RESUMEN
[reaction: see text] In the course of natural product synthetic studies, 5-(4-pentenyl)oxazole and 5-(5-hexenyl)oxazole were N-methylated. The initial N-methylated 5-alkenyloxazolium salt adducts were found to be only intermediates and were ultimately transformed into hydroindole and hydroisoquinoline compounds, respectively.
Asunto(s)
Oxazoles/química , Cristalografía por Rayos X , Indoles/síntesis química , Indoles/química , Isoquinolinas/síntesis química , Isoquinolinas/química , Espectroscopía de Resonancia Magnética/métodos , Metilación , Estructura Molecular , Oxazoles/síntesis químicaRESUMEN
Two new alkaloids, haplotubinone (3) and haplotubine (4), were isolated from the aerial parts of Haplophyllum tuberculatum together with the known lignan diphyllin. The structures of the new alkaloids were established by spectroscopic methods in conjunction with X-ray crystallographic analysis of 3. In addition, the amide N-(2-phenylethyl)-benzamide has been identified in this source for the first time.
Asunto(s)
Alcaloides/química , Alcaloides/aislamiento & purificación , Plantas Medicinales/química , Benzamidas/química , Benzamidas/aislamiento & purificación , Factores Biológicos/química , Factores Biológicos/aislamiento & purificación , Cristalografía por Rayos X , Extractos Vegetales/química , Arabia SauditaRESUMEN
[reaction: see text] The first total synthesis of (+)-himandravine (1) is described, starting from (2S,6S)-cis-2-formyl-6-methyl-N-Boc-piperidine (8) in 11 linear steps and 17% overall yield. The key step involves a highly diastereoselective intramolecular Diels-Alder reaction of the key intermediate 5 that contains the entire latent carbon framework and functional group substitution of himandravine.
Asunto(s)
Alcaloides/síntesis química , Piperidinas/síntesis química , Extractos Vegetales/síntesis química , Alcaloides/química , Piperidinas/química , Extractos Vegetales/química , EstereoisomerismoRESUMEN
Microbial bioconversion studies conducted on the diterpene psiadin have revealed that it was metabolized by Aspergillus niger (NRRL 2295) to give 2alpha-hydroxydeoxopsiadin, Cunninghamella blakesleeana (ATCC 8688a) to give 11beta-hydroxypsiadin, and Cylindrocephalum aureum (ATCC 12720), Gongronella butleri (ATCC 22822), Kloeckera africana (ATCC 20111), and Kluyveromyces marxianus var. lactis (ATCC 2628) to yield 7alpha-hydroxypsiadin. Their structures have been established on the basis of spectral data. The structure and relative stereochemistry of 7alpha-hydroxypsiadin was confirmed by single-crystal X-ray analysis.
Asunto(s)
Diterpenos/metabolismo , Hongos/metabolismo , Aspergillus niger/metabolismo , Biotransformación , Cunninghamella/metabolismo , Diterpenos/química , Fermentación , Hidroxilación , Kluyveromyces/metabolismo , Modelos Moleculares , Conformación Molecular , Oxidación-ReducciónRESUMEN
A series of disubstituted 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogues (1-10) were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. 5-Methoxy-4-methyl DCK (8) was the most promising compound with an EC(50) value of 7.21 x 10(-6) microM and a therapeutic index of >2.08 x 10,(7) which were much better than those of lead compound DCK in the same assay. Another six disubstituted DCK analogues (1-5 and 7) were more potent than AZT but less active than DCK. Conformational analysis suggested that resonance of the coumarin system is an essential structural feature for potent anti-HIV activity. Steric compression of C(4) and C(5) substituents of the coumarin moiety can reduce the overall planarity and thus resonance of the coumarin nucleus, resulting in a decrease or lack of anti-HIV activity.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Cumarinas/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular , Cumarinas/química , Cumarinas/farmacología , Cristalografía por Rayos X , VIH-1/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Relación Estructura-Actividad , Linfocitos T/citología , Linfocitos T/virología , Replicación ViralRESUMEN
The cis-isomer (2) of the previously isolated parthenolid-9-one (1) was isolated from Anvillea garcinii and the structures and relative stereochemistries of both were determined from NMR data in combination with single-crystal X-ray analysis. In vitro cytotoxicity and in vivo antitumor activity for both compounds are reported.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Asteraceae/química , Plantas Medicinales/química , Antineoplásicos Fitogénicos/farmacología , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Espectroscopía de Resonancia Magnética , Conformación Molecular , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacología , Espectrofotometría Ultravioleta , Células Tumorales CultivadasRESUMEN
L-Rhamnal is readily converted into an allyl 2, 3-unsaturated-C-glycopyranoside. The (S) configuration of the alphaL-anomer defines the stereochemical outcome of the future IMDA reaction, leading to the absolute stereochemistry for the trans-decalin moiety in naturally occurring terpenoids. Selective cleavage of the terminal double bond of the allyl group provides an aldehydo function which serves for an aldol/Claisen addition with ethyl sorbate. Of the four possible diastereomers, one is obtained in pure form and processed to give the IMDA precursor. Cyclocondensation is achieved by heating in xylene to give a tricyclic trans-decalin whose structure is established by NMR and X-ray analysis.
