RESUMEN
Identification of a common Diels-Alder pattern in three classes of bioactive natural products led us to study the synthesis and cycloaddition of a new class of cyclic dienes readily available from ß,γ-unsaturated lactams. A practical and readily scalable route to the parent p-methoxybenzyl-protected 6- and 7-membered ß,γ-unsaturated lactams was developed. These were readily transformed into the corresponding O-silylated dienes, which were reacted with dimethyl and diethyl fumarate to yield stereoselectively highly functionalized bicyclic adducts. These exhibited unexpected and versatile transformations upon acid hydrolysis depending on the nature of the dienophile substituents and the acid catalyst. All reactions have been performed on multigram quantities. These transformations provide a convenient, economical, and easily scalable pathway for the rapid construction of functionally and stereochemically dense privileged scaffolds for the construction of libraries of natural products-inspired molecules of pharmacological relevance.
Asunto(s)
Productos Biológicos , Productos Biológicos/síntesis química , Productos Biológicos/química , Catálisis , Reacción de Cicloadición , Hidrólisis , Lactamas/químicaRESUMEN
Herein, we report a convenient synthesis of unprecedented aza-diketopiperazines (aza-DKPs). The strategy is based on selective diversification of bicyclic aza-DKP scaffolds by click reaction, N-acylation, and/or N-alkylation. These scaffolds containing either azido or amino groups were obtained by a key Rh(I)-catalyzed hydroformylative cyclohydrocarbonylation reaction of allyl-substituted aza-DKP. The methodology is readily amenable to the parallel synthesis of original aza-DKPs to enlarge the chemical diversity of aza-heterocycles.
RESUMEN
In search of a next generation molecule to the novel wake-promoting agent modafinil, a series of aryl-heteroayl-derived wakefulness enhancing agents (in rats) was developed. From this work, compound 16 was separated into its enantiomers to profile them individually.
Asunto(s)
Compuestos de Bencidrilo/química , Estimulantes del Sistema Nervioso Central/química , Sulfóxidos/química , Tiofenos/química , Animales , Área Bajo la Curva , Compuestos de Bencidrilo/síntesis química , Compuestos de Bencidrilo/farmacocinética , Estimulantes del Sistema Nervioso Central/síntesis química , Estimulantes del Sistema Nervioso Central/farmacocinética , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Semivida , Modafinilo , Unión Proteica , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sulfóxidos/síntesis química , Sulfóxidos/farmacocinética , Simportadores/química , Simportadores/metabolismo , Tiofenos/síntesis química , Tiofenos/farmacocinética , Vigilia/efectos de los fármacosRESUMEN
In search of a next generation molecule to the novel wake promoting agent modafinil, a series of diphenyl ether derived wakefulness enhancing agents (in rat) was developed. From this work, racemic compound 16 was separated into its chiral enantiomers to profile them individually.
Asunto(s)
Compuestos de Bencidrilo/farmacología , Vigilia/efectos de los fármacos , Animales , Compuestos de Bencidrilo/química , Inhibidores Enzimáticos del Citocromo P-450 , Descubrimiento de Drogas , Humanos , Modafinilo , RatasRESUMEN
Structure-activity relationship on a novel ketone class of H(3)R antagonists/inverse agonists is disclosed. Compound 4 showed excellent target potency, selectivity and brain penetration. Evaluation of antagonist 4 in the rat EEG/EMG model demonstrated robust wake activity thereby establishing preclinical proof of concept.
Asunto(s)
Agonistas de los Receptores Histamínicos/farmacología , Cetonas/química , Morfolinas/química , Receptores Histamínicos H3 , Vigilia/efectos de los fármacos , Animales , Electroencefalografía , Agonistas de los Receptores Histamínicos/química , Humanos , Cetonas/farmacología , Masculino , Estructura Molecular , Morfolinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Successful identification of new chemical entities with drug-like properties in pharmaceutical and academic research groups involves an early screen and the use of a large number of public and proprietary chemical libraries. Before applying high-throughput experimental screening approaches, virtual screening strategies have been put in place in order to sort and filter this massive amount of compounds and data available at these very early stages. Chemoinformatic tools have a crucial role in this selection process and enable therapeutic chemists to focus very early on promising candidates. Virtual screening has conventionally been based either on models of the target or the ligand (molecule), but today these models include biopharmaceutical filters addressing right from the start of the project the ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of the molecules. Above all, chemoinformatic tools help chemists understand better the chemical diversity they can work with, especially when comparing chemical libraries. This paper will focus on exemples of the day-to-day use of chemoinformatics in screening programs. A large part will be dedicated to new tools (chemographic and pharmacographic approaches) being developed for the representation and analysis of chemical diversity, but also for combining chemical and biological information to expedite research programs.
