RESUMEN
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.
RESUMEN
We herein document a large collection of 108 2-amino-4,6-disubstituted-pyrimidine derivatives as potent, structurally simple, and highly selective A1AR ligands. The most attractive ligands were confirmed as antagonists of the canonical cyclic adenosine monophosphate pathway, and some pharmacokinetic parameters were preliminarilly evaluated. The library, built through a reliable and efficient three-component reaction, comprehensively explored the chemical space allowing the identification of the most prominent features of the structure-activity and structure-selectivity relationships around this scaffold. These included the influence on the selectivity profile of the aromatic residues at positions R4 and R6 of the pyrimidine core but most importantly the prominent role to the unprecedented A1AR selectivity profile exerted by the methyl group introduced at the exocyclic amino group. The structure-activity relationship trends on both A1 and A2AARs were conveniently interpreted with rigorous free energy perturbation simulations, which started from the receptor-driven docking model that guided the design of these series.
Asunto(s)
Antagonistas del Receptor de Adenosina A1/química , Pirimidinas/química , Antagonistas del Receptor de Adenosina A1/metabolismo , Antagonistas del Receptor de Adenosina A1/farmacocinética , Sitios de Unión , Línea Celular , Diseño de Fármacos , Estabilidad de Medicamentos , Humanos , Cinética , Simulación del Acoplamiento Molecular , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Receptor de Adenosina A1/química , Receptor de Adenosina A1/metabolismo , Receptor de Adenosina A2A/química , Receptor de Adenosina A2A/metabolismo , Relación Estructura-ActividadRESUMEN
A novel family of structurally simple, potent, and selective nonxanthine A2BAR ligands was identified, and its antagonistic behavior confirmed through functional experiments. The reported alkyl 2-cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahy-dropyrimidine-5-carboxylates (16) were designed by bioisosteric replacement of the carbonyl group at position 2 in a series of 3,4-dihydropyrimidin-2-ones. The scaffold (16) documented herein contains a chiral center at the heterocycle. Accordingly, the most attractive ligand of the series [(±)16b, Ki = 24.3 nM] was resolved into its two enantiomers by chiral HPLC, and the absolute configuration was established by circular dichroism. The biological evaluation of both enantiomers demonstrated enantiospecific recognition at A2BAR, with the (S)-16b enantiomer retaining all the affinity (Ki = 15.1 nM), as predicted earlier by molecular modeling. This constitutes the first example of enantiospecific recognition at the A2B adenosine receptor and opens new possibilities in ligand design for this receptor.
Asunto(s)
Pirimidinas/química , Receptor de Adenosina A2B/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Espectroscopía de Protones por Resonancia Magnética , Espectrometría de Masa por Ionización de Electrospray , EstereoisomerismoRESUMEN
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.
Asunto(s)
Antimitóticos/síntesis química , Bencimidazoles/síntesis química , Cinesinas/antagonistas & inhibidores , Antimitóticos/química , Antimitóticos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Técnicas Químicas Combinatorias , Células HeLa , Humanos , Cinesinas/metabolismo , Simulación del Acoplamiento MolecularRESUMEN
Three novel families of A2B adenosine receptor antagonists were identified in the context of the structural exploration of the 3,4-dihydropyrimidin-2(1H)-one chemotype. The most appealing series contain imidazole, 1,2,4-triazole, or benzimidazole rings fused to the 2,3-positions of the parent diazinone core. The optimization process enabled identification of a highly potent (3.49 nM) A2B ligand that exhibits complete selectivity toward A1, A2A, and A3 receptors. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The main SAR trends identified within the series were substantiated by a molecular modeling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human A2A receptor.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Descubrimiento de Drogas , Pirimidinonas/farmacología , Receptor de Adenosina A2B/metabolismo , Antagonistas del Receptor de Adenosina A2/síntesis química , Antagonistas del Receptor de Adenosina A2/química , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Pirimidinonas/síntesis química , Pirimidinonas/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antagonistas del Receptor de Adenosina A3/química , Antagonistas del Receptor de Adenosina A3/farmacología , Pirazinas/química , Pirazinas/farmacología , Receptor de Adenosina A3/metabolismo , Descubrimiento de Drogas , Humanos , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antimitóticos/síntesis química , Antineoplásicos/síntesis química , Técnicas Químicas Combinatorias , Mitosis/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Animales , Antimitóticos/química , Antimitóticos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Aurora Quinasas/antagonistas & inhibidores , Aurora Quinasas/metabolismo , Descubrimiento de Drogas , Humanos , Microtúbulos/química , Microtúbulos/efectos de los fármacos , Simulación del Acoplamiento Molecular , Proteínas Motoras Moleculares/antagonistas & inhibidores , Proteínas Motoras Moleculares/metabolismo , Neoplasias/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Huso Acromático/química , Huso Acromático/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Diseño de Fármacos , Cinesinas/antagonistas & inhibidores , Antineoplásicos/síntesis química , Bencimidazoles/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Cinesinas/química , Cinesinas/metabolismo , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Nitrilos/síntesis química , Pirimidinas/síntesis química , Bibliotecas de Moléculas Pequeñas/síntesis química , Técnicas Químicas Combinatorias , Nitrilos/química , Pirimidinas/química , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
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.