Asunto(s)
Carbohidratos/química , Química/métodos , Naftalenos/química , Cristalografía por Rayos X , Glicósidos/química , Espectroscopía de Resonancia Magnética , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Estereoisomerismo , Terpenos/química , Rayos XRESUMEN
Three new eudesmane sesquiterpenes, plectranthone (1), desacetylplectranthone (2), isodeacetylplectranthone (3), and the three known flavonols pachypodol, casticin, and chrysosplenol D were isolated for the first time from the aerial parts of Plectranthus cylindraceus. Their structures have been established on the basis of spectral data. The structures and relative stereochemistries of 1 and 2 were confirmed by single-crystal X-ray analysis.
Asunto(s)
Antiinfecciosos/aislamiento & purificación , Lamiaceae/química , Sesquiterpenos/aislamiento & purificación , Antiinfecciosos/química , Antiinfecciosos/farmacología , Cristalografía por Rayos X , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Sesquiterpenos/química , Sesquiterpenos/farmacologíaRESUMEN
Two new sesquiterpenes, leitneridanin A (1) and leitneridanin B (2), and seven known compounds, lirioresinol B, (-)-pinoresinal, (+)-lariciresinol, quassimarin (3), simalikalactone D (4), 1-methoxycanthinone (5), and 5-methoxycanthinone (6), were isolated from Leitneria floridana. Their structures were identified on the basis of spectral data. In vitro biological evaluation showed that 5 is a potent anti-HIV agent (EC(50) 0.26 g/mL; TI >39) and that 3-6 suppressed the growth of a panel of human tumor cell lines (KB, A-549, HCT-8, CAKI-1, MCF-7, and SK-MEL-2). Compounds 3 and 4 were significantly active, with ED(50) values in the range of 0.26-0.012 g/mL.
Asunto(s)
Fármacos Anti-VIH/aislamiento & purificación , Antineoplásicos Fitogénicos/aislamiento & purificación , Rosales/química , Sesquiterpenos/aislamiento & purificación , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Sesquiterpenos/química , Sesquiterpenos/farmacología , Análisis Espectral , Células Tumorales CultivadasRESUMEN
Following the discovery of the first dual antagonist of platelet-activating factor (PAF) and histamine, 1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin- 11-ylidene)piperidine, Sch 37370, 1, a related series of structures, exemplified by (+/-)-1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b] pyridin-11-yl)piperazine, Sch 40338, 2, were prepared. Interestingly, the compounds exhibited a parallel structure antiallergy activity relationship, suggesting that the two series may adopt a common conformation at the PAF receptor. Conformational analysis led to a proposal for this bioactive conformation accessible to both series. The synthesis of novel conformationally constrained analogues that might mimic the proposed bioactive conformation of these compounds, and the evaluation of their in vitro antiallergy activity form the subject matter of this report.
Asunto(s)
Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Isoquinolinas/química , Isoquinolinas/farmacología , Factor de Activación Plaquetaria/antagonistas & inhibidores , Piridinas/química , Piridinas/farmacología , Animales , Antialérgicos/química , Antialérgicos/farmacología , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Cobayas , Antagonistas de los Receptores Histamínicos/metabolismo , Humanos , Concentración 50 Inhibidora , Loratadina/química , Ratones , Modelos Moleculares , Conformación Molecular , Imitación Molecular , Piperazinas/química , Piperazinas/farmacología , Piperidinas/química , Piperidinas/farmacología , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Ratas , Receptores Histamínicos H1/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The structures and absolute stereochemistries of tomenphantins A (1) and B (2), cytotoxic germacranolides isolated from Elephantopus tomentosus, are reported herein. 1H and 13C NMR spectroscopic data, chemical transformation, and single-crystal X-ray analysis were used in these determinations.
