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PubMed2005

Estrogen receptor ligands. Part 10: Chromanes: old scaffolds for new SERAMs.

The discovery, synthesis, and SAR of chromanes as ER alpha subtype selective ligands are described. X-ray studies revealed that the origin of the ER alpha-selectivity resulted from a C-4 trans methyl substitution to the cis-2,3-diphenyl-chromane platform. Selected compounds from this class demonstrated very potent in vivo antagonism of estradiol in an immature rat uterine weight assay, effectively inhibited ovariectomy-induced bone resorption in a 42 days treatment paradigm, and lowered serum cholesterol levels in ovx'd adult rat models. The best antagonists 8F and 12F also exhibited potent inhibition of MCF-7 cell growth and were shown to be estrogen receptor down-regulators (SERDs).

Animals↗
PubMed2005

Synthesis and evaluation of 6-hydroxy-7-methoxy-4-chromanone- and chroman-2-carboxamides as antioxidants.

A series of 6-hydroxy-7-methoxy-4-chromanone- (2a-e) and chroman-2-carboxamides (3a-e) were synthesized and their antioxidant activities were evaluated. While compounds 2a-e were less active, compounds 3a-e exhibited more potent inhibition of lipid peroxidation initiated by Fe(2+) and ascorbic acid in rat brain homogenates. Among them, N-arylsubstituted-chroman-2-carboxamides (3d and 3e) exhibited 25-40 times more potent inhibition than trolox (1). The DPPH radical scavenging activity of compound 3d was comparable to that of trolox.

Anthraquinones↗
PubMed2006

Inhibitory effect of chroman carboxamide on interleukin-6 expression in response to lipopolysaccharide by preventing nuclear factor-kappaB activation in macrophages.

6-Hydroxy-7-methoxychroman-2-carboxylic acid (3-nitrophenyl)amide (CP-1158) is a synthetic chroman carboxamide with trolox-like chemical structure. In the present study, CP-1158 was found to inhibit interleukin (IL)-6 production in lipopolysaccharide (LPS)-stimulated macrophages RAW 264.7. The CP-1158 attenuated LPS-induced synthesis of IL-6 transcript but also inhibited LPS-induced IL-6 promoter activity. Further, CP-1158 attenuated LPS-induced syntheses of tumor necrosis factor (TNF)-alpha, IL-1beta, interferon-inducible protein (IP)-10 and macrophage inflammatory protein (MIP)-1beta transcripts. Nuclear factor (NF)-kappaB has been evidenced to play a major mechanism in LPS-induced expression of IL-6 or other inflammatory cytokines. CP-1158 prevented LPS-induced nuclear translocation of NF-kappaB complex and subsequently inhibited DNA binding activity of NF-kappaB complex as well as NF-kappaB transcriptional activity in macrophages RAW 264.7. However, CP-1158 did not affect LPS-induced phosphorylation and degradation of inhibitory kappaB (IkappaB). In another experiment, CP-1158 inhibited IL-6 promoter activity elicited by expression vectors encoding NF-kappaB p50 or p65 subunit. Taken together, CP-1158 inhibited LPS-induced expression of inflammatory cytokines including IL-6, targeting NF-kappaB activating pathway downstream IkappaB degradation, and thus could provide an anti-inflammatory potential of chroman carboxamide.

Active Transport, Cell Nucleus↗
PubMed2000

Chroman amide 12P inhibition of lipid peroxidation and protection against learning and memory impairment.

Structure modification of the cerebroprotective chroman amide 12 to improve the drug delivery to the target organ by protecting the active hydroxy functional group was carried out in this study. Chroman amide 12P, which the O-acetyl group was served to protect the active group to be delivered to the target organ, was synthesized. Ex vivo antilipid peroxidation activity of 12P was significantly greater than the activity of 12 while the in vitro inhibition of 12P was found to be lower. These indicated that 12P with protected active group effectively reached the brain, the target site, but in vitro, 12P was unable to release its parent or released slowly. Neuropharmacological effect of 12P was investigated in mice. 12 and 12P (50-100 mg/kg, i.p.) showed significant suppression on the hypermotility induced by methamphetamine. 12P (100 mg/kg, i.p.) was more potent than 12, 54.36% and 38.73% suppression, respectively. The result suggested the enhancement of brain delivery and the antagonism against aberrant dopamine release. In the water maze test, 12P (200 mg/kg) as well as tacrine (3 mg/kg) significantly reduced the learning and memory impairment induced by scopolamine (0.5 mg/kg). The results support the enhanced brain delivery and the additional role of radical scavengers in the modulation of brain neurotransmitters in the aberrant condition.

