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The identification (by gas chromatography-mass spectrometry and n.m.r.) for the first time of the weak oestrogen equol [7-hydroxy-3-(4'-hydroxyphenyl)chroman] in human urine is described. Preliminary results of its quantitative excretion in urine are reported and the potential significance of the occurrence of this compound is discussed.
Investigation of a cytotoxic chloroform-soluble fraction of the stem of Casearia membranacea (Flacourtiaceae) led to the isolation of five new compounds, including one butenolide, casealactone (1), one chroman, caseamemin (2), two dolabellane diterpenoids, casearimene A (3) and casearimene B (4), one benzoquinol ether, casearinone (5), together with fifteen known compounds, including two amides, N- trans-feruloyltyramine (6) and N- cis-feruloyltyramine (7), six steroids, beta-sitosterol (8), stigmast-5-ene-3beta,7alpha-diol (9), stigmast-5-ene-3beta,7beta-diol (10), stigmastane-3beta,5alpha,6beta-triol (11), beta-sitostenone (12), beta-sitosterol 3- O-beta-glucoside (13), two triterpenoids, squalene (14) and friedelin (15), one lignan, (+/-)-syringaresinol (16), two benzenoids, syringaldehyde (17) and vanillic acid (18), one ester, methyl hexadecanoate (19), and anthraquinone (20), respectively. Among these isolates, 1 showed cytotoxicity against P-388 and HT-29 cancer cell lines in vitro, and 6 and 7 showed cytotoxicity against the P-388 cancer cell line. The structures of these compounds were determined by means of spectroscopic techniques, and the structure of 3 was confirmed by X-ray crystallographic analysis.
A series of chroman amide and nicotinyl amide derivatives was designed and synthesized for the treatment of traumatic and ischemic CNS injury. Five compounds were significantly more potent inhibitors of lipid peroxidation in vitro than the reference antioxidant, trolox (p < 0.01). Quantitative structure activity studies demonstrated that the inhibitory action was related to the ability to donate electrons, charge on hydroxy group and E(LUMO), to scavenging radicals and to the lipophilicity log P, which determines penetration of membrane lipids. ESR study indicated the ability of 12 to scavenge the hydroxyl radicals. The most promising compound, [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2yl)ca rbonyl]-3'-(aminoethyl) indole (12), inhibited ex vivo lipid peroxidation in a head injury model and showed potent in vivo neuroprotective efficacy. Improvement of neurological recovery within 1 h of injury (grip test score) by as much as 200% was observed together with significant anti-anoxia activity. Compound 12 was a potent antagonist of methamphetamine-induced hypermotility resulting from dopamine release in the mouse brain. These results support the importance of cerebroprotective radical-scavenging agents for the treatment of traumatic injury and anoxia as well as provide additional evidence for the role of oxygen radicals and dopamine in brain damage.
5-Methoxy-3-(di-n-propylamino)chroman (5-MeO-DPAC) caused a dose-dependent decrease in the accumulation of 5-hydroxytryptophan after decarboxylase inhibition in rat striatum, hippocampus and frontal cortex. The decreased 5-hydroxytryptamine (5-HT) turnover may have resulted from activation of 5-HT receptors on cell bodies of 5-HT neurons that project to the striatum and other brain regions, since 5-MeO-DPAC had earlier been reported to lack affinity for striatal binding sites.
