Harnessing the Potential of Electron Donor-Acceptor Complexes and N-Centered Radicals: Expanding the Frontiers of Isoquinoline Derivative Synthesis.

Research on synthesizing nitrogen-containing heterocyclic scaffolds is important because these structures are commonly found in Nature, such as in the alkaloids' family. In our study, we propose a new method to synthesize the isoquinoline core using an electron donor-acceptor (EDA) complex strategy. Our mechanistic investigations have confirmed that our synthesis process operates through an EDA mechanism, which is not extensively discussed in the literature, particularly regarding its applications on alkynyl substrates. This EDA strategy has proven to be a simple and straightforward way to produce isoquinoline scaffolds and their derivatives without the need for metal catalysts.

PSL Chemical Biology Symposia Third Edition: A Branch of Science in its Explosive Phase.

This symposium is the third PSL (Paris Sciences & Lettres) Chemical Biology meeting (2016, 2019, 2023) held at Institut Curie. This initiative originally started at Institut de Chimie des Substances Naturelles (ICSN) in Gif-sur-Yvette (2013, 2014), under the directorship of Professor Max Malacria, with a strong focus on chemistry. It was then continued at the Institut Curie (2015) covering a larger scope, before becoming the official PSL Chemical Biology meeting. This latest edition was postponed twice for the reasons that we know. This has given us the opportunity to invite additional speakers of great standing. This year, Institut Curie hosted around 300 participants, including 220 on site and over 80 online. The pandemic has had, at least, the virtue of promoting online meetings, which we came to realize is not perfect but has its own merits. In particular, it enables those with restricted time and resources to take part in events and meetings, which can now accommodate unlimited participants. We apologize to all those who could not attend in person this time due to space limitation at Institut Curie.

Synthesis of Isoquinolines and Related Heterocycles under Visible-Light Conditions.

Visible-light catalysis is now widely acknowledged as a potent approach for efficiently constructing various types of frameworks, particularly bioactive compounds, with high yields. However, there is still a strong need for further advancements in these methods because certain delicate compounds cannot be synthesized due to structural sensitivity. In this context, a seamless reaction pathway toward 6-membered ring nitrogen-containing heterocycles is presented here, offering access to isoquinoline derivatives and related heterocycles.

Polycyclic nitrogen heterocycles as potential thymidine phosphorylase inhibitors: synthesis, biological evaluation, and molecular docking study.

New polycyclic heterocycles were synthesised and evaluated as potential inhibitors of thymidine phosphorylase (TP). Inspired by the pharmacophoric pyrimidinedione core of the natural substrate, four series have been designed in order to interact with large empty pockets of the active site: pyrimidoquinoline-2,4-diones (series A), pyrimidinedione linked to a pyrroloquinoline-1,3-diones (series B and C), the polycyclic heterocycle has been replaced by a pyrimidopyridopyrrolidinetetraone (series D). In each series, the tricyclic nitrogen heterocyclic moiety has been synthesised by a one-pot multicomponent reaction. Compared to 7-DX used as control, 2d, 2l, 2p (series A), 28a (series D), and the open intermediate 30 showed modest to good activities. A kinetic study confirmed that the most active compounds 2d, 2p are competitive inhibitors. Molecular docking analysis confirmed the interaction of these new compounds at the active binding site of TP and highlighted a plausible specific interaction in a pocket that had not yet been explored.

Spotlight on Photoinduced Aryl Migration Reactions.

Rearrangement reactions are certainly one of the most useful approaches towards complex structures in organic chemistry. With efficient conditions, it is indeed possible to convert simple substrates into highly functionalized products. Moreover, combining this approach with an attractive initiation process, such as visible-light catalysis, makes these reactions particularly powerful. Recently, tremendous improvements have been made, owing to a better understanding of photoredox mechanisms. In this review, recent progress on visible-light aryl migration reactions is discussed, focusing especially on Smiles rearrangement and related reactions.

Light-Enabled Radical 1,4-Aryl Migration Via a Phospho-Smiles Rearrangement.

