RESUMEN
The enantiospecific total synthesis of natural roseophilin has been completed in 7.0% overall yield over 15 steps by means of an asymmetric cyclopentannelation. This establishes the absolute configuration of the natural product as 22R,23R. Cyclopentenone (+)-12 was prepared in 78% yield and 86% ee in the key step.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/síntesis química , Pirroles/síntesis química , Compuestos Heterocíclicos con 3 Anillos/química , Pirroles/química , Estereoisomerismo , Streptomyces/químicaRESUMEN
A combination of parallel chemical synthesis and biocatalysis has been used to prepare and amplify a library of cross-conjugated cyclopentenones. A number of marine and terrestrial natural products with antibiotic activity are known to incorporate this pharmacophore. The library was screened for anticancer, antimycobacterial, antifungal, and antibacterial activity. The positive results from the screens provide an indication of the structural features that are associated with activity in the various assays and suggest promising avenues for further inquiry.
Asunto(s)
Ciclopentanos/síntesis química , Enzimas/química , Biotransformación , Técnicas Químicas Combinatorias , Endopeptidasas/química , Indicadores y Reactivos , Lipasa/química , Oxidación-Reducción , Peroxidasas/metabolismo , Saccharomyces cerevisiae/metabolismo , Glycine max/enzimologíaRESUMEN
An effective synthesis of tricyclic, nonclassical cannabinoids has been developed on the basis of a cation-olefin cyclization that forms the two nonaromatic rings with the desired stereochemistry in a single step.
Asunto(s)
Cannabinoides/síntesis química , Alquenos , Animales , Encéfalo/metabolismo , Cannabinoides/metabolismo , Cromatografía Líquida de Alta Presión , Ciclización , Cinética , Receptores de Cannabinoides , Receptores de Droga/metabolismo , Bazo/metabolismo , EstereoisomerismoRESUMEN
An enantioselective variant of the synthesis of cross-conjugated cyclopentenones, based on D-glucose-derived chiral auxiliaries, is described. Minor modification of the method makes it applicable to the preparation of both enantiomeric series of products. Both enantiomers of the key intermediate in our roseophilin synthesis have been prepared.
Asunto(s)
Ciclopentanos/síntesis química , Ciclopentanos/química , Indicadores y Reactivos , Modelos Moleculares , Conformación Molecular , EstereoisomerismoRESUMEN
[formula: see text] The formal total synthesis of the macrocyclic core of roseophilin 4 has been accomplished in 12 steps from 5-hexenal 8. The cyclopentannelation reaction was used to form the aliphatic five-membered ring of 3. Diene 2 was assembled by means of a Stetter reaction. Ring-closing metathesis of 2, reduction, and Knorr reaction of the 1,4-diketone 5 gave the ketopyrrole 3.
Asunto(s)
Ciclopentanos/química , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/química , Oxidación-Reducción , Pirroles/síntesis química , Pirroles/química , Streptomyces/químicaRESUMEN
The stereoelectronic requirements for interaction of the southern aliphatic hydroxyl of cannabimimetic pharmacophores with the CB1 and CB2 receptors are explored. The stereoselective syntheses of three series of classical/nonclassical hybrid cannabinoids are described. These compounds were designed to investigate the importance of the southern aliphatic hydroxyl (SAH) pharmacophore for cannabimimetic activity. Variation in the chain length of the SAH moiety in these 6beta-(hydroxyalkyl)dihydrobenzopyran analogues, from 6beta-hydroxymethyl to 6beta-(omega-hydroxyethyl) and 6beta-(omega-hydroxypropyl), and the effects of replacing the hydroxyl functionality by hydride and iodide are reported. Our results indicate that the SAH pharmacophore has less pronounced effects than the C-3 aliphatic chain on cannabinoid activity. Furthermore, it appears that this southern molecular component is capable of interacting with two different subsites on the receptor and that the nature of this interaction is determined by the terminal substituent on the C-6beta alkyl group. One of the subsites can accommodate the relatively polar SAH pharmacophore, while the second subsite interacts with more hydrophobic C-6beta substituents and can accommodate large spherical pharmacophores separated by three methylene carbons from the tricyclic cannabinoid template.