Mutations in the KvLQT1 gene are the cause for the long QT syndrome [Circulation 94:1996-2012 (1996)]. Coexpression of KvLQT1 in association with the channel regulator protein IsK produces a K+ current with characteristics reminiscent of the slow component of the delayed rectifier in cardiac myocytes. We explored the pharmacological properties of trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dime thyl- chromane (293B), a chromanol compound, on the K+ current produced by direct intranuclear injection of KvLQT1 and IsK cDNA plasmids in COS-7 cells. Injected cells were recorded by means of the whole-cell and cell-attached patch-clamp configurations under chloride-free conditions. Cells injected with KvLQT1 cDNA alone exhibited a fast-activating outward K+ current, whereas cells coinjected with KvLQT1 plus IsK cDNAs exhibited a time-dependent outward current with slower activation kinetics. The chromanol 293B blocked the K+ current related to KvLQT1 expression in both the absence or presence of IsK. The IC50 value for 293B to block KvLQT1-related current was not significantly modified by the presence of IsK (9.9 microM in the absence of IsK versus 9.8 microM in its presence). The block produced by 293B was strongly voltage-dependent inasmuch as it was close to 0 at -80 mV and occurred during a depolarizing voltage step. The time constants for the drug to block the current were in the same order of magnitude as activation kinetics of the current. Kinetics for drug unblock at the holding potential were much faster, in the order of a few tenths of a msec. KvLQT1 currents recorded in the cell-attached configuration were also blocked by externally applied 293B, suggesting that the compound penetrated the cell to block the channel. Cromakalim, another chromanol compound, also blocked KvLQT1 currents. Our results show that the chromanol compound 293B is targeted to KvLQT1 channels but not to the IsK regulator.
The extract of Anemarrhenae Rhizoma (rhizomes of Anemarrhena asphodeloides BUNGE) showed neurotrophic activity toward rat pheochromocytoma (PC-12) cells. Bioassay-guided purification afforded four compounds, 2,6,4'-trihydroxy-4-methoxybenzophenone (1), 7-hydroxy-3-(4-hydroxybenzyl)chroman (2), broussonin B (3), and cis-hinokiresinol (4). Compounds 1-3 induced neurite outgrowth in PC-12 cells at concentration of 50 microg/ml, while 4 was less active. In addition, compounds 2-4 showed moderate inhibitory activities against a chymotrypsin-like activity of the proteasome.
(+)-trans-4-(3-dodecanoyl-2,4,6-trihydroxyphenyl)-7-hydroxy-2-(4- hydroxyphenyl)chroman (YM-26567-1), a novel natural product isolated from the fruit of Horsfieldia amygdaline, dose-dependently inhibited group II phospholipase A2 (PLA2) prepared from rabbit platelet with an IC50 value of 6.7 microM (4.6-9.6 microM, n = 4). In contrast to irreversible PLA2 inhibitors such as manoalide and p-bromophenacyl bromide, the PLA2 inhibition of YM-26567-1 was independent of preincubation time. Lineweaver-Burk analysis revealed that YM-26567-1 behaved as a competitive inhibitor of rabbit platelet PLA2 with a Ki value of 1.6 +/- 0.3 microM (n = 5). Although YM-26567-1 also competitively inhibited group I PLA2 derived from porcine pancreas, the Ki value was approximately 10-fold greater for porcine pancreas than for rabbit platelet PLA2. In vivo, topical application of YM-26567-1 to the mouse ear inhibited 12-O-tetradecanoylphorbol-13-acetate (1 micrograms/ear)-induced mouse ear edema in a dose-dependent manner with a 50% effective dose of 28 micrograms/ear (13-63 micrograms/ear, n = 10/dose), but did not improve arachidonic acid (4 mg/ear)-induced mouse ear edema at 1 mg/ear. These results suggest that YM-26567-1 is a competitive PLA2 inhibitor showing a higher affinity for group II than group I PLA2, and that it may act as a potent anti-inflammatory compound through its direct inhibition of PLA2.
In this study, some N'-(chroman-4-yliden)-4-aryl-2-thiazolylhidrazide derivatives were synthesized. Their structures were elucidated by IR, NMR and microanalyses. The vasodilatory activities of the compounds obtained were examined in vitro.