Asunto(s)
Antineoplásicos Fitogénicos/química , Furanos/química , Plantas/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Cristalografía por Rayos X , Furanos/aislamiento & purificación , Estructura Molecular , Análisis Espectral , EstereoisomerismoRESUMEN
Blocking farnesylation of oncogenic Ras proteins is a mechanism based therapeutic approach that is of current interest for the development of antitumor agents to treat ras associated tumors. As part of a SAR study on the lead farnesyl protein transferase (FPT) inhibitor I, we report here the synthesis of novel geometric isomers II and III and the FPT inhibition activity of their N-acyl and N-sulfonamido derivatives 15-65. The N-acyl derivatives are markedly less active than the lead inhibitor I thereby demonstrating that the spatial location of the N-acyl group in I is critical for binding of the compound to FPT. In contrast to I, the N-sulfonamido-II series is a novel lead of non-sulfhydryl, nonpeptidic compounds that are dual FPT/GGPT inhibitors. In light of recent reports on the alternative prenylation of N- and K-Ras, dual FPT/GGPT inhibitors may be required to control cell proliferation in tumors containing activated Ras.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Piperidinas/síntesis química , Prenilación de Proteína , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Piridinas/síntesis química , Pirrolidinas/síntesis química , Sulfonamidas/síntesis química , Transferasas Alquil y Aril/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Piperidinas/química , Piperidinas/farmacología , Piridinas/química , Piridinas/farmacología , Pirrolidinas/química , Pirrolidinas/farmacología , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
The metabolism of SCH 40120, which is the clinically effective antipsoriatic drug 10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzol[b][1,8]naphthyrid in-5(7H)-one, was determined in vitro. Rat, dog, cynomolgus monkey, and human liver slices hydroxylated the aliphatic, cyclohexenyl ring of the drug and conjugated the resulting carbinol. The identified metabolites comprised the corresponding 6-, 7-, and 9-carbinols, the glucuronide of the 6-carbinol, and the 6-ketone derived from the parent drug. Although the three carbinols appeared in the liver isolates of all species studied, the relative amounts of these metabolites varied across species. With a high, non-physiological ratio of substrate to liver, the 6-carbinol and its glucuronide were the major metabolites in human and monkey, whereas the 6-ketone was a minor metabolite in dog. Containing a stereogenic axis and center, the 6-carbinol existed as diastereomeric atropisomers. Its structure was established by 13C and 1H NMR spectroscopy, mass spectrometry, and comparison to an authentic sample.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Hígado/metabolismo , Naftiridinas/farmacocinética , Psoriasis/tratamiento farmacológico , Animales , Preescolar , Perros , Humanos , Hidroxilación , Técnicas In Vitro , Macaca fascicularis , Masculino , Ratas , Ratas Sprague-Dawley , Especificidad de la EspecieRESUMEN
The structure of an unusual dienone-phenol rearrangement product 4 obtained during the synthesis of mometasone furoate (Sch 32088) was assigned on the basis of NMR and x-ray crystallographic data. The mechanism of formation is discussed.
Asunto(s)
Antiinflamatorios/síntesis química , Fenoles/química , Pregnadienodioles/síntesis química , Antiinflamatorios/química , Cristalografía por Rayos X , Espectroscopía de Resonancia Magnética , Estructura Molecular , Furoato de Mometasona , Pregnadienodioles/químicaRESUMEN
The C3 phenylpropyl side chain of N-phenylazetidinones related to SCH 56524 was modified by replacing the hydroxymethylene with various isoelectronic or isosteric groups. Modifications at the 3' position led to less-active compounds; however, modifications at the 1' position provided compounds with improved cholesterol absorption inhibitory activity. An enantioselective route for the synthesis of C3 1'-sulfur-substituted azetidinones and the development of structure-activity relationships for this series of compounds are presented.