Asunto(s)
Informática Médica , Modelos Moleculares , Compuestos Orgánicos/química , Preparaciones Farmacéuticas/química , Relación Estructura-Actividad Cuantitativa , Interfaz Usuario-ComputadorRESUMEN
Drug discovery is complex and risky, and the chances of success are low. One starting point to discover a new drug is the selective screening of a collection of high value and good quality compounds. Selection of compounds for screening is one of the challenging initial steps in the drug discovery process and is crucial for the success of the project. Optimal selection will enhance the chances of successful hit finding with regard to both number and quality of hits. Several scenarios for compound selection can be envisaged, and are primarily driven by knowledge of the target. Deciding the most appropriate scenario is important and appropriate software packages and chemoinformatics tools are available for these purposes. After screening, researchers may face challenges in selecting the best hits for further optimization. Numerous chemoinformatics tools have emerged recently to address challenges in hit analysis, prioritization and optimization.
Asunto(s)
Diseño de Fármacos , Descubrimiento de Drogas/métodos , Ensayos Analíticos de Alto Rendimiento , Animales , Simulación por Computador , Diseño Asistido por Computadora , Bases de Datos como Asunto , Humanos , Ligandos , Modelos Moleculares , Bibliotecas de Moléculas Pequeñas , Relación Estructura-ActividadRESUMEN
A series of aza analogues of the marine alkaloids wakayin and tsitsikammamines A and B have been synthesized. The strategy used was based on [3 + 2] cycloaddition reactions involving 3-ethylamine-indole-4,7-dione and different diazo reagents. All the compounds were evaluated in vitro for antiproliferative activity against five distinct cancer cell lines and for their inhibitory effect on topoisomerase isoenzymes I and II. Some of the compounds inhibited the topoisomerase I and/or II catalyzed relaxation of supercoiled DNA at a concentration comparable to the drugs camptothecin and etoposide. Only a few of them exhibited cytotoxic activity with IC50 values in the micromolar range.
Asunto(s)
Antineoplásicos/síntesis química , Alcaloides Indólicos/síntesis química , Pirazoles/síntesis química , Pirroles/síntesis química , Quinolinas/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacología , Pirazoles/química , Pirazoles/farmacología , Pirroles/química , Pirroles/farmacología , Quinolinas/química , Quinolinas/farmacología , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I , Inhibidores de Topoisomerasa IIRESUMEN
Two aza-analogues of the marine pyrroloquinoline alkaloids wakayin and tsitsikammamines A and B have been synthesized. The strategy used was based on a 1,3-dipolar cycloaddition reaction between indole 4,7-dione and a diazo-aminopropane derivative. One of the two analogues partially inhibits human topoisomerase I, whereas synthetic intermediates inhibit the enzyme DNA cleavage activity at a concentration comparable to that of the control drug camptothecin.
Asunto(s)
Compuestos Aza/síntesis química , Alcaloides Indólicos/síntesis química , Pirroles/química , Pirroles/síntesis química , Quinolinas/química , Quinolinas/síntesis química , Inhibidores de Topoisomerasa I , Animales , Compuestos Aza/química , Compuestos Aza/farmacología , Ciclización , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacología , Estructura Molecular , Pirroles/farmacología , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
A series of cycle C and D-substituted phenanthrolin-7-ones, analogues of the marine pyridoacridines meridine and ascididemin have been synthesized on the basis of Diels-Alder reactions involving quinoline-5,8-dione and 2- (or un)-substituted-N,N-dimethylhydrazones. All the compounds were evaluated for in vitro cytotoxic activity against 12 distinct human cancer cell lines. They all exhibit cytotoxic activity with IC(50) values at least of micromolar order.
Asunto(s)
Alcaloides/síntesis química , Alcaloides/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Fenantrolinas/síntesis química , Fenantrolinas/farmacología , Acridinas/química , División Celular/efectos de los fármacos , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Estructura Molecular , Fenantrolinas/química , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
A series of substituted pyrido[4,3,2-de][1,7] or [1,10]-phenanthrolin-7-ones, analogues of the marine pyridoacridines meridine and ascididemin, have been synthesized on the basis of Diels-Alder reactions involving different quinoline-5,8-diones and N,N-aldehyde-dimethylhydrazones. All the compounds were evaluated for in vitro cytotoxic activity against 12 distinct human cancer cell lines. They all exhibit cytotoxic activity with IC(50) values at least of micromolar order.