Amnesia↗
PubMed2002

Synthesis and biological evaluation of novel thio-substituted chromanes as high-affinity partial agonists for the estrogen receptor.

Synthesis of (+/-)-cis-7-hydroxy-3-phenyl-4-(4-(2-piperidinoethanethio)phenyl)chromane (13) and (+/-)-cis-7-hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethanethio)phenyl)chromane (15) is presented. These compounds are representatives of a novel class of compounds with high in vitro binding affinity for the estrogen receptor (IC(50)=7-10 nM), and very low in vitro uterotrophic activity (max stim.=5-17% rel to moxestrol; EC(50)=0.5-1.8 nM).

Animals↗
PubMed1999

Novel derivatives of 3-(dipropylamino)chroman. Interactions with 5-HT1A and D2A receptors.

Novel 8-aryl and 8-aroyl substituted derivatives of 3-(dipropylamino)chroman are described. The compounds have been prepared by a palladium catalyzed reaction of iodoarenes and a stannylated derivative of [eta6-3-(dipropylamino)chroman]Cr(CO)3. Several of the compounds have high affinity for 5-HT1A receptors whereas the affinity for D2A receptors is lower, the 8-arylated derivatives being slightly more potent than the 8-aroylated analogues.

Animals↗
PubMed2004

Synthesis of chiral chromans by the Pd-catalyzed asymmetric allylic alkylation (AAA): scope, mechanism, and applications.

The Pd-catalyzed asymmetric allylic alkylation (AAA) of phenol allyl carbonates serves as an efficient strategy to construct the allylic C-O bond allowing access to chiral chromans in up to 98% ee. The effect of pH and the influence of olefin geometry, as well as substitution pattern on the ee and the absolute configuration of the chiral chromans were explored in detail. These observations suggest a mechanism involving the cyclization of the more reactive pi-allyl palladium diastereomeric intermediate as the enantiodiscriminating step (Curtin-Hammett conditions). This methodology led to the enantioselective synthesis of the vitamin E core, the first enantioselective total synthesis of (+)-clusifoliol and (-)-siccanin, and the synthesis of an advanced intermediate toward (+)-rhododaurichromanic acid A.

Alkylation↗
PubMed2001

2-(2-Piperidyl)- and 2-(2-pyrrolidyl)chromans as nicotine agonists: synthesis and preliminary pharmacological characterization.

As part of an effort to develop a new class of subtype selective nicotine agonists, we have synthesized and tested a group of 12 hydroxylated 2-(2-piperidyl)- and 2-(2-pyrrolidyl)chromans. In rat brain membranes, all 12 compounds displayed poor affinity for [(125)I]-alpha-bunagarotoxin binding sites. In contrast, three compounds, 17c, 24, and 26, displayed moderate to high affinity for [(3)H]cytisine binding sites, while three (17b, 18b,c) and six (17a,d,e and 18a,d,e) compounds showed weak and poor affinity, respectively, for these same sites. In subsequent studies, compounds 17a and 17c were found to stimulate the efflux of (86)Rb(+) from rat cortical synaptosomes, an indication of agonist activity. Further, both 17c and 26 displayed high intrinsic activity in stimulating the release of [(3)H]dopamine from striatal synaptosomes; however, only 17c was effective at stimulating the release of [(3)H]acetylcholine from cortical synaptosomes, suggesting differential selectivity. In cloned human nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes, both 17c and 26 activated alpha7 and alpha3beta2 receptor subtypes in a dose-dependent manner, but 26 was clearly the more potent agonist. Last, neither compound displayed dose-dependent activation of alpha4beta2 nAChRs. We conclude that 2-(2-azacyclic)chromans appear to be a promising new class of nicotine agonists.

