- Synthesis and properties of peptide nucleic acids containing a psoralen unit.
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We prepared the psoralen PNA unit from 8-methoxypsoralen and synthesized various PNAs containing psoralen by a typical (t)()Boc method. PNAs containing psoralen (P-PNA) at strand end formed a stable duplex with complementary DNA. The hybridization of P-PNA with complementary DNA resulted in a considerable decrease of the psoralen fluorescence.
- Okamoto,Tanabe,Saito
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- Synthesis of 8-geranyloxypsoralen analogues and their evaluation as inhibitors of CYP3A4
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Furanocoumarins have been shown to inhibit CYP3A4 in vitro with varying degrees of potency [Pharmacogenetics 1997, 7, 391-396; Chem. Res. Toxicol. 1998, 11, 252-259; Drug Metab. Dispos. 1997, 25, 1228-1233; Br. J. Pharmacol. 2000, 130, 1369-1377]. In this study, we report the effects of a series of novel furanocoumarins based on the naturally occurring derivative 8-geranylepoxypsoralen which has been shown to be a more potent inhibitor of CYP3A4 than its 5-position-substituted counterpart bergamottin [Drug Metab. Dispos. 2000, 28, 766-771; Jpn. J. Pharmacol. 2000, 82, 122-129]. Compounds were designed, synthesised and tested for their ability to inhibit CYP3A4 activity in human liver microsomes using testosterone as the marker substrate. Both the saturated and unsaturated phenolic furanocoumarin derivatives were found to be inactive. However, the 8-alkyloxy-furanocoumarin analogues were shown to inhibit CYP3A4 activity in a dose dependent manner, with IC50 values ranging from 0.78 ± 0.11 to 3.93 ± 0.53 μM. The reduced furan derivative dihydro-8-geranyloxypsoralen showed a 4-fold decrease in inhibitory potency, suggesting that the furan moiety plays a role in the interaction between these compounds and CYP3A4.
- Row,Brown,Stachulski,Lennard
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- Efficient cleavage of DNA by iron(III) triazacyclononane derivatives
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Compounds based on (1,4,7-trimethyl-1,4,7-triazacyclononane)iron(III) chloride have been synthesized. Exceedingly low concentrations (approximately 0.5 μM) of these reagents are required to effect single-stranded oxidative cleavage of plasmid DNA at physiological pH and temperature. Approximately 3 breaks per plasmid per micromolar of reagent occur in 1 h at 37°C. The addition of dithiothreitol dramatically increased the effectiveness of these compounds; only 0.05 μM of reagent was required for DNA cleavage. When psoralen (a DNA photocross-linking agent) was attached to the iron complex, irradiation further increased the cleavage efficiency. The DNA cleaving abilities rival those of the cytotoxic antitumor drug bleomycin. Unlike bleomycin, the synthetic agents cut DNA with little sequence specificity. The lability of the chloride ligands, the hard acid character of iron(III), and the absence of base specificity in the DNA cleaving reaction suggest that a cationic iron species binds to the phosphate backbone of DNA. The reaction's dependence on reductants and dissolved oxygen suggests that it proceeds by a redox mechanism. Crystals of (1,4,7-trimethyl-1,4,7-triazacyclononane)FeCl3 (L'FeCl3) belong to the monoclinic space group P21/c, with a = 12.321(2) A?, b = 7.3220(10) A?, c = 15.903(3) A?, V = 1434.7(5) A?3, and Z = 4 at 293 K. Refinement of 145 least squares parameters for 2613 independent reflections with F > 4.0σ(F) converged to R = 3.43% and R(w) = 6.45%. The coordination geometry around iron(III) approximates a trigonally distorted octahedron. The N-Fe-N bond angles (77.8°-78.8°) are compressed, while the Cl-Fe-Cl angles (96.7°-97.0°) are expanded from the octahedral value.
- Silver, Gail C.,Trogler, William C.
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- Noncovalent attachment of psoralen derivatives with DNA: Hartree-Fock and density functional studies on the probes.
