The Southern European Atlantic Diet and Its Supplements: The Chemical Bases of Its Anticancer Properties.

Scientific evidence increasingly supports the strong link between diet and health, acknowledging that a well-balanced diet plays a crucial role in preventing chronic diseases such as obesity, diabetes, cardiovascular issues, and certain types of cancer. This perspective opens the door to developing precision diets, particularly tailored for individuals at risk of developing cancer. It encompasses a vast research area and involves the study of an expanding array of compounds with multilevel "omics" compositions, including genomics, transcriptomics, proteomics, epigenomics, miRNomics, and metabolomics.

3D-Printing of Capsule Devices as Compartmentalization Tools for Supported Reagents in the Search of Antiproliferative Isatins.

The application of high throughput synthesis methodologies in the generation of active pharmaceutical ingredients (APIs) currently requires the use of automated and easily scalable systems, easy dispensing of supported reagents in solution phase organic synthesis (SPOS), and elimination of purification and extraction steps. The recyclability and recoverability of supported reagents and/or catalysts in a rapid and individualized manner is a challenge in the pharmaceutical industry. This objective can be achieved through a suitable compartmentalization of these pulverulent reagents in suitable devices for it.

Multicatalysis Combining 3D-Printed Devices and Magnetic Nanoparticles in One-Pot Reactions: Steps Forward in Compartmentation and Recyclability of Catalysts.

A tricatalytic compartmentalized system that immobilizes metallic species to perform one-pot sequential functionalization is described: a three-dimensional (3D)-printed palladium monolith, ferritic copper(I) magnetic nanoparticles, and a 3D-printed polypropylene capsule-containing copper(II) loaded onto polystyrene-supported 1,5,7-triazabicyclo[4.4.0]dec-5-ene (PS-TBD) allowed the rapid synthesis of diverse substituted 1-([1,1'-biphenyl]-4-yl)-1-1,2,3-triazoles.

Multicomponent Assembly of the Kinesin Spindle Protein Inhibitor CPUYJ039 and Analogues as Antimitotic Agents.

The potent kinesin spindle protein inhibitor CPUYJ039 and a set of analogues were prepared by a target-oriented approach based on a Ugi reaction that uses 2-nitrophenyl isocyanides as key building blocks. The herein documented strategy provides straightforward and atom economical access to potent benzimidazole-based antimitotic agents by exploring the versatility and exploratory power of the Ugi reaction. The results of docking studies and biological activity evaluations of the benzimidazole compounds are also reported.

Pyrazin-2(1H)-ones as a novel class of selective A3 adenosine receptor antagonists.

Background: A3AR antagonists are promising drug candidates as neuroprotective agents as well as for the treatment of inflammation or glaucoma. The most widely known A3AR antagonists are derived from polyheteroaromatic scaffolds, which usually show poor pharmacokinetic properties. Accordingly, the identification of structurally simple A3AR antagonists by the exploration of novel diversity spaces is a challenging goal.

Multicomponent reactions in antimitotic drug discovery.

As enabling technology, the development and application of multicomponent reactions (MCRs) are now an integral part of the work of any major medical research unit. Targeted MCR approaches focused on specific antimitotic pathways afford new solutions for the medicinal chemistry of the XXI century. In this review, the contribution of these procedures to the discovery of antimitotic drugs that are currently in clinical trials or already in the market is discussed.

Structure-based design of new KSP-Eg5 inhibitors assisted by a targeted multicomponent reaction.

An integrated multidisciplinary approach that combined structure-based drug design, multicomponent reaction synthetic approaches and functional characterization in enzymatic and cell assays led to the discovery of new kinesin spindle protein (KSP) inhibitors with antiproliferative activity. A focused library of new benzimidazoles obtained by a Ugi+Boc removal/cyclization reaction sequence generated low-micromolar-range KSP inhibitors as promising anticancer prototypes. The design and functional studies of the new chemotypes were assessed by computational modeling and molecular biology techniques.

Discovery of 3,4-Dihydropyrimidin-2(1H)-ones As a Novel Class of Potent and Selective A2B Adenosine Receptor Antagonists.

