- Kv1.3-blocking 5-phenylalkoxypsoralens: A new class of immunomodulators
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The lymphocyte potassium channel Kv1.3 is widely regarded as a promising new target for immunosuppression. To identify a potent small-molecule Kv1.3 blocker, we synthesized a series of 5-phenylalkoxypsoralens and tested them by whole-cell patch clamp. The
- Vennekamp, Julia,Wulff, Heike,Beeton, Christine,Calabresi, Peter A.,Grissmer, Stephan,Haensel, Wolfram,Chandy, K. George
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- Photo-protective effects of selected furocoumarins on β-pinene, R-(+)-limonene and γ-terpinene upon UV-A irradiation
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The effect of furocoumarins on terpene photo-oxidation under UV-A light was investigated. For this purpose, four furocoumarins (8-methoxypsoralen, bergapten, bergaptol, bergamottin) each at a level of 5%, was added to solutions of the terpenes β-pinene, R-(+)-limonene and γ-terpinene in ethanol followed by UV irradiation at 366 nm. Bergaptol and bergamottin were synthesized and fully elucidated by NMR spectroscopy. UV-induced transformation of all terpenes was substantially reduced in the presence of furocoumarins. Best photo-protection was observed for γ-terpinene with the addition of bergaptol, i.e. degradation was reduced by 73% compared to the neat substance over a time period of ten days. Bergamottin (50.2%), bergapten (39.8%) and 8-methoxypsoralen (39.6%) also reduced degradation substantially. The protective effect of bergaptol was even noticeable at low concentrations of 0.1%. The main oxidation product of γ-terpinene was p-cymene. Limonene and β-pinene showed a predominated hydroperoxide formation under UV light which could almost completely prevented in the presence of furocoumarins. The protective effect of furocoumarins was presumably due to energy dissipation as a result of the conversion of high energetic radiation (UV-A) into visible light via fluorescence. Phosphorescence or self-quenching within the triplet state were further mechanisms avoiding reactions of excited furocoumarins with the terpenes under investigation. Hence, the photo-stability of the furocoumarins themselves correlated with the extent of their protective effect on all three terpenes.
- Bitterling, Hannes,Kammerer, Dietmar R.,Lorenz, Peter,Stintzing, Florian C.,Vetter, Walter
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- AChE/BACE1/GSK-3beta three-target inhibitor, preparation method thereof and application of AChE/BACE1/GSK-3beta three-target inhibitor in resisting Alzheimer disease
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The invention relates to an AChE/BACE1/GSK-3beta three-target inhibitor, a preparation method of the AChE/BACE1/GSK-3beta three-target inhibitor and application of the AChE/BACE1/GSK-3beta three-target inhibitor in resisting Alzheimer's disease, and the A
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Paragraph 0060-0063
(2021/08/07)
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- Syntheses and evaluation of the antioxidant activity of novel methoxypsoralen derivatives
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A series of 5- and 8-methoxypsoralen (MOP) analogs, suitable for structure-antioxidative/anti-inflammatory activity relationship studies, were synthesized using as key-reactions the selective monobromination of MOPs with N-bromosaccharin and either a Heck reaction or a Suzuki coupling or a Suzuki coupling followed by a Wittig reaction to install side-chains of the acrylate- or benzoate- or cinnamate-type, respectively. The 8-MOP analogs 19 and 24, incorporating at position 5 of the psoralen nucleus a butyl acrylate or a tert-butyl cinnamate moiety, were the most powerful inhibitors of soybean LOX and inhibited effectively lipid peroxidation. Analog 19 was a more potent anti-inflammatory agent than the reference compound indomethacin and of comparable cytocompatibility to 8-MOP whereas analog 24 was a weaker inhibitor of inflammation than indomethacin and significantly more cytotoxic than 8-MOP. The results of the biological tests are discussed in terms of structural characteristics.