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Two psoralen derivatives (probes) were prepared. Their geometries were optimized at the Hartree-Fock (HF) and Density Functional (B3LYP) levels employing 6-31G** and cc-pVDZ basis sets. Their interaction with DNA was investigated using spectrophotometric and computational techniques. Both of them have shown strong binding to calf thymus DNA. The red-shift and hypochromism that detected in the spectrum were taken as an evidence for the strong interaction between these probes and DNA. The spectrophotometric DNA titration data were treated by two different methodologies to calculate the intercalation affinity. Half-reciprocal plots gave binding constants of 5.5065 x 10(4) and 6.4727 x 10(4) for 8-butoxypsoralen (8-BOP) and 8-hexoxypsoralen (8-HOP), respectively. Schatchard plots gave a comparable intercalation binding constants and also the surface binding constants along with the number of intercalated probe molecules per base pair. The interaction between these probes and DNA were studied theoretically. The energy of interaction was computed using molecular mechanics method. Strength of interaction of these probes with different types of DNA was computed and compared. Calculated energies of interaction were compared with the observed intercalation affinities. HOMO and LUMO energies were computed and used to account for the strength of interaction.
- El-Gogary, Tarek M,El-Gendy, Eman M
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- A clickable psoralen to directly quantify DNA interstrand crosslinking and repair
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DNA interstrand crosslinks (ICLs) represent physical obstacles to advancing replication forks and transcription complexes. A range of ICL-inducing agents have successfully been incorporated into cancer therapeutics. While studies have adopted UVA-activated psoralens as model ICL-inducing agents for investigating ICL repair, direct detection of the lesion has often been tempered by tagging the psoralen scaffold with a relatively large reporter group that may perturb the biological activity of the parent psoralen. Here a minimally-modified psoralen probe was prepared featuring a small alkyne handle suitable for click chemistry. The psoralen probe, designated 8-propargyloxypsoralen (8-POP), can be activated by UVA in vitro to generate ICLs that are susceptible to post-labeling with an azide-tagged fluorescent reporter via a copper-catalyzed reaction. A modified alkaline comet assay demonstrated that UVA-activated 8-POP proficiently generated ICLs in cells. Cellular 8-POP-DNA lesions were amenable to click-mediated ligation to fluorescent reporters in situ, which permitted their detection and quantitation by fluorescence microscopy and flow cytometry. Small molecule DNA repair inhibitors to 8-POP-treated cells attenuated the removal of 8-POP-DNA lesions, validating 8-POP as an appropriate probe for investigating cellular ICL repair. The post-labeling strategy applied in this study is inexpensive, rapid and highly modular in nature with the potential for multiple applications in DNA repair studies.
- Evison, Benjamin J.,Actis, Marcelo L.,Fujii, Naoaki
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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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- Synthesis and In Vitro Biological Evaluation of Psoralen-Linked Fullerenes
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Photodynamic therapy (PDT) is a widely used medicinal treatment for the cancer therapy that utilizes the combination of a photosensitizer (PS) and light irradiation. In this study, we synthesized two novel C60 fullerene derivatives, compounds 1 and 2, with a psoralen moiety that can covalently bind to DNA molecules via cross-linking to pyrimidine under photoirradiation. Along with several fullerene derivatives, the biological properties of several novel compounds have been evaluated. Compounds 1 and 2, which have been shown to induce the production of hydroxyl radicals using several ROS detecting reagents, induced DNA strand breaks with relatively weak activities in the in vitro detection system using a supercoiled plasmid. However, the psoralen-bound fullerene with carboxyl groups (2) only showed genotoxicity in the genotoxicity assay system of the umu test. Compound 2 was also seen to have cytotoxic activities in several cancer cell lines at higher doses compared to water-soluble fullerenes.
- Hashimoto, Akiko,Takamura-Enya, Takeji,Oda, Yoshimitsu
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- WAMPETIN, A FUROCOUMARIN FROM CLAUSENA WAMPI
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A new furocoumarin wampetin has been isolated from Clausena wampi (syn.Clausena lansium).The structure was established from 1H NMR, 13C NMR, MS and chemical data. - Key Word Index: Clausena wampi (Syn.Clausena lansium); Rutaceae; wampetin; furocoumarin; 13C NMR data.
