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. The most active compounds-20 (IC50 =1.49 µM, EC50 =3.63 µM) and 22 (IC50 =1.37 µM, EC50 =6.90 µM)-were synthesized with high efficiency by taking advantage of the multicomponent reactions.

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.

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.

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. We review here the components of the Southern European Atlantic Diet (SEAD) from both a chemical and pharmacological standpoint. The information sources consulted, complemented by crystallographic data from the Protein Data Bank, establish a direct link between the SEAD and its anticancer properties. The data collected strongly suggest that SEAD offers an exceptionally healthy profile, particularly due to the presence of beneficial biomolecules in its foods. The inclusion of olive oil and paprika in this diet provides numerous health benefits, and scientific evidence supports the anticancer properties of dietary supplements with biomolecules sourced from vegetables of the brassica genus. Nonetheless, further research is warranted in this field to gain deeper insights into the potential benefits of the SEAD's bioactive compounds against cancer.

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. This work deals with the use of customized polypropylene permeable-capsule devices manufactured by 3D printing, using the fused deposition modeling (FDM) technique, adaptable to any type of flask or reactor. The capsules fabricated in this work were easily loaded "in one step" with polymeric reagents for use as scavengers of isocyanides in the work-up process of Ugi multicomponent reactions or as compartmentalized and reusable catalysts in copper-catalyzed cycloadditions (CuAAC) or Heck palladium catalyzed cross-coupling reactions (PCCCRs). The reaction products are different series of diversely substituted isatins, which were tested in cancerous cervical HeLa and murine 3T3 Balb fibroblast cells, obtaining potent antiproliferative activity. This work demonstrates the applicability of 3D printing in chemical processes to obtain anticancer APIs.

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.

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)-1H-1,2,3-triazoles. The procedure is based on the Chan-Lam azidation/copper alkyne-azide cycloaddition/Suzuki reaction strategy in the solution phase. This catalytic system enabled the efficient assembly of the final compounds in high yields without the need for special additives or intermediate isolation. The monolithic catalyst-containing immobilized palladium species was synthesized by surface chemical modification of a 3D-printed silica monolith using a soluble polyimide resin as a key reagent, thus creating an extremely robust composite. All three immobilized catalysts described here were easily recovered and reused in numerous cycles. This work exemplifies the role of 3D printing in the design and manufacture of devices for compartmented multicatalytic systems to carry out complex one-pot transformations.

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., 14e, 14k, 14p, 14v, IC50 congruent with 1 microM) were identified. Structure-activity relationships studies on these compounds revealed the key molecular determinants of this new family of antiplatelet agents: (a) two ester groups in the alkoxy moieties; (b) lipophilic substituents at the N2 position of the pyridazin-3-one. The preliminary results of a pharmacological study aimed at determining the mechanism of action of a set of representative compounds revealed that, unlike other pyridazinones, the documented antiplatelet effect is not a consequence of a PDE-III inhibitory activity.

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.

Straightforward three-component palladium-catalysed synthesis of pyridazin-3(2H)-one libraries.

A simple and straightforward three-component methodology for the solution phase high-throughput synthesis of 2,5-disubstituted pyridazin-3(2H)-one libraries has been developed. The diversity at position 5 of the heterocycle is determined by the use of Suzuki, Sonogashira, Heck or Stille coupling.

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. RESULTS: A convergent and efficient Ugi-based multicomponent approach enabled the discovery of pyrazin-2(1H)-ones as a novel class of A3AR antagonists. A combined experimental/computational strategy accelerated the establishment of the most salient features of the structure-activity and structure-selectivity relationships in this series. CONCLUSION: The optimization process provided pyrazin-2(1H)-ones with improved affinity and a plausible hypothesis regarding their binding modes was proposed.

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.

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.

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.

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.