Acetylcholine↗
PubMed2005

Importance of chroman ring and tyrosine phosphorylation in the subtype-specific translocation and activation of diacylglycerol kinase alpha by D-alpha-tocopherol.

Diacylglycerol kinase (DGK) has been suggested to be a pharmacological target of D-alpha-tocopherol for diabetic renal dysfunctions. However, the DGK subtypes involved in the D-alpha-tocopherol-induced improvement of diabetic renal dysfunctions and the activation mechanisms of DGK by D-alpha-tocopherol are still unknown. Therefore, using GFP-tagged DGKalpha, beta, gamma, epsilon and zeta, we analyzed their response to D-alpha-tocopherol and its derivatives. Only DGKalpha was translocated from the cytoplasm to the plasma membrane with elevation of kinase activity. In addition, troglitazone and trolox possessing 'chroman ring' similarly to D-alpha-tocopherol, induced the subtype-specific translocation of DGKalpha. Furthermore, the translocation of DGKalpha was abolished by pretreatment with tyrosine kinase inhibitors or by mutation on Tyr-334 of the kinase (YF mutant). D-alpha-tocopheryl succinate enhanced the Src-mediated tyrosine phosphorylation of wild-type DGKalpha but the same reagent did not enhance that of the YF mutant. These results demonstrate that tyrosine phosphorylation on Tyr-334 and chroman ring are important for the D-alpha-tocopherol-induced translocation of DGKalpha.

Animals↗
PubMed1998

Effects of chroman derivatives on platelet aggregation induced by some aggregating agents in rabbits.

1. We synthesized 10 chroman derivatives (CD-1 to CD-10) derived from khellactone, including praeruptorin A and praeruptorin B and examined the effects of these compounds on rabbit platelet aggregation. 2. These compounds exhibited an inhibitory effect on platelet-activating factor (PAF)-induced platelet aggregation and their effects were more potent on PAF-induced platelet aggregation than on adenosine triphosphate (ADP)-, arachidonate (AA)- or collagen-induced platelet aggregation. In particular, (+/-)-cis-5-methoxy-6-methoxycarbonyl-2,2-dimethyl-3,4-ditiglyloxychr oman (CD-6), (+/-)-cis-5-methoxy-6-(2-methoxycarbonylethenyl)-2,2-dimethyl- 3,4-ditiglyloxychroman (CD-8), (+/-)-cis-3,4-diacetoxy-5-methoxy-2,2-dimethyl-6-propylchroman (CD-9) and (+/-)-cis-5-methoxy-2,2-dimethyl-6-propyl-3,4-ditiglyloxychroman (CD-10) showed a moderate inhibition of PAF-induced platelet aggregation. 3. From these findings, it is suggested that compounds with potent PAF antagonist activities have the following features: (i) a tiglyloxy moiety is required at the 3 and 4 positions; and (ii) the methoxy moiety is also required at the 5 position of chroman skeleton in khellactone.

Adenosine Diphosphate↗
PubMed1977

Oxidation products of N-methyl-2,2,7,8-tetramethyl-6-amino-chroman, a model compound of N-methyl-gamma-tocopheramine with potassium ferricyanide.

N-Methyl-2,2,7,8-tetramethyl-6-amino-chroman, a model compound of N-methyl-gamma-tocopheramine, was submitted to an oxidation study with alkaline potassium ferricyanide. As oxidative products, 2,2,7,8-tetramethyl-6-amino-chroman and dimeric (VI) were identified. Also, a trace of compound C which might be a azochroman was detected. It was concluded that an N radical formation is necessary to take the role of a biological antioxidant of N-methyl-gamma-tocopheramine.

Antioxidants↗
PubMed2004

Isolation and anti-fungal activities of 2-hydroxymethyl-chroman-4-one Produced by Burkholderia sp. MSSP.