Asunto(s)
Anticolesterolemiantes/síntesis química , Azetidinas/síntesis química , Animales , Anticolesterolemiantes/farmacología , Azetidinas/química , Azetidinas/farmacocinética , Azetidinas/farmacología , Bilis/metabolismo , Colesterol/metabolismo , Absorción Intestinal/efectos de los fármacos , Macaca fascicularis , Masculino , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Several new acetyl-4H,9H-naphtho[2,3-b]thiophene-4,9-diones were synthesized and evaluated for in vitro cytotoxicity by NCI against seven cancer cell types. 2,7-Diacetyl naphtho[2,3-b]thiophene-4,9-dione (9) showed significant cytotoxicity against leukemia cells with log GI50 values of -7.61 against SR cells and -7.18 against MOLT-4 cells. 3-Acetyl-naphtho[2,3-b]thiophene-4,9-dione (6) also demonstrated potent cytotoxicity in the latter cell line with log GI50 < -8.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Naftoles/síntesis química , Naftoles/farmacología , Tiofenos/síntesis química , Tiofenos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células KB/efectos de los fármacos , Resonancia Magnética Nuclear Biomolecular/métodos , Células Tumorales CultivadasRESUMEN
A series of novel 7-O-substituted deacetamidothiocolchicine derivatives has been synthesized and evaluated for their inhibitory activity against tubulin polymerization, the binding of [3H]-colchicine to tubulin, and the growth of human Burkitt lymphoma cells. Of these new derivatives, thiocolchicone (8), wherein an acetamido group in thiocolchicine is replaced by a carbonyl oxygen at C(7), was obtained from deacetythiocolchicine (6) by Schiffs base equilibration and acid hydrolysis. Reduction of thiocolchiocone with sodium borohydride yielded the racemic alcohol 9, the structure of which was verified by X-ray crystallographic analysis. Optically pure alcohols 9a,b were obtained by treatment of 9 with the optically pure reagent (1S)-(-)-camphanic chloride followed by chromatographic separation of the camphanate esters and hydrolysis of the diastereomers. X-ray crystallographic analysis established the aS,7S-configuration of 9a. Racemic and optically active esters 11-15, 11a,b, 12a, 14a, and 15a were obtained by esterification of the corresponding alcohols. The compounds showing activity equivalent to or greater than (-)-thiocolchicione (2a) in all the biological assays were three (-)-aS,7S optically pure enantiomers: the alcohol 9a, the acetate 11a (an oxygen isostere of thiocolchicine), and the isonicotinoate 15a. In addition, the ketone 8 and two (-)-aS,7S enantiomers (12a, 14a) had high activity in the biochemical assays with tubulin but reduced antiproliferative activity. In all cases, optically pure isomers with the (-)-aS,7S configuration exhibited greater biological activity than racemic mixtures or isomers or isomers with the (+)-aR,7R configuration.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Colchicina/análogos & derivados , Moduladores de Tubulina , Antineoplásicos/química , División Celular/efectos de los fármacos , Colchicina/síntesis química , Colchicina/química , Colchicina/farmacología , Cristalografía por Rayos X , Ésteres/síntesis química , Ésteres/química , Ésteres/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Moleculares , Estructura Molecular , Tubulina (Proteína)/metabolismo , Células Tumorales CultivadasRESUMEN
Pseudolarolide J (1), a novel nortriterpene lactone, has been isolated from the seeds of Pseudolarix kaempferi and structurally characterized from spectral data and X-ray crstallographic analysis.
Asunto(s)
Plantas Medicinales/química , Triterpenos/química , China , Cristalografía por Rayos X , Conformación MolecularRESUMEN
The structure of an unusual rearrangement product obtained during the production of mometasone furoate (Sch 32088) was assigned on the basis of NMR and X-ray crystallography data.
Asunto(s)
Pregnadienodioles/síntesis química , Pregnatrienos/síntesis química , Administración Tópica , Antiinflamatorios/síntesis química , Cristalografía por Rayos X , Glucocorticoides , Espectroscopía de Resonancia Magnética , Estructura Molecular , Furoato de Mometasona , Pregnadienodioles/química , Pregnatrienos/químicaRESUMEN
Three new neolignans, piperulins [corrected] A [1], B [2], and C [3], were isolated from Piper puberulum. Their structures and relative stereochemistries were determined from spectral data and the X-ray crystallographic analysis of 1. Compounds 1 and 3 inhibit specific platelet activating factor receptor binding with IC50 values of 7.3 and 5.7 microM, respectively.