Asunto(s)
Alcaloides/síntesis química , Antineoplásicos/síntesis química , Fenantrolinas , Alcaloides/química , Alcaloides/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidrazonas/química , Quinolinas/química , Relación Estructura-ActividadRESUMEN
Marine compounds with pyridoacridine skeletons are known to exhibit interesting antitumor activities. Ascididemin has already been reported as displaying significant antitumor activities in vitro and has also been found to have a relatively high global toxicity in vivo. We synthesized a series of 16 analogues (among which 11 compounds were different from previously described ones) with the aim of developing new anticancer agents with significantly improved efficacy/tolerability ratios. These compounds were obtained either by total synthesis from 5,8-quinolinedione and substituted 2-aminoacetophenones or by the direct substitution of ascididemin. The different compounds and ascididemin used as the control compound were tested at six different concentrations on 12 different human cancer cell lines of various histopathological types (glioblastomas and breast, colon, lung, prostate, and bladder cancers). The IC(50) value (i.e., the drug concentration inhibiting the mean growth value of the 12 cell lines by 50%) of these compounds ranged over five log concentrations, i.e., between 10 000 and 0.1 nM. For several new chemical entities, the antitumor activity (determined in vitro) and tolerability (determined in vivo) were superior to those of the parent alkaloids, i.e., ascididemin and 2-bromoleptoclinidone.
Asunto(s)
Acridinas/síntesis química , Alcaloides/síntesis química , Antineoplásicos/síntesis química , Fenantrolinas , Quinolinas , Acridinas/farmacología , Acridinas/toxicidad , Alcaloides/farmacología , Alcaloides/toxicidad , Animales , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , División Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Ratones , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Among 25 3-aryl-2-quinolone derivatives synthesized, the antitumor activity of some of them was characterized both in vitro and in vivo. In this series, no compound appeared to be cytotoxic in vitro, as was known by the colorimetric MTT assay carried out on 12 distinct human cancer cell lines obtained from the American Type Culture Collection. Indeed, the concentration values decreasing the growth of the 12 cell lines by at least 50% (IC(50) index) were always higher than 10(-5) M. We then made use of a computer-assisted phase-contrast videomicroscopy system to quantitatively determine in vitro the level of migration of living MCF-7 human breast cancer cells. For example, at 10(-7) M, compounds 7, 13, 16, and 28 markedly decreased the migration level of these MCF-7 human breast cancer cells. The in vivo determination of the maximum tolerated dose showed that all compounds tested were definitively nontoxic. When the nontoxic, antimigratory compound 16 was combined with either doxorubicin or etoposide, two cytotoxic compounds routinely used in the clinic, this led to additive in vivo benefits from this treatment (as compared to individual administrations of the drugs) when the MXT mouse mammary adenocarcinoma was used. Thus, nontoxic antimigratory compounds, including the 2-quinolone derivatives synthesized here, can actually improve the efficiency of antitumor treatment when combined with conventional cytotoxic agents.
Asunto(s)
Antineoplásicos/síntesis química , Quinolonas/síntesis química , Tetrazoles/síntesis química , Adenocarcinoma/tratamiento farmacológico , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Movimiento Celular/efectos de los fármacos , Doxorrubicina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Etopósido/farmacología , Femenino , Humanos , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Ratones , Microscopía de Contraste de Fase , Trasplante de Neoplasias , Quinolonas/química , Quinolonas/farmacología , Relación Estructura-Actividad , Tetrazoles/química , Tetrazoles/farmacología , Células Tumorales CultivadasRESUMEN
Synthesis of 1,3-disubstituted indoles derivatives as potential glycoprotein (GP) IIb/IIIa antagonists was reported. Substitution of the indolic nitrogen atom by piperidino or benzamidino moieties was used as mimics of an arginine residue. The acid carboxylic group was linked to the indole scaffold in position-3 via a methylene unit (compounds 4, 9, 10). Introduction of a beta-alanine chain was carried out on the acids (17-22) which after deprotection and basic hydrolysis afforded the final compounds 39-46. The distance between the indole scaffold and the amide bond was modulated from no methylene unit (compound 39) to 1 (compounds 40, 41) or 2 methylene units (compounds 42-46). The presence of a tosylamino group on the beta-alanine chain (compound 56) slightly increased the inhibiting action on platelet aggregation initiated by collagen.