In the course of screening for biological active compounds from microbial origins, various strains were isolated from roots of Mimosa pudica using standard dilution agar plate method. One isolate was selected for further studies of bacterial anti-fungal properties. It was designated MSSP and identified as Burkholderia sp. by many biological characteristics such as carbohydrate utilization, biochemical and physiological test and 16S rDNA sequence homology search. To investigate antagonistic principle, anti-fungal compounds were extracted and fractionated by different solvent systems. An anti-fungal compound was isolated from its culture filtrate using organic solvent extraction, column chromatography and thin layer chromatography and pure solid form compound (MSSP2) was obtained. The chemical structure of anti-fungal compound was identified as 2-Hydroxymethyl-chroman-4-one based on the data obtained from spectroscopic analysis such as mass spectral analyses and NMR spectral data. The compound 2-Hydroxymethyl-chroman-4-one exhibited good activities against phytopathogen such as Pythium ultimum, Phytophthora capsici and Sclerotinia sclerotiorum.

Antifungal Agents↗
PubMed1976

[Studies on screening for cholesterol-lowering agents using phenyl- and chromane substituted compounds (author's transl)].

Sixteen phenyl compounds and twenty chromane compounds substituted by geranoyl, farnesoyl, phytonoyl, retinoyl and linolenoyl synthesized by Eisai Co., Ltd were used. Male mice were fed a cholesterol or a normal basal diet which 0.3% compound was added for 10 or 31 days. Effect of these compounds on the cholesterol level of serum and liver were examined and compared to that of CPIB. As a results of this series of experiments hypocholesteremic agents were screened as follows: 3 phenyl compounds (N76009, N76011, N76012), and 6 chromane compounds (N-76-H-23, N-76-H-25, N-76-H-27, N-76-H-35, N-76-H-37, N-76-H-38). Among these compounds, N-76-H-38, (formula: see text) was found to be the most favorable cholesterol-lowering agent.

Animals↗
PubMed1997

N-(chroman-4-ylidene)aryloxyacetohydrazones: synthesis and antimicrobial activity.

In this study, some N-(chroman-4-ylidene)phenoxyacetohydrazone and N-(chroman-4-ylidene)phenoxyacetohydrazone compounds were synthesized. Structure of the compounds were identified by using IR, H NMR and MASS spectral data and by elemental analysis. Particularly, some compounds showed interesting antimycobacterial activities.

Anti-Bacterial Agents↗
PubMed1989

Polymorphism and crystal structure of 2R,4S,6-fluoro-2-methyl-spiro[chroman-4,4'-imidazoline]-2',5-dione (M79175).

Two polymorphic forms, alpha and beta, of 2R,4S,6-fluoro-2-methyl-spiro-[chroman-4,4'-imidazoline]-2',5-dione (1, M79175) were studied by X-ray crystallography and solid-state infrared spectroscopy. The molecular and crystal structures of the beta-form were determined by single-crystal X-ray diffraction analysis. The molecules in the beta-form crystal are arranged orderly along the b-axis, and the plate-like moieties (chroman ring) of 1 are stacked by van der Waals forces. The molecular packing structure of each crystalline form was investigated by comparing wave numbers of hydantoin rings from which solid-state infrared photoacoustic spectra (FT-IR-PAS) were obtained. From the FT-IR-PAS data of both forms, it became clear that the hydrogen bond in an alpha-form crystal is stronger than that in the beta-form crystal. The cohesion of the polymorphic crystal system is mainly due to hydrogen bonds and van der Waals forces. Based on the polymorphism of 1, it was clarified that thermodynamic stability depends on the mode of hydrogen bonding, while the enthalpy of fusion results from van der Waals forces.

Crystallization↗
PubMed1994

Anticonflict and discriminative stimulus effects in the pigeon of a new methoxy-chroman 5-HT1A agonist, (+)S 20244 and its enantiomers (+)S 20499 and (-)S 20500.

