RESUMEN
Imatinib mesylate was the first representative BCR-ABL1 tyrosine kinase inhibitor (TKI) class for the treatment of chronic myeloid leukemia. Despite the revolution promoted by TKIs in the treatment of this pathology, a resistance mechanism occurs against all BCR-ABL1 inhibitors, necessitating a constant search for new therapeutic options. To develop new antimyeloproliferative substances, we applied a medicinal chemistry tool known as molecular hybridization to design 25 new substances. These compounds were synthesized and biologically evaluated against K562 cells, which express BCR-ABL1, a constitutively active tyrosine kinase enzyme, as well as in WSS-1 cells (healthy cells). The new compounds are conjugated hybrids that contain phenylamino-pyrimidine-pyridine (PAPP) and an isatin backbone, which are the main pharmacophoric fragments of imatinib and sunitinib, respectively. A spiro-oxindole nucleus was used as a linker because it occurs in many compounds with antimyeloproliferative activity. Compounds 2a, 2b, 3c, 4c, and 4e showed promise, as they inhibited cell viability by between 45% and 61% at a concentration of 10 µM. The CC50 of the most active substances was determined to be within 0.8-9.8 µM.
Asunto(s)
Antineoplásicos , Supervivencia Celular , Mesilato de Imatinib , Oxindoles , Humanos , Células K562 , Mesilato de Imatinib/farmacología , Oxindoles/farmacología , Oxindoles/síntesis química , Oxindoles/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Supervivencia Celular/efectos de los fármacos , Relación Estructura-Actividad , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Relación Dosis-Respuesta a Droga , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/metabolismo , Compuestos de Espiro/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/síntesis química , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
Leishmaniasis is an infectious disease with several limitations regarding treatment schemes. This work reports the anti-Leishmania activity of spiroacridine compounds against the promastigote (IC50 = 1.1 to 6.0 µg / mL) and amastigote forms of the best compounds (EC50 = 4.9 and 0.9 µg / mL) inLeishmania (L.) infantumand proposes an in-silico study with possible selective therapeutic targets for L. infantum. The substituted dimethyl-amine compound (AMTAC 11) showed the best leishmanicidal activity in vitro, and was found to interact with TryRandLdTopoI. comparisons with standard inhibitors were performed, and its main interactions were elucidated. Based on the biological assessment and the structure-activity relationship study, the spiroacridine compounds appear to be promisinganti-leishmaniachemotherapeutic agents to be explored.
Asunto(s)
Acridinas/farmacología , Compuestos de Espiro/farmacología , Tripanocidas/farmacología , Acridinas/síntesis química , Acridinas/metabolismo , Acridinas/toxicidad , ADN-Topoisomerasas de Tipo I/metabolismo , Eritrocitos/efectos de los fármacos , Leishmania infantum/efectos de los fármacos , Ligandos , Simulación del Acoplamiento Molecular , Estructura Molecular , NADH NADPH Oxidorreductasas/metabolismo , Pruebas de Sensibilidad Parasitaria , Unión Proteica , Proteínas Protozoarias/metabolismo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/metabolismo , Compuestos de Espiro/toxicidad , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/metabolismo , Tripanocidas/toxicidadRESUMEN
BACKGROUND: Triple-negative BC is the most aggressive type of breast cancer and its lack of responsiveness to conventional therapies requires screening of new chemical entities. Anti-migratory compounds are promising to treat metastatic cancer since they inhibit one of the main steps of the metastatic cascade. Spirocyclic compounds are non-conventional structures used as building blocks for the synthesis of biologically active molecules and considered interesting structures in the search for new targets in cancer research. OBJECTIVE: Here, we evaluated the potential of eight synthetic spirocyclohexadienones as cell migration inhibitors. METHODS: The anti-migratory ability of compounds was tested by wound healing and Boyden chamber approaches. Experiments in tubulin were performed by fluorescence and tubulin polymerization techniques. Finally, compounds were submitted to cell proliferation inhibition and flow cytometry assays to explore the mechanism by which they inhibit cell migration. RESULTS: Four compounds inhibited cell migration significantly. Analogs containing the 3,4,5-trimethoxyphenil ring at R1 position were the most potent and, thus, selected for additional experiments. Tubulin polymerization and fluorescence assays highlighted a possible binding of spirocyclohexadienones in the colchicine binding site; however, these compounds did not affect the cell cycle to the same extent as colchicine. Cell proliferation was affected and, notably, the most potent analogs induced apoptosis of tumor cells, suggesting a different mechanism by which they inhibit cell migration. CONCLUSION: We presented, for the first time, a series of eight synthetic spirocyclohexadienones with the ability to inhibit TNBC cell migration. These compounds represent a new category to be explored as anticancer agents.