Rearrangement reactions in organic chemistry are attractive strategies to build efficiently complex scaffolds, in just one step, from simple starting materials. Among them, aryl migrations are certainly one of the most useful and straightforward rearrangement for building attractive carbon-carbon bonds. Of note, anionic aryl migration reactions have been largely described compared to their radical counterparts. Recently, visible-light catalysis has proven its efficiency to generate such radical rearrangements due to the concomitant loss of a particle (often CO2 or SO2), which is the driving-force of the reaction. Here, we disclose a Smiles-type rearrangement, triggered by a phosphorus-containing unit (arylphosphoramidate), therefore called "phospho-Smiles" rearrangement, allowing a Csp2-Csp2 bond formation thanks to a 1,4-aryl migration reaction. In addition, combining this approach with a radical hydroamination/amination reaction produces an amination/phospho-Smiles cascade particularly attractive, for instance, to investigate the synthesis of the phthalazine core, a scarcely described scaffold of interest for medicinal chemistry projects.

Silver-catalyzed tandem cycloisomerization/hydroarylation reactions and mechanistic investigations for an efficient access to 1,2-dihydroisoquinolines.

An efficient silver-catalyzed tandem reaction for the formation of 1,2-dihydroisoquinoline derivatives is herein reported. Highly functionalized multiheterocyclic scaffolds are accessible in a straightforward manner using readily accessible starting materials under mild conditions. This methodology offers an attractive route for the synthesis and development of a biologically relevant new heterocyclic pharmacophore, merging the biological activities of isoquinolines with those of various nitrogen-containing heterocycles (indoles, pyrroles) incorporated during the tandem reaction. Mechanistic investigations were also conducted along with a large scope and limitation study, modifying various sites of this pharmacophore.

Malnutrition inequalities in Ecuador: differences by wealth, education level and ethnicity.

OBJECTIVE: To describe and quantify the magnitude and distribution of stunting, wasting, anaemia, overweight and obesity by wealth, level of education and ethnicity in Ecuador. DESIGN: We used nationally representative data from the 2012 Ecuadorian National Health and Nutrition Survey. We used the Multidimensional Poverty Index (MPI) as a proxy of wealth. The MPI identifies deprivations across three dimensions (health, education and standard of living). We defined education by years of schooling and ethnicity as a social construct, based on shared social, cultural and historical experiences, using Ecuadorian census categories. SETTING: Urban and rural Ecuador, including the Amazon rainforest and the Galapagos Islands. PARTICIPANTS: Children aged <5 years (n 8580), adolescent women aged 11-19 years (n 4043) and adult women aged 20-49 years (n 15 203). RESULTS: Among children <5 years, stunting and anaemia disproportionately affected low-wealth, low-education and indigenous groups. Among adolescent and adult women, higher rates of stunting, overweight and obesity were observed in the low-education and low-wealth groups. Stunting and short stature rates were higher in indigenous women, whereas overweight and obesity rates were higher in Afro-Ecuadorian women. CONCLUSIONS: Malnutrition differs significantly across sociodemographic groups, disproportionately affecting those in the low wealth tertile and ethnic minorities. Rates of stunting remain high compared with other countries in the region with similar economic development. The effective implementation of double-duty actions with the potential to impact both sides of the double burden is urgently required.

2nd PSL Chemical Biology Symposium (2019): At the Crossroads of Chemistry and Biology.

Chemical Biology is the science of designing chemical tools to dissect and manipulate biology at different scales. It provides the fertile ground from which to address important problems of our society, such as human health and environment.

Visible Light-Induced Regioselective Cycloaddition of Benzoyl Azides and Alkenes To Yield Oxazolines.

Visible light catalysis allows the regioselective synthesis of oxazolines in high yields. The mild photosensitized manifold leverages the intermolecular formation of oxazolines with a wide functional group tolerance on both benzoyl azides and alkenes partners. Mechanistic investigations suggest the sensitization of the azide moiety as the key activation step.

Synthesis, 3D-structure and stability analyses of NRPa-308, a new promising anti-cancer agent.

We report herein the synthesis of a newly described anti-cancer agent, NRPa-308. This compound antagonizes Neuropilin-1, a multi-partners transmembrane receptor overexpressed in numerous tumors, and thereby validated as promising target in oncology. The preparation of NRPa-308 proved challenging because of the orthogonality of the amide and sulphonamide bonds formation. Nevertheless, we succeeded a gram scale synthesis, according to an expeditious three steps route, without intermediate purification. This latter point is of utmost interest in reducing the ecologic impact and production costs in the perspective of further scale-up processes. The purity of NRPa-308 has been attested by means of conventional structural analyses and its crystallisation allowed a structural assessment by X-Ray diffraction. We also reported the remarkable chemical stability of this molecule in acidic, neutral and basic aqueous media. Eventually, we observed for the first time the accumulation of NRPa-308 in two types of human breast cancer cells MDA-MB231 and BT549.