- Bariamis, Stavros E.,Marin, Marilena,Athanassopoulos, Constantinos M.,Kontogiorgis, Christos,Tsimali, Zinovia,Papaioannou, Dionissios,Sindona, Giovanni,Romeo, Giovanni,Avgoustakis, Konstantinos,Hadjipavlou-Litina, Dimitra
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p. 155 - 169
(2013/04/10)
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- Structure-activity relationships for naturally occurring coumarins as β-secretase inhibitor
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The present study was demonstrated to evaluate the effects of naturally occurring coumarins (NOCs) including simple coumarins, furanocoumarins, and pyranocoumarins on the inhibition of β-secretase (BACE1) activity. Of 41 NOCs examined, some furanocoumarins inhibited BACE1 activity, but simple coumarins and pyranocoumarins did not affect. The most potent inhibitor was 5-geranyloxy-8-methoxypsoralen (31), which has an IC50 value of 9.9 μM. Other furanocoumarin derivatives, for example, 8-geranyloxy-5- methoxypsoralen (35), 8-geranyloxypsoralen (24), and bergamottin (18) inhibited BACE1 activity, with the IC50 values 25.0 μM. Analyses of the inhibition mechanism by Dixon plots and Cornish-Bowden plots showed that compounds 18, 31 and 35 were mixed-type inhibitor. The kinetics of inhibition of BACE1 by coumarins 24 was non-competitive inhibitors.
- Marumoto, Shinsuke,Miyazawa, Mitsuo
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supporting information; experimental part
p. 784 - 788
(2012/03/22)
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- Substituted 5-alkoxypsoralens as inhibitors of potassium channel activity in lymphocytes and other cells
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Compositions of matter comprising 5-phenylalkoxypsoralen compounds and their method of synthesis and use. The compounds are useable to treat diseases or disorders in human or veterinary patients, including autoimmune diseases such as multiple sclerosis. T
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Page/Page column 5-6
(2010/08/11)
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- Minor furanocoumarins and coumarins in grapefruit peel oil as inhibitors of human cytochrome P450 3A4
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A new cyclic acetal (1) of marmin (6′,7′-dihydroxy-7- geranyloxycoumarin), two new cyclic acetals (5, 6) of 6′,7′- dihydroxybergamottin, and the known compounds marmin (2), 7-geranyloxycoumarin (3), bergamottin (4), and 6′,7′-dihydroxybergamottin (7) were
- Cesar, Thais B.,Manthey, John A.,Myung, Kyung
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body text
p. 1702 - 1704
(2010/03/31)
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- Design, synthesis and evaluation of furanocoumarin monomers as inhibitors of CYP3A4
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A number of furanocoumarins isolated from grapefruit juice have been found to inhibit CYP3A4 activity in vitro. In this study, we have designed and synthesised a range of analogues based on bergamottin to investigate the relationship between chemical stru
- Row,Brown,Stachulski,Lennard
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p. 1604 - 1610
(2008/02/03)
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- Design of PAP-1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory t cells in autoimmune diseases
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The lymphocyte K+ channel Kv1.3 constitutes an attractive pharmacological target for the selective suppression of terminally differentiated effector memory T (TEM) cells in T cell mediated autoimmune diseases, such as multiple sclerosis and type 1 diabetes. Unfortunately, none of the existing small molecule Kv1.3 blockers is selective, and many of them, such as correolide, 4-phenyl-4-[3-(methoxyphenyl)-3-oxo-2- azapropyl] cyclohexanone, and our own compound Psora-4 inhibit the cardiac K+ channel Kv1.5. By further exploring the structure activity relationship around Psora-4 through a combination of traditional medicinal chemistry and whole-cell patch-clamp, we identified a series of new phenoxyalkoxypsoralens that exhibit 2- to 50-fold selectivity for Kv1.3 over Kv1.5, depending on their exact substitution pattern. The most potent and "druglike" compound of this series, 5-(4-phenoxybutoxy)psoralen (PAP-1), blocks Kv1.3 in a use-dependent manner, with a Hill coefficient of 2 and an EC50 of 2 nM, by preferentially binding to the C-type inactivated state of the channel. PAP-1 is 23-fold selective