Asunto(s)
Antineoplásicos/farmacología , Ciclohexenos/farmacología , Compuestos de Espiro/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Moduladores de Tubulina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Ciclohexenos/síntesis química , Ciclohexenos/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Polimerizacion/efectos de los fármacos , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Neoplasias de la Mama Triple Negativas/patología , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/químicaRESUMEN
The addition of 2-bromobenzylmagnesium bromide to chiral N- tert-butanesulfinyl imines derived from tetralone-type ketones proceeds with high levels of diastereocontrol. The resulting sulfinamide derivatives were transformed into dibenzoazaspiro compounds after a palladium-catalyzed intramolecular N-arylation. DFT calculations have been performed to rationalize the stereochemical course of the reaction. Similar results have been obtained considering either diethyl ether or toluene as a solvent, in both cases in an excellent agreement with experimental findings. NCI topological calculations have also been used to evidence crucial noncovalent interactions. In addition, the azaspiro compounds reduced the viability of chronic myeloid leukemia cells in the micromolar range. Notably, both the halogen-substituted ( R)- and ( S)-8g and -8h as well as ( R)-8j were at least two times more effective on a multidrug-resistant derivative than on the parental cell line, exerting a collateral sensitivity effect.
Asunto(s)
Alcanos/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Leucemia/metabolismo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Antineoplásicos/química , Teoría Funcional de la Densidad , Resistencia a Antineoplásicos , Halógenos , Leucemia/patología , Paladio , Compuestos de Espiro/química , EstereoisomerismoRESUMEN
Given the wide spectrum of biological uses of pyrazolo[1,5-c]quinazoline and spiro-quinazoline derivatives as anticancer, anti-inflammatory analgesic agents, and their therapeutic applications in neurodegenerative disorders, it is compulsory to find easy, efficient, and simple methods to obtain and chemically diversify these families of compounds, thereby improving their biological applications. In this paper, we report the design and eco-friendly two-step synthesis of novel, fused spiro-pyrazolo[1,5-c]quinazoline derivatives as cholinesterase inhibitors. In addition, we studied their protein-ligand interactions via molecular docking and MM/GBSA calculations for a further rational design of more potent inhibitors. In first step, 2-(1H-pyrazol-5-yl)anilines were obtained through microwave (MW) assisted solvent-free/catalyst-free conditions and the second step involved the synthesis of the spiro-pyrazolo[1,5-c]quinazolines by a cyclocondensation reaction between 2-(1H-pyrazol-5-yl)anilines and cyclic ketones, or acetophenones, using stirring at room temperature. The compounds were obtained in high purity, good yields (50-97%), and at varying reaction times. The spiro-compounds were evaluated as acetylcholinesterase and butyrylcholinesterase inhibitors (AChEIs/BuChEIs) respectively, and the most potent compound exhibited a moderate AChE inhibitory activity (5f: IC50â¯=â¯84⯵M). Molecular docking studies indicated that the binding mode of the compound 5f share common characteristics with the galantamine/donepezil-AChE complexes. Moreover, free binding energy (ΔG) calculations showed a good agreement with the experimental biological activity values. Our theoretical results indicated that halogen bond interactions could be involved with differential potency of these compounds and provide a new starting point to design novel pyrazolo[1,5-c]quinazolines as new anti-Alzheimer agents.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Pirazoles/farmacología , Teoría Cuántica , Quinazolinas/farmacología , Compuestos de Espiro/farmacología , Acetilcolinesterasa/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Humanos , Microondas , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Quinazolinas/síntesis química , Quinazolinas/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
Herein we report the straightforward preparation of novel conformationally-restricted steroids from trans-androsterone and estrone, decorated with spiranic oxazolidin-2-one or 2-aminooxazoline motifs at C-17 as potential antiproliferative agents. Such unprecedented pharmacophores were accessed using an aminomethylalcohol derivative at C-17 as the key intermediate; reaction of such functionality with triphosgene, or conversion into N-substituted thioureas, followed by an intramolecular cyclodesulfurization reaction promoted by yellow HgO, furnished such spirocycles in excellent yields. Title compounds were tested in vitro against a panel of six human tumor cell lines, named A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon), and the results were compared with steroidal chemotherapeutic agents (abiraterone and galeterone); the A-ring of the steroidal backbone, the nature of the heterocycle and the N-substituents proved to be essential motifs for establishing structure-activity relationships concerning not only the potency but also the selectivity against tumor cell lines. Estrone derivatives, particularly those bearing a spiranic 2-aminooxazoline scaffold were found to be the most active compounds, with GI50 values ranging from the low micromolar to the submicromolar level (0.34-1.5 µM). Noteworthy, the lead compounds showed a remarkable increase in activity against the resistant cancer cell lines (T-47D and WiDr) compared to the anticancer reference drugs (up to 120-fold).