An Original L-shape, Tunable N-Heterocyclic Carbene Platform for Efficient Gold(I) Catalysis.

The synthesis and characterization of original NHC ligands based on an imidazo[1,5-a]pyridin-3-ylidene (IPy) scaffold functionalized with a flanking barbituric heterocycle is described as well as their use as tunable ligands for efficient gold-catalyzed C-N, C-O, and C-C bond formations. High activity, regio-, chemo-, and stereoselectivities are obtained for hydroelementation and domino processes, underlining the excellent performance (TONs and TOFs) of these IPy-based ligands in gold catalysis. The gold-catalyzed domino reactions of 1,6-enynes give rise to functionalized heterocycles in excellent isolated yields under mild conditions. The efficiency of the NHC gold 5Me complex is remarkable and mostly arises from a combination of steric protection and stabilization of the cationic AuI active species by ligand 1Me .

Overweight, obesity, and food consumption in Galapagos, Ecuador: a window on the world.

BACKGROUND: In order to understand why rates of overweight and obesity are so high in the Ecuadorian province of Galapagos, this study analyzes changes in household food expenditures and perceptions and practices related to food consumption patterns. Galapagos is understood as an unusual but not unique case because conditions there graphically illustrate trends observed in communities and countries worldwide. A mixed methods approach was employed: a quantitative component was based on expenditures for foods classified according to the NOVA system, and a qualitative component utilized focus group discussions, key informant interviews, and structured observations. RESULTS: Galapagos residents increased consumption of processed and ultra-processed foods and decreased consumption of unprocessed and minimally processed foods. Perceived barriers to healthy diets include price, availability, and quality of fresh produce, as well as easy access to industrialized processed and ultra-processed foods. CONCLUSIONS: Changes in consumption patterns represent both local conditions and global trends; in that sense, the factors that affect Galapagos residents are not unique. Hence, these findings help elucidate processes observed in communities around the world.

The double burden of chronic malnutrition and overweight and obesity in Ecuadorian mothers and children, 1986-2012.

BACKGROUND:: The simultaneous presence of undernutrition and over-nutrition represents a paradox in global public health and is of increasing concern in Ecuador, where chronic malnutrition and overweight and obesity occur in the context of demographic and epidemiologic transitions. Two overlapping trends are present in Ecuador; while levels of stunting have decreased slowly in the past three decades, increasing proportions of children <5 years and women of reproductive age suffer from overweight and obesity. AIM:: To analyze stunting and overweight and obesity in children <5 and their mothers aged from 15 to 49 years in the context of demographic and household characteristics between 1986 and 2012. METHODS:: This study compares data from nationally-representative surveys conducted in Ecuador in 1986, 2004, and 2012, each of which collected information on children <5 and mothers aged 15-49 years. RESULTS:: The prevalence of chronic malnutrition in children <5 decreased at different rates among Ecuadorians who differ in terms of residence, socioeconomic status, and mothers' level of education, while overweight and obesity increased dramatically in the same period. CONCLUSION:: Chronic malnutrition in children <5 and overweight in children <5 and mothers 15-49 years represent a double burden of malnutrition in Ecuador. The phenomena differ in their effects, and, while the prevalence of stunting is declining in Ecuador as it is in many parts of the world, the problem of overweight and obesity has emerged in dramatic fashion, and currently represents an extraordinary challenge to public health.

Palladium-Catalyzed Regioselective Alkynylation of Pyrroles and Azoles under Mild Conditions: Application to the Synthesis of a Dopamine D-4 Receptor Agonist.

A mild and general method for the direct alkynylation of azoles such as pyrrole, indole, and 7-azaindole is described here. Using a simple catalytic system such as Pd(OAc)2 (2.5 mol %), P(tBu)2Me·HBF4 (5 mol %), and NaOAc (2 equiv) allowed the regioselective introduction of various alkynyl residues at the C-2 position of pyrroles. Interestingly, C-2 alkynylation was also observed on C-3-substituted indoles, whereas classical C-3 alkynylation was obtained on selected unsubstituted indoles and 7-azaindole. Our methodology has been illustrated by the efficient synthesis of a potential schizophrenia drug (dopamine D-4 inhibitor).

Cyclin-dependent kinase inhibitors as marketed anticancer drugs: where are we now? A short survey.