over Kv1.5, 33- to 125-fold selective over other Kv1-family channels, and 500- to 7500-fold selective over Kv2.1, Kv3.1, Kv3.2, Kv4.2, HERG, calcium-activated K+ channels, Na+, Ca2+, and Cl- channels. PAP-1 does not exhibit cytotoxic or phototoxic effects, is negative in the Ames test, and affects cytochrome P450-dependent enzymes only at micromolar concentrations. PAP-1 potently inhibits the proliferation of human TEM cells and suppresses delayed type hypersensitivity, a TEM cell-mediated reaction, in rats. PAP-1 and several of its derivatives therefore constitute excellent new tools to further explore Kv1.3 as a target for immunosuppression and could potentially be developed into orally available immunomodulators. Copyright
- Schmitz, Alexander,Sankaranarayanan, Ananthakrishnan,Azam, Philippe,Schmidt-Lassen, Kristina,Homerick, Daniel,Haensel, Wolfram,Wulff, Heike
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p. 1254 - 1270
(2007/10/03)
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- SYNTHESIS OF SPIRO ORTHO ESTERS, SPIRO ORTHO CARBONATES, AND INTERMEDIATES
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Ortho esters and ortho carbonates can be produced by alkylating esters and carbonates with, for example, the hexafluorophosphate salt of a trialkyl oxonium ion. The spiro species are useful intermediates in the synthesis of complex organic molecules. Synt
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- Synthesis and biological evaluation of 6',7'-dihydroxybergamottin (6,7-DHB, a naturally occurring inhibitor of cytochrome P450 3A4
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The recently isolated inhibitor of cytochrome P450 CYP3A4, 6',7'-dihydroxybergamottin (6,7-DHB), was synthesized by an efficient route that is readily adaptable to the production of analogues. The compound was evaluated as an inhibitor of 3A4 in a purified enzyme preparation, as well as against human liver microsomes and human 3A4 expressed in Escherichia coil membrane. In each case, 6,7-DHB proved to be a potent NADPH- and time dependent inactivator of 3A4.
- Bellevue III, Frank H.,Woster, Patrick M.,Edwards, David J.,He, Kan,Hollenberg, Paul F.
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p. 2593 - 2598
(2007/10/03)
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- MONOTERPENOID FURANOCOUMARIN LACTONES FROM CLAUSENA ANISATA
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A reinvestigation of Clausena anisata has yielded imperatorin, xanthotoxol, lansamide-I and three new furanocoumarin lactone derivatives: indicolactone, anisolactone and 2',3'-epoxyanisolactone.The structures of these compounds have been elucidated by a combination of spectroscopic and chemical methods.Key Word Index - Clausena anisata; Rutaceae; furanocoumarin lactone derivatives; indicolactone; anisolactone; 2',3'-epoxyanisolactone.
- Lakshmi, Vijai,Prakash, Dhan,Raj, Kanwal,Kapil, Randhir S.,Popli, Satya P.
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p. 2629 - 2632
(2007/10/02)
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- THE COUMARIN COMPOSITION OF Seseli tortuosum
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The results are given of the identification of the known pyranocoumarin campestrinol (I), and the structures of four new coumarin derivatives have been studied - tortuosin (II), tortuosinin (III), tortuosinol (IV), and tortuosidin (V).On the basis of their spectral characteristics and chemical transformations, the corresponding structures have been established for compounds (II)-(V).
- Abyshev, A. Z.,Abyshev, D. Z.
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p. 668 - 672
(2007/10/02)
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- 5-Oxy-substituted derivatives of Psoralene useful in dermatology
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An improved process for obtaining 5-methoxy-psoralene from bergamot oil, a method for preparing the compound 5-hydroxy-psoralene from 5-methoxy-psoralene and a method of making novel psoralene derivatives by replacing the hydrogen atom of the 5-hydroxy group with an R group are disclosed. These compounds are prepared by reacting the 5-hydroxy-psoralene with a halide RX in the presence of sodium hydride. Compounds of particular interest are those of which the radical R is: alkanoyl of not more than 10 carbon atoms; orthoacetoxy-benzoyl; αthenoyl; O,O diethyl-phosphono; diethylaminoethyl, and 2'3'4'6' tetra α acetyl D-gluco pyranosyl.
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