We describe the discovery and optimization of 3,4-dihydropyrimidin-2(1H)-ones as a novel family of (nonxanthine) A2B receptor antagonists that exhibit an unusually high selectivity profile. The Biginelli-based hit optimization process enabled a thoughtful exploration of the structure-activity and structure-selectivity relationships for this chemotype, enabling the identification of ligands that combine structural simplicity with excellent hA2B AdoR affinity and remarkable selectivity profiles.

Copper-catalyzed Huisgen 1,3-dipolar cycloaddition under oxidative conditions: polymer-assisted assembly of 4-acyl-1-substituted-1,2,3-triazoles.

We herein document the first example of a reliable copper-catalyzed Huisgen 1,3-dipolar cycloaddition under oxidative conditions. The combined use of two polymer-supported reagents (polystyrene-1,5,7-triazabicyclo[4,4,0]dec-5-ene/Cu and polystyrene-2-iodoxybenzamide) overcomes the thermodynamic instability of copper(I) species toward oxidation, enabling the reliable Cu-catalyzed Huisgen 1,3-dipolar cycloadditions in the presence of an oxidant agent. This polymer-assisted pathway, not feasible under conventional homogeneous conditions, provides a direct assembly of 4-acyl-1-substituted-1,2,3-triazoles, contributing to expand the reliability and scope of Cu(I)-catalyzed alkyne-azide cycloaddition.

Three-component assembly of structurally diverse 2-aminopyrimidine-5-carbonitriles.

An expedient route for the synthesis of libraries of diversely decorated 2-aminopyrimidine-5-carbonitriles is reported. This approach is based on a three-component reaction followed by spontaneous aromatization.

Multicomponent assembly of diverse pyrazin-2(1H)-one chemotypes.

An expedient and concise Ugi-based approach for the rapid assembly of pyrazin-2(1H)-one-based frameworks has been developed. This convergent approach encompasses skeletal, functional and stereochemical diversity, exhibiting an unusually high bond-forming efficiency as well as high structure and step economies. The method involves the use of readily available commercial reagents and is an example of the reconciliation of structural complexity with operational simplicity in a time- and cost-effective manner.

Selective and potent adenosine A3 receptor antagonists by methoxyaryl substitution on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold.

The influence of diverse methoxyphenyl substitution patterns on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold is herein explored in order to modulate the A(3) adenosine receptor antagonistic profile. As a result, novel ligands exhibiting excellent potency (K(i) on A(3) AR < 20 nM) and selectivity profiles (above 100-fold within the adenosine receptors family) are reported. Moreover, our joint theoretical and experimental approach allows the identification of novel pharmacophoric elements conferring A(3)AR selectivity, first established by a robust computational model and thereafter characterizing the most salient features of the structure-activity and structure-selectivity relationships in this series.

Discovery and preliminary SAR of 5-arylidene-2,2-dimethyl-1,3-dioxane- 4,6-diones as platelet aggregation inhibitors.

We herein document the discovery of 5-arylidene-2,2-dimethyl-1,3-dioxane-4,6-diones as a novel family of platelet aggregation inhibitors. The preliminary optimization study enabled us to establish the most salient features of the structure-activity relationships in this series as well as to identify novel derivatives that are upto 60 times more potent than the hit structure 1 and slightly superior to the reference drug Milrinone.

Supported TBD-assisted solution phase diversification of formyl-aza-heterocycles through alkylation-knoevenagel one pot sequences.

An efficient solution-phase parallel procedure to perform the structural diversification of some formyl-nitrogen heterocycles (A) using the reusable TBD supported base is described. The library synthesis is based in a consecutive Alkylation-Knoevenagel functionalisation that uses alkyl halides (B), Michael acceptors (C) and activated methylene compounds (D) as diversity elements.

Supported p-toluenesulfonic acid as a highly robust and eco-friendly isocyanide scavenger.

We document here the use of polymer-supported p-toluenesulfonic acid as a highly effective, robust, economical and eco-friendly isocyanide scavenger. The herein described strategy circumvent the intense and repulsive odor of volatile isocyanides, enabling simplified and odorless workup and purifications. The usefulness of the new scavengers has been validated in a set of diverse isocyanide-based organic transformations and this approach is also amenable to parallel synthesis techniques.