In the early 2000s, the anticancer drug imatinib (Glivec®) appeared on the market, exhibiting a new mode of action by selective kinase inhibition. Consequently, kinases became a validated therapeutic target, paving the way for further developments. Although these kinases have been thoroughly studied, none of the compounds commercialized since then target cyclin-dependent kinases (CDKs). Following a recent and detailed review on the subject by Galons et al., we concentrate our attention on an updated list of compounds under clinical evaluation (phase I/II/III) and discuss their mode of action as ATP-competitive inhibitors. CDK inhibition profiles and clinical development stages are reported for the 14 compounds under clinical evaluation. Also, tentative progress for forthcoming potential ATP non-competitive inhibitors and allosteric inhibitors are briefly described, along with their limitations.

Photoredox synthesis of 6- and 7-membered ring scaffolds via N-centered radicals.

N-Containing heterocycles are important scaffolds due to their ubiquitous presence in bioactive compounds. Their synthesis has been considered as an important research field. In this work we report the access to 6- and 7-membered rings via a photoinduced strategy. To our knowledge, this work represents the first exemple of photo-induced 7-endo-trig cyclization with N-centered radicals.

Synthesis and reactivity of furoquinolines bearing an external methylene-bond: access to reduced and spirocyclic structures.

A family of furoquinolines were efficiently obtained through a tandem acetalization/cycloisomerization process catalyzed by (5 mol%) silver imidazolate polymer and triphenylphosphine, and diversity was brought by the use of 7 different alcohol groups. From these furoquinolines, 3 examples of reduced derivatives could be obtained (d.r. up to 94 : 6), 10 different spiroketal derivatives by hetero-Diels-Alder reaction (d.r. up to 20 : 1), 8 hetero-[5,5]-spirocycles by cycloaddition with dibromoformaldoxime (d.r. up to 86 : 14) and finally 6 hetero-[5,6]-spirocycles by [4 + 2] cycloaddition with ethyl 3-bromo-2-(hydroxyimino)propanoate (d.r. up to 90 : 10).

Breastfeeding practices and complementary feeding in Ecuador: implications for localized policy applications and promotion of breastfeeding: a pooled analysis.

BACKGROUND: Best practices in breastfeeding are often not followed despite appropriate levels of knowledge and positive attitudes regarding the benefits of human milk. For many reasons, some women do not initiate breastfeeding, suspend breastfeeding early, or initiate complementary feeding earlier than recommended. Usual measurement methods use large sample surveys at a national scale, which are not well suited for monitoring sub-national differences. METHODS: In order to understand how local infant feeding practices could influence policy and promotion practices, we apply data pooling methodology to analyse breastfeeding patterns in different Ecuadorian settings: Cumbayá parish, located near Quito, the Ecuadorian capital; the city of Macas and rural surroundings in the Amazon basin province of Morona Santiago; and the province of Galapagos. Surveys were conducted independently between August 2017 and August 2018; while they are representative of each respective setting, sampling designs and survey methods differ, but the same demographic information and data based on standard breastfeeding indicators established by the World Health Organization (WHO) were collected. In order to account for differences in the different settings, the design effect of each survey was considered in the analysis. RESULTS: Significant differences were found in breastfeeding practices between the suburban Cumbayá parish near Quito and Galapagos on one hand, and urban and rural parts of Morona Santiago, on the other. The rates of early breastfeeding initiation and age-appropriate breastfeeding are significantly higher in urban and rural Morona Santiago then in Cumbayá or Galapagos, while the rate of exclusive breastfeeding is highest in rural parts of Morona Santiago. No significant differences were found in complementary feeding practices between Cumbayá and Galapagos, but there are with urban and rural Morona Santiago. Initiation of breastfeeding in the first hour after birth occurs in only 36.2% of cases in Cumbayá but in 75.4% of cases in urban Morona. CONCLUSIONS: Differences among regions reflect specific opportunities and barriers to practices related to promoting optimal infant health and nutrition. Consequently, regional or local conditions that often are not apparent in national-level data should orient policies and promotion activities in specific populations.

Visible light amination/Smiles cascade: access to phthalazine derivatives.

We report the synthesis of various phthalazines via a new cascade reaction, initiated by visible light photocatalysis, involving a radical hydroamination reaction followed by a radical Smiles rearrangement. Phthalazine derivatives are obtained in high yields and from a broad scope readily accessible ortho-alkynylsulfonohydrazone precursors. The mild photoredox conditions ensure an excellent functional group tolerance. Application of this strategy to a one-pot protocol starting from the corresponding carbonyl compounds, and subsequent functionalization allow the rapid synthesis of structurally diverse structures.