioxa-[3,3]-Sigmatropic Rearrangement of Substituted Allylic Carbamates: Application to the Synthesis of Novel 1,3-Oxazine-2,4-dione Derivatives

International audienceIn a first instance, the effect of the microwave irradiation on the 1,3-Dioxa-[3,3]-sigmatropic rearrangement of aryl allylic carbamates was investigated. Under these new conditions, the reaction acceleration was clearly highlighted compared to conventional heating conditions. Depending on the electronic nature of substituents on the aromatic group, this type of rearrangement can be faster with similar or improved yields. Due to this experimental improvement, the diversity of aryl allylic carbamates able to undergo this rearrangement in a reasonable reaction time (30 min.) and with acceptable to high yields was greatly extended. Finally, an original synthetic way involving this microwave-assisted process to access new six-membered heterocyclic structures such as (E)-5-arylidene-1,3-oxazinane-2,4-diones was developed from Morita-Baylis-Hillman (MBH) adducts showing the interest of this molecular rearrangement approach. DFT and Fragment Distortion studies showed in general polar transition structures and connected high deformation and interaction energies with lower activation barriers

A Cationic Rh(III) Complex That Efficiently Catalyzes Hydrogen Isotope Exchange in Hydrosilanes

3 páginas, 2 figuras, 1 tabla, 3 esquemas.The synthesis and structural characterization of a mixed-sandwich (η5-C5Me5)Rh(III) complex of the cyclometalated phosphine PMeXyl2 (Xyl = 2,6-C6H3Me2) with unusual κ4-P,C,C′,C′′ coordination (compound 1-BArf; BArf = B(3,5-C6H3(CF3)2)4) are reported. A reversible κ4 to κ2 change in the binding of the chelating phosphine in cation 1+ induced by dihydrogen and hydrosilanes triggers a highly efficient Si−H/Si−D (or Si−T) exchange applicable to a wide range of hydrosilanes. Catalysis can be carried out in an organic solvent solution or without solvent, with catalyst loadings as low as 0.001 mol %, and the catalyst may be recycled a number of times.Financial support (FEDER support) from the Spanish Ministerio de Educación (Project No. CTQ2007-62814), Consolider-Ingenio 2010 (No. CSD2007-0000), and the Junta de Andalucía (Projects Nos.FQM-119 and P09-FQM-4832) is gratefully acknowledged. J.C. thanks the Ministerio de Educación for a research grant (Ref. AP20080256), and A.C.E. thanks CONACYT (Mexico) for a research grant (Ref. No. 22934).Peer reviewe