- Khan, Nizam U.,Naqvi, S. W. I.,Ishratullah, Khwaja
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- Biotransformation of isoimperatorin and imperatorin by Glomerella cingulata and β-secretase inhibitory activity
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Biotransformation studies conducted on the furanocoumarins isoimperatorin (1) and imperatorin (3) have revealed that 1 was metabolized by Glomerella cingulata to give the corresponding reduced acid, 6,7-furano-5-prenyloxy hydrocoumaric acid (2), and 3 was transformed by G. cingulata to give the dealkylated metabolite, xanthotoxol (4) in high yields (83% and 81%), respectively. The structures of the new compound 2 have been established on the basis of spectral data. The metabolites 2 and 4 were tested for the β-secretase (BACE1) inhibitory activity in vitro, and metabolite 2 slightly inhibited the β-secretase activity with an IC50 value of 185.6 ± 6.8 μM. The metabolite 4 was less potent activity than compounds 1-3. In addition, methyl ester (2Me), methyl ether (2a) and methyl ester and ether (2aMe) of 2 were synthesized, and investigated for the ability to inhibit β-secretase. Compound 2aMe exhibited the best β-secretase inhibitory activity at the IC50 value 16.2 ± 1.2 μM and found to be the 2aMe showed competitive mode of inhibition against β-secretase with Ki value 11.3 ± 2.8 μM.
- Marumoto, Shinsuke,Miyazawa, Mitsuo
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- Design, synthesis, and evaluation of new series of Imperatorin analogs with potential vasodilatory activity
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Two series of imperatorin analogs were synthesized based on our previous research and evaluated for their vasodilatation activities on in vitro rat mesenteric artery, basilar artery, and renal artery ring models. Target compounds were characterized by infrared, 1H NMR, and mass spectra. Most derivatives possessed significant vasodilatory activity on the mesenteric artery, and compound 3a exhibited favorable and broad vasodilatation activities on three kinds of rat artery ring models. The pharmacological results indicated that introducing nitrogen-contained ring in side chain or large steric hindrance at the distal end could increase the vasodilatory activity. Further, replacement of oxygen atom (–O–) in the skeleton of furocoumarin derivatives with nitrogen (–NH–) could cause the decrease of vasodilatory activity. The molecular docking also indicated that compound 3a showed a best affinity with α-1C receptor (PDB ID: 3G43). All these results suggested compound 3a would be a potential vasodilatory agent for hypertension.
- Hou, Ya-Jing,Wang, Cheng,Wang, Tao,Huang, Li-Min,Lin, Yuan-Yuan,He, Huai-Zhen
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- Trideuteromethylation Enabled by a Sulfoxonium Metathesis Reaction
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A conceptually novel sulfoxonium metathesis reaction between TMSOI and cost-effective DMSO-d6 is developed for the efficient generation of a new trideuteromethylation reagent TDMSOI. The new reagent TDMSOI is produced highly efficiently by simply heating a mixture of TMSOI and DMSO-d6 and directly used for subsequent trideuteromethylation in a "one-pot" operation. The preparative power of the new versatile reagent and the "one-pot" protocol is demonstrated by its use to install the ?CD3 moiety into broad functionalities including phenols, thiophenols, acidic amines, and enolizable methylene units in high yield and at a useful level of deuteration (>87% D).