Silica-supported aluminum chloride-assisted solution phase synthesis of pyridazinone-based antiplatelet agents.

A solution phase protocol that enabled the synthesis of three diverse libraries of pyridazin-3-ones incorporating α,β-unsaturated moieties at position 5 of the heterocyclic core has been developed using silica-supported aluminum trichloride as a heterogeneous and reusable catalyst. This robust procedure has facilitated the hit to lead process for these series of compounds and allowed the identification of new potent derivatives that elicit antiplatelet activity in the low micromolar range.

Pyrimidine derivatives as potent and selective A3 adenosine receptor antagonists.

Two regioisomeric series of diaryl 2- or 4-amidopyrimidines have been synthesized and their adenosine receptor affinities were determined in radioligand binding assays at the four human adenosine receptors (hARs). Some of the ligands prepared herein exhibit remarkable affinities (K(i) < 10 nm) and, most noticeably, the absence of activity at the A(1), A(2A), and A(2B) receptors. The structural determinants that support the affinity and selectivity profiles of the series were highlighted through an integrated computational approach, combining a 3D-QSAR model built on the second generation of GRid INdependent Descriptors (GRIND2) with a novel homology model of the hA(3) receptor.

Convergent assembly of structurally diverse quinazolines.

A convergent and versatile Vilsmeier-Haack-based carbo-annulation strategy that exhibits an unusually elevated bond-forming efficiency has been developed. By virtue of its innovative approach, structure economy and simple execution conditions the methodology reported here constitutes a very attractive protocol that enables the rapid assembly of structurally diverse quinazoline chemotypes.

Divergent solution-phase synthesis of diarylpyrimidine libraries as selective A3 adenosine receptor antagonists.

A practical and divergent solution-phase synthetic strategy has been optimized to prepare a highly diverse library of 2,4-diaryl- and 2,6-diarylpyrimidines. Structural elaboration of the starting heterocyclic scaffolds was accomplished by exploiting the potential for diversity offered by the Suzuki-Miyaura cross-coupling reaction. These studies enabled the identification of structurally simple, highly potent, and selective A(3) adenosine receptor antagonists.

Synthetic applications of polystyrene-supported 1,1,3,3-tetramethylguanidine.

Several applications of polystyrene-supported 1,1,3,3-tetramethylguanidine (PS-TMG) in synthetic organic chemistry have been explored. This study evidenced the effectiveness and versatility of this new member of the supported guanidine superbases as an attractive candidate to replace the bases usually employed in organic synthesis during the implementation of environmentally friendly preparative processes.

2-Substituted 4-, 5-, and 6-[(1E)-3-oxo-3-phenylprop-1-en-1-yl]pyridazin-3(2H)-ones and 2-substituted 4,5-bis[(1E)-3-oxo-3-phenylprop-1-en-1-yl]pyridazin-3(2H)-ones as potent platelet aggregation inhibitors: design, synthesis, and SAR studies.

A set of regioisomeric 2-substituted pyridazin-3(2H)-ones containing a 3-oxo-3-phenylprop-1-en-1-yl fragment at either position 4, 5 or 6 and 2-substituted pyridazin-3(2H)-ones containing the same fragment both at positions 4 and 5 have been synthesized and evaluated as antiplatelet agents. The study allows the identification of a new highly potent platelet aggregation inhibitor (4c).

Design, synthesis, and structure-activity relationships of a novel series of 5-alkylidenepyridazin-3(2H)-ones with a non-cAMP-based antiplatelet activity.

5-alkylidenepyridazin-3-ones with four points of diversity (R2, R6, X, Y) have been synthesized and evaluated as platelet aggregation inhibitors. Several derivatives eliciting antiplatelet activity in the low micromolar range (e.g.

Straightforward entry to libraries of diversely substituted azinones by a consecutive aza-Michael/palladium-catalyzed functionalization strategy.

A highly divergent, flexible, and conceptually simple sequence allowing the parallel solution-phase assembly of functionalized azinone libraries has been developed in a one-pot consecutive fashion. Structural decoration of in situ-generated heterocyclic aza-Michael adducts AB was accomplished by exploiting the diversity potential of Heck, Suzuki, Sonogashira, and Stille reactions.