Asunto(s)
Cannabinoides/síntesis química , Cannabinoides/metabolismo , Receptor Cannabinoide CB2 , Receptores de Droga/metabolismo , Animales , Cannabinoides/química , Diseño de Fármacos , Ratones , Prosencéfalo/metabolismo , Prosencéfalo/ultraestructura , Ratas , Receptores de Cannabinoides , Bazo/metabolismo , Bazo/ultraestructura , Relación Estructura-Actividad , Sinaptosomas/metabolismoRESUMEN
The small molecule S9a was derived from an established tumor necrosis factor-alpha (TNF-alpha) inhibitor (Canventol) by replacement of the isopropylidine group with a phenyl ring. S9a at 10 to 100 nM inhibited HIV production as potently as 3'-azido-3'-deoxythymidine (AZT), an inhibitor of viral reverse transcriptase. Furthermore, S9a and AZT in combination, at noncytoxic concentrations strongly inhibited HIV-1 replication that was more than additive and substantially prolonged the appearance of virus both in acutely infected CD4+ lymphocytes (SupT) in culture and in peripheral blood mononuclear cells (PBMCs) infected with a primary HIV-1 isolate. S9a inhibited TNF-alpha promoter-driven reporter gene activity. It was proposed that the mechanism of antiviral action of S9a was on the host cell, by blocking TNF-alpha transcription via a Tat-induced tar-independent loop, which decreases downstream NF-kappaB activation of HIV-1 long terminal repeat (LTR). S9a was superior to the first generation compound Canventol, which was superior to the natural compound sarcophytol A, demonstrating that further structure-based enhancement of potency of these compounds is feasible. This study suggests a therapeutic approach against AIDS by application of two drugs, one against a cellular and the other a viral target, which may provide an approach to the problem of frequent emergence of resistant variants to combinations of drugs that target only HIV genes.
Asunto(s)
Fármacos Anti-VIH/farmacología , Anticarcinógenos/farmacología , Ciclohexanoles/farmacología , VIH-1/efectos de los fármacos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Replicación Viral/efectos de los fármacos , Zidovudina/farmacología , Anticarcinógenos/química , Antineoplásicos/farmacología , Linfocitos T CD4-Positivos/virología , Línea Celular , Ciclohexanoles/química , Diterpenos/química , Diterpenos/farmacología , Combinación de Medicamentos , Sinergismo Farmacológico , Productos del Gen tat/antagonistas & inhibidores , VIH-1/genética , VIH-1/fisiología , Humanos , Células Jurkat/virología , FN-kappa B/antagonistas & inhibidores , Secuencias Repetitivas de Ácidos Nucleicos/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/farmacología , Transfección , Productos del Gen tat del Virus de la Inmunodeficiencia HumanaRESUMEN
Canventol, a synthetic compound, is a new inhibitor of tumor promotion on mouse skin by okadaic acid. We previously reported that canventol acts by inhibiting both protein isoprenylation and tumor necrosis factor-alpha (TNF-alpha) release. In this study we examined the potencies of 10 newly synthesized canventol analogs through their effect on mevalonate metabolism, and then examined 3 representative analogs for inhibition of protein isoprenylation. Since canventol in vitro did not directly inhibit farnesyl protein transferase or geranylgeranyl protein transferase-I, the effects of canventol and its synthetic analogs on the fate of [3H]mevalonate in cells were studied. Canventol at 500 microM changed the ratio of newly synthesized sterols (cholesterol and lathosterol) to ubiquinones from 0.7 to 8.2 in NIH/3T3 cells which had previously been labeled with [3H]mevalonate, suggesting that the altered pattern of mevalonate metabolism is associated with inhibition of protein isoprenylation in the cells. We named this ratio the inhibition of protein isoprenylation index (IPI index). The 10 analogs showed a wide range of IPI indices. Two analogs, S3 and S9 had effects similar to, or stronger than, canventol. Three analogs, C44, C46 and C47, with lower IPI indices, inhibited tumor promotion on mouse skin slightly less than canventol itself did. This study shows that inhibition of protein isoprenylation in the cells, indicated by an increase in the IPI index, is a new biomarker for estimating inhibition of tumor promotion.