- Shen, Zuyuan,Zhang, Shilei,Geng, Huihui,Wang, Jiarui,Zhang, Xinyu,Zhou, Anqi,Yao, Cheng,Chen, Xiaobei,Wang, Wei
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supporting information
p. 448 - 452
(2019/01/14)
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- Structural modifier of 8-methoxypsoralen as well as preparation method and application of structural modifier
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The invention discloses a structural modifier of 8-methoxypsoralen as well as a preparation method and application of the . The structural modifier of the 8-methoxypsoralen provided by the invention is a compound B20 shown as a formula 1 or a compound A10 shown as a formula 2. The bacteriostatic activity of the compound B20 for enterotoxigenic escherichia coli at the concentration of 64 mu g/mL is2.3 times of that of the 8-methoxypsoralen; the bacteriostatic activity of the compound A10 for enterotoxigenic escherichia coli at the concentration of 64 mu g/mL is 2.4 times of the 8-methoxypsoralen. The compound B20 and the compound A10 can be applied to the preparation of a medicament for treating and/or preventing piglet diarrhea. The formula 1 and the formula 2 are shown in the description.
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Paragraph 0076; 0084; 0086-0087
(2019/04/04)
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- A biphenyl type furocoumarin compounds and its preparation method and application
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The invention discloses a biphenyl furocoumarin compound and a preparation method and an application thereof; the provided biphenyl furocoumarin compound is a new compound with vasodilating activity, which is obtained by modifying and optimizing the structure based on a natural product imperatorin, reserving the pharmacological activity, improving the physicochemical property and enhancing the druggability. The preparation method of the biphenyl furocoumarin compound provided by the invention has the advantages of easily-obtained material source, mild reaction conditions, simple operation in reaction process, and cheap and easily-obtained reagents. The prepared biphenyl furocoumarin compound is a ramification of the imperatorin and has the effect similar to the imperatorin; an in vitro vascular ring tension research shows that the biphenyl furocoumarin compound has a relaxant effect on the mesenteric microvessels of rats, so that the biphenyl furocoumarin compound can be applied to preparing antihypertensive drugs.
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Paragraph 0046; 0047; 0048; 0049; 0050
(2017/07/14)
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- Design and synthesis of new triazoles linked to xanthotoxin for potent and highly selective anti-gastric cancer agents
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Two series of xanthotoxin-triazole derivatives were designed, synthesized, and studied for their antiproliferative properties. The in vitro cytotoxicity of the compounds in the AGS cancer cell line and the L02 normal cell line was evaluated via MTT assay. Among the synthesized compounds, 9-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-7H-furo[3,2-g]chromen-7-one (6p) was found to have the greatest antiproliferative activity against AGS cells (IC50 = 7.5 μM) and showed better activity than the lead compound (xanthotoxin, IC50 > 100 μM) and the reference drug (5-fluorouracil, IC50 = 29.6 μM) did. The IC50 value of 6p in L02 cells was 13.3 times higher than that in the AGS cells. Therefore, the compound exhibited better therapeutic activity and specificity compared with the positive control 5-fluorouracil. Cell cycle analysis revealed that compound 6p inhibited cell growth via the induction of S/G2 phase arrest in AGS cells. Compound 6p was identified as a promising lead compound for the further development and identification of 1,2,3-triazole-based anticancer agents.
- Shen, Qing-Kun,Liu, Chuan-Feng,Zhang, Hong-Jian,Tian, Yu-Shun,Quan, Zhe-Shan
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supporting information
p. 4871 - 4875
(2017/09/27)
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- Synthesis and evaluation of linear furanocoumarins as potential anti-breast and anti-prostate cancer agents
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A series of 22 furanocoumarin derivatives were synthesized and evaluated for cytotoxicity against breast cancer (MCF-7 and MDA-MB-231) and prostate cancer (PC-3) cell lines along with normal cell line. Several analogs were synthesized by replacing prenyl moiety with alkyl, aromatic, and heteroaromatic functionality to study the structure-activity relationship. Compounds 20 and 22 with adamantoylamino, diprenylamino and substituted benzene sulfonamide substituents showed potent antiproliferative activity in MCF-7 cell line with IC50 values of 0.48 and 0.53 μM, respectively. Both the compounds showed higher IC50 value in MCF-10A cell lines indicating nontoxicity in normal cell lines.
- Chauthe, Siddheshwar K.,Mahajan, Shivani,Rachamalla, Mahesh,Tikoo, Kulbhushan,Singh, Inder P.