Polymorphic differences in alpha- and beta-form crystals of 2R, 4S, 6-fluoro-2-methyl-spiro[chroman-4,4'-imidazoline]-2',5-dione (M79175; 1) were studied by X-ray diffractometry, infrared spectroscopy, and differential scanning calorimetry. X-ray powder diffraction indicated the longest spacing of the unit cells to be 14.9 and 12.4 A for the alpha- and beta-form crystals, respectively. The infrared spectra showed the absorption band assigned to NH streching vibration for the alpha-form crystals to be centered at 3250 cm-1 and that for the beta-form crystals to split into two peaks, at 3150 and 3425 cm-1. The enthalpies of fusion were 26.3 kJ/mol at 517.5 K and 31.3 kJ/mol at 501.0 K, respectively. Transformation from the beta- to alpha-form was observed at various heating rates, which were enhanced by the presence of a small amount of alpha-form crystals previously added to the beta-form. The former appeared to serve as a source of nuclei for the growth of both forms. These results confirm that the alpha-form crystal is more stable than the beta-form.
The effects of a new aldose reductase inhibitor (ARI), (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-ca rboxamide (SNK-860), on the slowing of motor nerve conduction velocity (MNCV) and metabolic abnormalities in sciatic nerve were investigated in acute streptozotocin (STZ)-induced diabetic rats. MNCV in the diabetic rats was significantly slower 2 weeks after STZ injection. In the following 2 weeks, treatment with SNK-860 improved MNCV in a dose-dependent manner. The efficacy of 1 mg/kg SNK-860 was equipotent to that of 20 mg/kg sorbinil. Four weeks after STZ injection, increases in sorbitol levels, decreases in myo-inositol levels, and reductions in Na+, K(+)-adenosine triphosphatase (ATPase) activity were observed in sciatic nerves of diabetic rats. Administration of SNK-860 for 14 days beginning 2 weeks after the induction of diabetes inhibited these metabolic abnormalities in a dose-dependent manner. SNK-860 restored all of these parameters to normal levels at a dose of 2 mg/kg. In addition, close correlations were observed between MNCV and sorbitol levels (r = -.95) and between MNCV and myo-inositol levels (r = .93) in the sciatic nerve; a close correlation was also observed between sorbitol and myo-inositol levels in the sciatic nerve (r = -.86). Therefore, it is suggested that the effect of SNK-860 on the slowing of MNCV results from normalizing the above-mentioned metabolic abnormalities in the sciatic nerve of diabetics. Thus, SNK-860 may be useful in the treatment of diabetic neuropathy.
We studied the long-term effects of a new aldose reductase inhibitor, (2S,4S)-6-fluoro-2',5'-dioxospiro-[chroman-4,4'-imidazolidine]-2- carboxamide (SNK-860), on functional, biochemical, and structural changes in peripheral nerve of streptozotocin (STZ)-induced diabetic rats. During the experimental period of 26 weeks, the delayed motor-nerve conduction in diabetic rats was significantly prevented by SNK-860 treatment, and elevated sorbitol levels and reduced myo-inositol levels were normalized to 100% and 71% of control levels, respectively. Teased nerve fiber studies demonstrated that the frequency of abnormal fibers was significantly reduced in treated diabetic rats. Morphometric analysis of myelinated fibers also disclosed prevention of axonal atrophy, distorted axonal circularity and preservation of large-sized fibers following SNK-860 treatment. These results suggest that long-term treatment with SNK-860 has a beneficial preventive effect on the development of experimental diabetic neuropathy.
Based on the 7-OH-2-(aminomethyl)chroman dopamine D(2) template (2) is described the preparation and resolution of two bioisosteric analogues. The benzimidazol-2-one derivative (6) had similar affinity to the known indolone derivative (4).
A metal-free approach to chroman derivatives by the reaction of different allylphenyl ethers with Ipy2BF4 is described. The access to this frame, by direct cyclization of the starting materials, takes place smoothly. In addition, an unusual and selective sequence that comprises initial rearrangement and further cyclization could be accomplished, with temperature as an excellent element of control. The process can be extended to the synthesis of tetrahydroquinolines when using allylamines. Also, two cascade reactions, leading to relevant oxygen and nitrogen-containing skeletons, have been devised.