Asunto(s)
Transferasas Alquil y Aril , Anticarcinógenos/farmacología , Ciclohexanoles/farmacología , Prenilación de Proteína/efectos de los fármacos , Neoplasias Cutáneas/prevención & control , Células 3T3/efectos de los fármacos , Células 3T3/metabolismo , Animales , Carcinógenos , Inhibidores Enzimáticos/farmacología , Femenino , Metabolismo de los Lípidos , Ácido Mevalónico/análogos & derivados , Ácido Mevalónico/metabolismo , Ratones , Ratones Endogámicos , Ácido Ocadaico , Neoplasias Cutáneas/inducido químicamente , Esteroles/biosíntesis , Transferasas/antagonistas & inhibidores , Ubiquinona/biosíntesisRESUMEN
The cannabinoid side chain is a key pharmacophore in the interaction of cannabinoids with their receptors (CB1 and CB2). To study the stereochemical requirements of the side chain, we synthesized a series of cannabinoids in which rotation around the C1'-C2' bond is blocked. The key steps in the synthesis were the cuprate addition of a substituted resorcinol to (+)-apoverbenone, the TMSOTf-mediated formation of the dihydropyran ring, and the stereospecific introduction of the beta-11-hydroxymethyl group. All the analogs tested showed nanomolar affinity for the receptors, the cis-hept-1-ene side chain having the highest affinity for CB1 (Ki = 0.89 nM) and showing the widest separation between CB1 and CB2 affinities. The parent n-heptyl-beta-11-hydroxyhexahydrocannabinol was the least potent binding to CB1 (Ki = 8.9 nM) and had the lowest selectivity between CB1 and CB2.
Asunto(s)
Cannabinoides/química , Dronabinol/análogos & derivados , Receptor Cannabinoide CB2 , Receptores de Droga/metabolismo , Animales , Membrana Celular/metabolismo , Simulación por Computador , Dronabinol/química , Dronabinol/metabolismo , Ratones , Modelos Moleculares , Prosencéfalo/metabolismo , Ratas , Receptores de Cannabinoides , Bazo/metabolismo , Relación Estructura-Actividad , Sinaptosomas/metabolismoRESUMEN
SUMMARY: Canventol (2-isopropyl-4-isopropyldencyclohex-2-ene-l-ol), a blocker of tumor necrosis factor alpha (TNF-alpha) release, inhibits human immunodeficiency virus type (HIV-1) production in chronically and acutely infected cells. This effect of Canventol on virus replication could be correlated with its inhibitory influence on necrosis factor (NF)-kappa B activation and HIV-1 long terminal repeat (LTR)-driven reporter gene expression in Jurkat cells and these could be overcome by the administration of TNF-alpha. Canventol inhibits activation of the promoter by the viral protein Tat through a TAR-independent mechanism. The HIV-1 promoter is synergistically upregulated when both the TAR-independent and the TAR-dependent modes of Tat action are in operation. Tat-induced downstream events, such as the production of cytokines like TNF-alpha and NF-kappa B activation, are central for this upregulation. Inhibitors of the respective modes of action of Tat downregulate HIV-1 LTR activation and virus replication.