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p. 2476 - 2484
(2015/02/19)
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- Design, synthesis and evaluation of 9-hydroxy-7H-furo [3,2-g]chromen-7-one derivatives as new potential vasodilatory agents
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Two new 9-hydroxy-7H-furo[3,2-g]chromen-7-one derivatives were designed, synthesized and evaluated for their in vitro vasodilatory activity. The structures of two compounds were elucidated by infrared, 1H NMR, and mass spectral data. The invitro pharmacological evaluation indicated that both of them possessed well vasodilatory activity compared with imperatorin. The molecule docking also showed two target compounds docked well with L-calcium channel (PDB code: 3G43). The result suggested that they would be potential vasodilatory agents for hypertension.
- Wang, Cheng,Wang, Tao,Zhou, Nan,Pan, Xiao-Yan,He, Huai-Zhen
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p. 304 - 311
(2014/02/14)
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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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- Novel porphyrin-psoralen conjugates: Synthesis, DNA interaction and cytotoxicity studies
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A Cu(i)-catalyzed azide-alkyne cycloaddition reaction (CuAAC) has been utilized to prepare novel triazole-linked cationic porphyrin-psoralen conjugates that exhibited significant photocytotoxicity against A549 cancer cells (IC 50 = 84 nM).
- Kumar, Dalip,Mishra, Bhupendra A.,Chandra Shekar,Kumar, Anil,Akamatsu, Kanako,Kurihara, Ryohsuke,Ito, Takeo
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supporting information
p. 6675 - 6679
(2013/10/01)
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- Design, synthesis, and vasorelaxation activity of novel imperatorin derivatives
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In this study, a series of novel imperatorin derivatives 7a-7e were designed and synthesized. Their vasorelaxation activities were evaluated by the pharmacological experiments in vitro. Most of the tested compounds exhibited better water solubility and vasorelaxation activity in different degrees, especially 7b and 7c with EC50 values of 2.29 and 2.63 μM, respectively on mesenteric artery, 7d and 7e with EC50 values of 1.04 and 2.65 μM, respectively on brain artery. The results indicated that these novel compounds have a potential interest for the development of novel and potent vasorelaxant agents for different kinds of arteries.
- Zhou, Nan,He, Jian-Yu,Wang, Tao,Zhang, Jie,He, Huai-Zhen
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p. 650 - 657
(2013/07/26)
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- Synthesis of imperatorin analogs and their evaluation as acetylcholinesterase and butyrylcholinesterase inhibitors
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In this study, we synthesized several imperatorin analogs using imperatorin and xanthotoxin as substrates. The anti-cholinesterase activities of all compounds were evaluated in in vitro experiments according to the modified Ellman's method. For each synthesized compound, IC50 values for both enzymes were established. Galantamine hydrobromide was used as a positive control in the enzymatic experiments. All active compounds showed selectivity toward butyrylcholinesterase (BuChE) rather than acetylcholinesterase. The most active ones were 8-(3-methylbutoxy)-psoralen and 8-hexoxypsoralen with IC 50 values for BuChE of around 16.5 and 16.4 μM, respectively. The results of our study may be considered as the beginning of a search for potential anti-Alzheimer's disease drugs based on the structure of natural furocoumarins. Several imperatorin analogs were synthesized using imperatorin and xanthotoxin as substrates. Their anti-cholinesterase activities were evaluated, and all active compounds showed selectivity toward butyrylcholinesterase (BuChE) rather than acetylcholinesterase. The most active compounds were 8-(3-methylbutoxy)-psoralen and 8-hexoxypsoralen with IC 50 values for BuChE of around 16.5 and 16.4 μM, respectively.