Asunto(s)
Antineoplásicos/farmacología , Compuestos Heterocíclicos/farmacología , Compuestos de Espiro/farmacología , Esteroides/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Humanos , Modelos Moleculares , Estructura Molecular , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Esteroides/síntesis química , Esteroides/química , Relación Estructura-ActividadRESUMEN
Two spirosteroid analogues were synthesized and evaluated for their in vitro neuroprotective activities in PC12 cells, against glutamate-induced excitotoxicity and mitochondrial damage in glucose deprivation conditions, as well as their anti-inflammatory potential in LPS/IFNγ-stimulated microglia primary cultures. We also evaluated the in vitro anti-excitotoxic and anti-inflammatory activities of natural and endogenous steroids. Our results show that the plant-derived steroid solasodine decreased PC12 glutamate-induced excitotoxicity, but not the cell death induced by mitochondrial damage and glucose deprivation. Among the two synthetic spirosteroid analogues, only the (25R)-5α-spirostan-3,6-one (S15) protected PC12 against ischemia-related in vitro models and inhibited NO production, as well as the release of IL-1ß by stimulated primary microglia. These findings provide further insights into the role of specific modifications of the A and B rings of sapogenins for their neuroprotective potential.
Asunto(s)
Antiinflamatorios , Microglía/metabolismo , Fármacos Neuroprotectores , Compuestos de Espiro , Esteroides , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Muerte Celular/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Femenino , Interleucina-1beta/biosíntesis , Microglía/patología , Mitocondrias/metabolismo , Mitocondrias/patología , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Óxido Nítrico/biosíntesis , Células PC12 , Ratas , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Esteroides/síntesis química , Esteroides/química , Esteroides/farmacologíaRESUMEN
In the title compound, C31H29N3O2, the reduced pyridine ring adopts a conformation intermediate between the envelope and half-chair forms. The aryl rings of the benzyl and phenyl substituents are nearly parallel and overlap, indicative of an intramolecular π-π stacking interaction. A combination of two C-HâââO hydrogen bonds and one C-HâââN hydrogen bond links the molecules into a bilayer having tert-butyl groups on both faces.
Asunto(s)
Indanos/química , Pirazoles/química , Piridinas/química , Compuestos de Espiro/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Indanos/síntesis química , Espectrometría de Masas , Estructura Molecular , Pirazoles/síntesis química , Piridinas/síntesis química , Compuestos de Espiro/síntesis químicaRESUMEN
Solanum nudum Dunal steroids have been reported as being antimalarial compounds; however, their concentration in plants is low, meaning that the species could be threatened by over-harvesting for this purpose. Swern oxidation was used for hemisynthesis of diosgenone (one of the most active steroidal sapogenin diosgenin compounds). Eighteen structural analogues were prepared; three of them were found to be more active than diosgenone (IC50 27.9 µM vs. 10.1 µM, 2.9 µM and 11.3 µM). The presence of a 4-en-3-one grouping in the A-ring of the compounds seems to be indispensable for antiplasmodial activity; progesterone (having the same functional group in the steroid A-ring) has also displayed antiplasmodial activity. Quantitative correlations between molecular structure and bioactivity were thus explored in diosgenone and several derivatives using well-established 3D-QSAR techniques. The models showed that combining electrostatic (70%) and steric (30%) fields can explain most variance regarding compound activity. Malarial parasitemia in mice became reduced by oral administration of two diosgenone derivatives.