Asunto(s)
Antivirales/farmacología , Ciclohexanoles/farmacología , Productos del Gen tat/fisiología , VIH-1/efectos de los fármacos , Pirroles , Replicación Viral/efectos de los fármacos , Antivirales/administración & dosificación , Secuencia de Bases , Benzodiazepinas/administración & dosificación , Línea Celular , Ciclohexanoles/administración & dosificación , Regulación hacia Abajo/efectos de los fármacos , Sinergismo Farmacológico , Productos del Gen tat/genética , Duplicado del Terminal Largo de VIH , VIH-1/genética , VIH-1/fisiología , Humanos , Datos de Secuencia Molecular , FN-kappa B/genética , Oligodesoxirribonucleótidos/genética , Regiones Promotoras Genéticas/efectos de los fármacos , Activación Transcripcional/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Replicación Viral/genética , Replicación Viral/fisiología , Productos del Gen tat del Virus de la Inmunodeficiencia HumanaRESUMEN
We have synthesized a range of hybrid classical/non-classical cannabinoids (CC/NCCs) combining the hexahydrocannabinol dibenzopyran structure with the hydroxyalkyl chain found in CP-55940, in order to investigate the role of the hydroxyalkyl pharmacophore in cannabimimetic activity. This was achieved by synthesizing CC analogs in which the 6 alpha- and 6 beta-methyl groups were modified to the corresponding hydroxyethyl groups. Our binding data indicated that beta position was the preferred orientation for the hydroxyalkyl moiety, affinity for the CB1 receptor being 20-fold greater for the 6 beta-hydroxyethyl than the corresponding 6 alpha-analog. Further studies using 6 beta-hydroxyalkyldibenzopyran analogs varying the southern aliphatic chain length from 6 beta-hydroxymethyl to 6 beta-hydroxyethyl to 6 beta-hydroxypropyl demonstrated little potency change with chain length. Therefore, we concluded that whilst the hydroxyalkyl pharmacophore was strongly affected by its configuration relative to the dibenzopyran ring, the chain length of the hydroxyalkyl moiety (up to the n = 3 homolog) was not critical.
Asunto(s)
Cannabinoides/química , Ciclohexanoles/química , Animales , Unión Competitiva , Cannabinoides/síntesis química , Cannabinoides/metabolismo , Ciclohexanoles/síntesis química , Ciclohexanoles/metabolismo , Técnicas In Vitro , Prosencéfalo/metabolismo , Ratas , Receptores de Cannabinoides , Receptores de Droga/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A synthetic compound named canventol, 2-isopropyl-4-isopropylidencyclohex-2-ene-1-ol, inhibited tumor promotion of okadaic acid on mouse skin initiated with 7,12-dimethylbenz(a)anthracene in two-stage carcinogenesis experiments more strongly than sarcophytol A, isolated from a soft coral, although canventol has a simpler structure than sarcophytol A. Their mechanisms of action were studied based on our recent evidence that tumor necrosis factor alpha release induced by okadaic acid is an essential mechanism of tumor promotion. Canventol inhibited mouse tumor necrosis factor alpha release from BALB/3T3 cells less strongly than sarcophytol A, indicating that canventol has additional activity. Canventol inhibited isoprenylation of proteins with various molecular weights, such as M(r) 22,000, 17,000, and 13,000, whereas sarcophytol A did not show significant inhibition. Thus, a potent anticarcinogenic activity of canventol is mediated through the inhibitory bifunctions of tumor necrosis factor alpha release and of protein isoprenylation. Since canventol is less toxic to cells than sarcophytol A, these bifunctions are useful markers for screening for new cancer chemopreventive agents.
Asunto(s)
Anticarcinógenos/farmacología , Ciclohexanoles/farmacología , Prenilación de Proteína/efectos de los fármacos , Neoplasias Cutáneas/prevención & control , Factor de Necrosis Tumoral alfa/metabolismo , Células 3T3 , 9,10-Dimetil-1,2-benzantraceno , Animales , Diterpenos/farmacología , Éteres Cíclicos/farmacología , Femenino , Ácido Mevalónico/análogos & derivados , Ácido Mevalónico/metabolismo , Ratones , Ácido Ocadaico , Neoplasias Cutáneas/inducido químicamenteRESUMEN
A cationic cyclopentannelation reaction has afforded a very simple route to a wide variety of methylenomycin analogs. The antibacterial activity of these readily accessible synthetic compounds parallels that of naturally occurring methylenomycin A. The in vitro antitumor activity of the synthetics assayed using human nasopharyngeal carcinoma (KB) cells is particularly promising.