- Granica, Sebastian,Kiss, Anna K.,Jaronczyk, Malgorzata,Maurin, Jan K.,Mazurek, Aleksander P.,Czarnocki, Zbigniew
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p. 775 - 782
(2013/12/04)
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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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- Design, Synthesis and Preliminary Evaluation of Novel Imperatorin Derivatives as Vasorelaxant Agents
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A series of novel imperatorin derivatives were synthesized from commercially available xanthotoxin. The in vitro pharmacological evaluation indicated that all of the compounds possessed potent vasodilatory activity. Among them, compounds (5b), (5d) and (5e) exhibited higher vasdilatory activity (with EC50 values of 0.68 μM, 0.59 μM and 0.49 μM, respectively) than imperatorin (EC50 = 1.12 μM). The program Volsurf was used to predict the derivatives' ADMErelevant descriptors. The results suggested that these novel compounds had a potential interest for the development of novel and potent vasorelaxant agents.
- Li, Na,He, Jianyu,Zhan, Yingzhuan,Zhou, Nan,Zhang, Jie
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experimental part
p. 18 - 23
(2012/01/11)
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- Psoralenquinones as a novel class of proteasome inhibitors: Design, synthesis and biological evaluation
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Proteasome subunit specificity: Psoralenquinones were identified as a novel class of nonpeptide proteasome inhibitors. Depending on the scaffold decoration, these compounds demonstrate interesting subunit specificity. Interactions with Thr1, Thr21 and Ser129 are critical for inhibition.
- Marzaro, Giovanni,Gandin, Valentina,Marzano, Christine,Guiotto, Adriano,Chilin, Adriana
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scheme or table
p. 996 - 1000
(2012/01/06)
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- Structural modification of a specific antimicrobial lead against Helicobacter pylori discovered from traditional Chinese medicine and a structure-activity relationship study
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Psoralen (1a) was found to be a specific and potent antimicrobial lead against Helicobacter pylori (H. pylori) from a traditional Chinese medicine (TCM) in the bioassay directed isolation. A series of structurally diverse analogues of 1a were thus designed and synthesized to improve the antimicrobial potency, some of which showed more potent activities than the lead compound (1a) against H. pylori. Among them, compound 25a is 16-fold stronger (MIC = 0.39 μg/mL) than 1a (MIC = 6.25 μg/mL), and is even potent than the positive control metronidazole (MIC = 0.50 μg/mL). The in vitro antimicrobial activities against H. pylori of these structurally diverse analogues based on the scaffold of 1a have also led to an outline of structure-activity relationship.
- Zhang, Bang-Le,Fan, Cheng-Qi,Dong, Lei,Wang, Fang-Dao,Yue, Jian-Min
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supporting information; experimental part
p. 5258 - 5264
(2011/01/04)
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- Synthesis and antidepressant-like action of 9-alkoxy-7H-furo[3,2-g]chromen- 7-ones in mice
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The present study describes the chemical synthesis and pharmacological evaluation of a series of 9-alkoxy-7H-furo[3,2-g]-chromen-7-ones. The pharmacological results of these compounds show that nine of them, given orally, reduced the immobility time in the forced swimming test. The results of the open-field test further confirmed that these compounds possessed an antidepressant-like effect. In the 5-hydroxytryptophan induced head-twitch test, 9-(3-chlorobenzyloxy)-7H-furo[3,2-g]chromen-7-one (3m, 40 mg/kg p.o.) significantly increased the cumulative number of head twitches. This finding suggested that the antidepressant-like profile seems to involve the serotonergic system as underlying mechanism. ECV · Editio Cantor Verlag.
- Deng, Xian-Qing,Wei, Cheng-Xi,Song, Ming-Xia,Quan, Zhe-Shan
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experimental part
p. 587 - 592
(2011/05/11)
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- Biotransformation of bergapten and xanthotoxin by glomerella cingulata
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The biotransformation of bergapten (1) by the fungus Glomerella cingulata gave the corresponding reduced acid, 6,7-furano-5-methoxy hydrocoumaric acid (2), a new compound. Xanthotoxin (3) was also converted to the corresponding reduced acid cnidiol b (4) and demethylated metabolite xanthotoxol (5) by G. cingulata. The structure of the new compound 2 was elucidated by highresolution mass spectrometry, extensive NMR techniques, including 1H NMR and 13C NMR, 1H-1H correlation spectroscopy, heteronuclear multiple quantum coherence, and heteonuclear multiple bond coherence. The methyl ester or methyl ether or methyl ester and ether derivatives of 2 and 4 were synthesized. All compounds were tested for the β-secretase (BACE1) inhibitory activity in vitro. The methyl ester and ether derivative 8 was shown to possess BACE1 inhibitory activity, and a IC 50 value was 0.64 ± 0.04 mM.