A stereoselective intramolecular 1,3-dipolar nitrone cycloaddition useful in the synthesis of chromanes is described. The reaction relies on the use of a chiral auxiliary on the nitrone partner. Key to the success of the reaction is the choice of auxiliary and the choice of Lewis acid catalyst. Utilizing an auxiliary with a pendant coordinating group, and Zn(OTf)(2) as the Lewis acid, diastereoselectivities up to 22:1 could be achieved.
A novel tandem reaction involving an oxa-Michael addition, followed by a Friedel-Crafts alkylation has been developed. This catalytic tandem reaction, which provides facile and efficient access to optically active functionalised chromanes, proceeds under the influence of bisoxazoline-based catalysts to give diastereomerically pure products in enantioselectivities up to 81% and excellent yields. The optimisation studies, the scope of the reaction, and a model that on the basis of PM3 calculations predicts the outcome of the reaction will be detailed.
1. Anti-inflammatory, analgesic, antipyretic and other pharmacological activities of a new chroman derivative, Centchroman, have been described.2. Centchroman was found to possess significant anti-inflammatory action in the carrageenin-induced oedema test in mice and rats. It inhibited granuloma formation in the cotton pellet test. The anti-arthritic activity was also evident in formaldehyde-induced arthritis and adjuvant-induced arthritis in rats.3. Centchroman had a lower ulcerogenic index than phenylbutazone.4. The mechanism of the anti-inflammatory action of Centchroman seemed to be independent of endogenous adrenocortical hormones or of its weak oestrogenic activity.5. Centchroman antagonized phenylquinone writhing and bradykinin-induced bronchospasm but was devoid of any antipyretic activity.
Swern oxidation of chromanol 1 led to ketone 3 with concomitant chlorination of the adjacent 4-position. Using Leuckart conditions, chromanone 2 was converted to enamine 5.--4-Bromochromene-3-carbaldehyde 8, which was obtained by Vilsmeier-Arnold reaction from 7, turned out to be a suitable intermediate for the insertion of the pyridone residue. 3-Chloro derivatives 16 and 19 resulted on heating the mesylate or tosylate with LiCl in DMF. Bromination of chromene 20 led to 21.--All compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats with a dose of 1 mg/kg.
The hypolipidemic properties of ethyl 6-chlorochroman-2-carboxylate (II), 6-phenylchroman-2-carboxylate (III) and 6-cyclohexylchroman-2-carboxylate (IV) were compared to clofibrate (I) in sucrose-fed fasted male Sprague-Dawley rats. All compounds were administered at doses of 0.2 and 0.4 mmol/kg, orally, twice daily for 7 consecutive days. In this model, II was a more effective hypocholesterolemic drug than clofibrate, whereas III and IV were inactive. Chlorochroman II, like clofibrate, decreased serum alpha-lipoprotein cholesterol and pre-beta-lipoprotein triglyceride concentrations and concomitantly increased serum beta-lipoprotein triglyceride concentrations. In clofibrate-treated rats, serum free cholesterol concentrations increased concurrent with a reduction in serum lecithin: cholesterol acyltransferase activity, but no such correlation was observed for II. Only II lowered liver cholesterol levels and increased liver triglyceride levels. No consistent inhibition of liver microsomal 3-hydroxy-3-methylglutaryl-CoA reductase activity was observed with these analogs. The observed changes in triglyceride and cholesterol concentrations among serum lipoproteins were of a greater magnitude after chlorochroman II and clofibrate administration to sucrose-fed rats than in our previous studies using chow-fed fasted rats. These data suggest that chloro-substitution at the 6-position of the phenylchroman ring is important for hypolipidemic activity of these cyclic clofibrate analogs.