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Triterpenos/síntesis química , Triterpenos/farmacología , 17-alfa-Hidroxiprogesterona/farmacología , Animales , Antimaláricos/química , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Resistencia a Medicamentos , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Malaria/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Parasitemia/tratamiento farmacológico , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Relación Estructura-Actividad Cuantitativa , Compuestos de Espiro/química , Triterpenos/químicaRESUMEN
An eco-friendly synthesis of highly functionalized epoxides and their incorporation into an organocatalytic multicomponent approach are reported. For this, a modified class of diarylprolinol silyl ethers was designed to enable high catalytic activity in an environmentally benign solvent system. The one-pot procedure showed great efficiency in promoting stereoselective multicomponent transformations in a tandem, 'green' fashion. Because of its non-residual, efficient and selective character, this synthetic design shows promise for large-scale applications in both diversity and target-oriented syntheses.
Asunto(s)
Éteres/química , Pirrolidinas/química , Silanos/química , Compuestos de Espiro/síntesis química , Catálisis , Estructura Molecular , Compuestos de Espiro/química , EstereoisomerismoRESUMEN
A series of carboxylic acids carrying various functionalization on C-7 of their common 3H-spiro[benzofuran-2,1'-cyclohexane] skeleton were synthesized from filifolinol, as analogs of the natural Complement inhibitor K-76 COOH. In order to probe the relevance of the C-7 functionalization on their bioactivity, the ability of the analogs to inhibit Complement activation through the classical pathway was determined. The observed results suggest that functionalization of C-7 can modulate the inhibitory activity of the tested compounds. The 7-trifluoromethyl derivative was the compound with the lowest IC(50) value among the tested analogs (IC(50) = 100 µM), being more potent than K-76 COOH (IC(50) = 570 µM).
Asunto(s)
Benzofuranos/síntesis química , Benzofuranos/farmacología , Proteínas del Sistema Complemento/metabolismo , Sesquiterpenos/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Benzofuranos/química , Técnicas de Química Sintética , Humanos , Compuestos de Espiro/químicaRESUMEN
The total synthesis of pteridic acids A and B is reported. The convergent asymmetric synthesis involved the use of a diastereoselective ethyl ketone aldol reaction followed by an efficient spiroketalization and provided pteridic acids A and B in 2.9% and 2.8% overall yield, respectively.
Asunto(s)
Ácidos Heptanoicos/síntesis química , Compuestos de Espiro/síntesis química , Ácidos Heptanoicos/química , Conformación Molecular , Compuestos de Espiro/química , EstereoisomerismoRESUMEN
Six 3H-spiro[benzofuran-2,1'-cyclohexane] derivatives were synthesized from naturally occurring filifolinol, and their classical complement pathway inhibitory activity was determined. IC(50) values of the most potent compounds were comparable to the activity of the natural complement inhibitor K76-COOH and some synthetic tricyclic analogs of it.
Asunto(s)
Vía Clásica del Complemento/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Extractos Vegetales/química , Animales , Benzofuranos/síntesis química , Benzofuranos/farmacología , Ciclohexanos/síntesis química , Ciclohexanos/farmacología , Hemólisis/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Extractos Vegetales/farmacología , Sesquiterpenos , Ovinos , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , TritioRESUMEN
[reaction: see text] A tandem Michael addition-enolate alkylation followed by Dieckmann cyclization and Beckmann rearrangement provided the corresponding [5.4.0] azaspirobicyclodecane, a key intermediate in our synthetic route to the marine alkaloid halichlorine (1).
Asunto(s)
Alcaloides/síntesis química , Compuestos de Espiro/síntesis química , Animales , Estructura Molecular , Poríferos/química , EstereoisomerismoRESUMEN
[reaction: see text] Initial efforts toward the total synthesis of the antifungal antibiotics spirofungins A and B are reported. A short and efficient synthesis of the C9-C20 6,6-spiroketal fragments of both compounds is described. This asymmetric approach uses a very efficient alkylation of a lithiated N,N-dimethylhydrazone followed by spiroketal formation under acidic conditions.