- Marumoto, Shinsuke,Miyazawa, Mitsuo
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experimental part
p. 7777 - 7781
(2011/09/20)
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- CINAMIC COMPOUNDS AND DERIVATIVES THEREFROM FOR THE INHIBITION OF HISTONE DEACETYLASE
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The invention relates to a compound represented by the following formula (I): and pharmaceutically acceptable salts, stereoisomers, enantiomers, prodrugs and solvates thereof. The compounds are useful as an agent for enhancing the neurite outgrowth and preventing or treating of diseases associated with HDAC in particular, tumor or cell proliferative diseases. In particular, the compounds of the invention can be used as an agent for anti-cancer, anti-diabetic, and anti-neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Spinocerebellar Ataxias (SCA), and human spinal muscular atrophy (SMA).
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Page/Page column 22-23
(2010/10/19)
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- Cinamic compounds and derivatives therefrom for the inhibition of histone deacetylase
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The invention relates to a compound represented by the following formula (I): and pharmaceutically acceptable salts, stereoisomers, enantiomers, prodrugs and solvates thereof. The compounds are useful as an agent for enhancing the neurite outgrowth and preventing or treating of diseases associated with HDAC in particular, tumor or cell proliferative diseases. In particular, the compounds of the invention can be used as an agent for anti-cancer, anti-diabetic, and anti-neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Spinocerebellar Ataxias (SCA), and human spinal muscular atrophy (SMA).
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Page/Page column 44-45
(2010/10/19)
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- 4-Phenoxybutoxy-substituted heterocycles - A structure-activity relationship study of blockers of the lymphocyte potassium channel Kv1.3
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The voltage-gated potassium channel Kv1.3 constitutes an attractive pharmacological target for the treatment of effector memory T cell-mediated autoimmune diseases such as multiple sclerosis and psoriasis. Using 5-methoxypsoralen (5-MOP, 1), a compound isolated from Ruta graveolens, as a template we previously synthesized 5-(4-phenoxybutoxy)psoralen (PAP-1, 2) which inhibits Kv1.3 with an IC50 of 2 nM. Since PAP-1 is more than 1000-fold more potent than 5-MOP, we here investigated whether attaching a 4-phenoxybutoxy side chain to other heterocyclic systems would also produce potent Kv1.3 blockers. While 4-phenoxybutoxy-substituted quinolines, quinazolines and phenanthrenes were inactive, 4-phenoxybutoxy-substituted quinolinones, furoquinolines, coumarins or furochromones inhibited Kv1.3 with IC50s of 150 nM to 10 μM in whole-cell patch-clamp experiments. Our most potent new compound is 4-(4-phenoxybutoxy)-7H-furo[3,2-g]chromene-7-thione (73, IC50 17 nM), in which the carbonyl oxygen of PAP-1 is replaced by sulfur. Taken together, our results demonstrate that the psoralen system is a crucial part of the pharmacophore of phenoxyalkoxypsoralen-type Kv1.3 blockers.
- Bodendiek, Silke B.,Mahieux, Cedrick,Haensel, Wolfram,Wulff, Heike
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experimental part
p. 1838 - 1852
(2009/09/08)
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- Facile total synthesis of xanthotoxol
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Xanthotoxol, a biologically active linear furocoumarin, has been efficiently synthesized from 7-hydroxycoumarin in six steps. The key steps included two efficient rearrangements - Fries rearrangement and Claisen rearrangement - and a Baeyer-Villiger oxidation process. The overall yield of xanthotoxol was 29%. This approach also provided a new strategy to furnish easily furocoumarins with a hydroxyl group in the framework. Copyright Taylor & Francis Group, LLC.