The present experiments examined the behavioral and receptor binding characteristics of new 5-HT1A methoxy-chroman derivatives in procedures known to be sensitive to the activity of 5-HT1A compounds. Key peck responding of pigeons was maintained by a 30-response fixed-ratio schedule of food delivery. In studies involving punished responding, every 30th response during one keylight stimulus also produced shock ("conflict" procedure). In drug discrimination studies, pigeons were trained to discriminate injections of the 5-HT1A agonist 8-OH-DPAT (0.3 mg/kg) from saline. Three forms of the methoxy-chroman compounds were tested: the enantiomers (+)S 20499 (0.01-3.0 mg/kg) and (-) S 20500 (0.3-5.6 mg/kg), as well as the racemic mixture (+)S 20244 (0.03-5.6 mg/kg). (+)S 20499 was approximately 10-fold more potent than (-)S 20500 in producing maximal increases in punished responding. (+)S 20244 was comparable in potency to (-)S 20500 in producing maximal increases in punished responding, but increases also occurred at much lower doses with (+)S 20244 and the magnitude of the effect with (-)S 20500 was less than that of the two other compounds. While increases in punished responding were observed with all three drugs at doses that did not affect unpunished responding, the highest doses of all drugs decreased unpunished responding. All compounds substituted for 8-OH-DPAT in the drug discrimination procedure, suggestive of 5-HT1A agonist activity. (+)S 20499 was approximately 30-fold more potent than (-)S 20500 in substituting for 8-OH-DPAT and 3-fold more potent than the racemate. All three compounds bound with high affinity to pigeon cerebrum receptor sites labelled by [3H]8-OH-DPAT. As in behavioral studies, (+)S 20499 was approximately 10-fold more potent than (-)S 20500 in displacing [3H]8-OH-DPAT (IC50 = 2.79 versus 20.3 nM). These studies demonstrate that the enantiomers of this compound, as well as the racemic mixture, are effective 5-HT1A compounds and that (+)S 20499 in particular is likely to be a clinically effective anxiolytic and/or antidepressant.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

N-[2-[(substituted chroman-8-yl)oxy]ethyl]-4-(4-methoxyphenyl)butylamines: synthesis and wide range of antagonism at the human 5-HT1A receptor.

A series of N-[2-[(substituted chroman-8-yl)oxy]ethyl]-4-(4-methoxyphenyl)butylamines was prepared and examined for their 5-HT1A receptor antagonist activity. The parent compound 3a and seven analogs bearing five kinds of substituents on the chroman ring were prepared from the corresponding 8-hydroxychroman intermediates. Radioligand binding assays proved the compounds 3a-h to have high affinity for the rat hippocampal 5-HT1A receptor with varied selectivity for adrenaline alpha1 and dopamine D2 receptors. Their antagonism was evaluated in a forskolin-stimulated adenylate cyclase assay performed with CHO cells expressing the human 5-HT1A receptor. Among the series, the C6-fluoro analog 3c showed both extremely potent affinity (Ki = 0.22 nM) and antagonism (EC50 = 13 nM) for the 5-HT1A receptor. Correlation analysis using substituent descriptors revealed a linear and negative correlation between molar refractivity of the C6-substituent and the binding affinity expressed in pKi.

Animals↗
PubMed2000

A potent aldose reductase inhibitor, (2S,4S)-6-fluoro-2', 5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide (Fidarestat): its absolute configuration and interactions with the aldose reductase by X-ray crystallography.

The absolute configuration of the aldose reductase (AR) inhibitor, (+)-(2S,4S)-6-fluoro-2',5'-dioxospiro¿chroman-4, 4'-imidazolidine-2-carboxamide (fidarestat), was established indirectly by single-crystal X-ray analysis of (+)-(2S, 4S)-8-bromo-6-fluoro-2',5'-dioxospiro¿chroman-4, 4'-imidazolidine-2-carboxylic acid (1). The crystal structure of human AR complexed with fidarestat was determined, and the specific inhibition activity was discussed on the basis of the three-dimensional interactions between them. The structure clarified that fidarestat was located in the active site by hydrophilic and hydrophobic interactions and that the carbamoyl group of fidarestat was a very effective substituent for affinity to AR and for selectivity between AR and aldehyde reductase (AHR). Explanations for the differences between the observed activities of fidarestat and its stereoisomer 2 were suggested by computer modeling.

Aldehyde Reductase↗