- He, Wei,Zhang, Bang-Le,Zhou, Si-Yuan,Sun, Xiao-Li,Zhang, Sheng-Yong
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p. 361 - 367
(2007/10/03)
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- A QSAR model for in silico screening of MAO-A inhibitors. Prediction, synthesis, and biological assay of novel coumarins
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This work explores the potential of the MARCH-INSIDE methodology to seek a QSAR for MAO-A inhibitors from a heterogeneous series of compounds. A Markov model was used to quickly calculate the molecular electron delocalization, polarizability, refractivity, and n-octanol/water partition coefficients for a series of 1406 active/nonactive compounds. LDA was subsequently used to fit a classification function. The model showed 92.8% and 91.8% global accuracy and predictability in training and validation studies. This QSAR model was validated through a virtual screening of a series of coumarin derivatives. The 15 selected compounds were prepared and evaluated as in vitro MAO-A inhibitors. The theoretical prediction was compared with the experimental results and the model correctly predicted 13 compounds with only two mistakes on compounds with activities very close to the cutoff point established for the model. Consequently, this method represents a useful tool for the "in silico" screening of MAO-A inhibitors.
- Santana, Lourdes,Uriarte, Eugenio,González-Díaz, Humberto,Zagotto, Giuseppe,Soto-Otero, Ramón,Méndez-álvarez, Estefanía
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p. 1149 - 1156
(2007/10/03)
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- On the Photobiological Properties of Chimeras Combining Quaternary Ammonium Derivatives of Retinoic Amides and Psoralen. A Study with Cultured Human Keratinocytes
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The effectiveness of the combination of retinoids with 8-methoxypsoralen (8-MOP) and ultraviolet-A (UV-A) light in the treatment of some cutaneous proliferative diseases has motivated the synthesis of new " chimera-type" molecules built from psoralen derivatives and retinoic amides and related molecules. The chimeras result from the combination of 8-(3-bromopropyloxy)-psoralen with amides prepared by reacting 4-amino-pyridine with 13E- and 13Z-retinoic acids or a "retinoid-like" derivative with an alkene chain of only three double bonds. The synthesis of chimeras built with the 8-(3-bromopropyloxy)-psoralen and the amide of cinnamic acid or its 4-methoxy derivative has also been carried out. In contrast to 8-MOP, all the chimeras exhibit strong molar absorptivities in the range 20 000-40 000 M -1 cm-1 in the 340-390 nm UV-A region. The "retinoid-like" and retinoid-psoralen chimeras are characterized by a marked dark toxicity toward proliferating NCTC 2544 keratinocytes (with a lethal dose corresponding to 50% cell survival [LD50] of 1-5 μM) as compared with that of the cinnamic acid derivative-psoralen chimeras (LD50 ≥ 50μM). This toxicity leads to alteration of the mitochondrial membrane potential. At nontoxic concentrations, the chimeras demonstrate effective psoralens + UV-A-induced photocytotoxicity. They are moderate photosensitizers of membrane lipid peroxidation. Cell apoptosis is a major photocytotoxic process as suggested by the fluorescence-activated cell-sorting technique using annexin-fluorescein isothiocyanate and propidium iodide as apoptotic markers.
- Lartillot, Veronique,Risler, Arnaud,Andriamialisoa, Zo,Giraud, Michel,Sa E Melos, Teresa,Michel, Laurence,Santus, Rene
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p. 623 - 632
(2007/10/03)
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- Alkoxypsoralens, novel nonpeptide blockers of Shaker-type K+ channels: Synthesis and photoreactivity
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A series of psoralens and structurally related 5,7-disubstituted coumarins was synthesized and investigated for their K+ channel blocking activity as well as for their phototoxicity to Artemia salina and their ability to generate singlet oxygen and to photomodify DNA. After screening the compounds on Ranvier nodes of the toad Xenopus laevis, the affinities of the most promising compounds, which proved to be psoralens bearing alkoxy substituents in the 5-position or alkoxymethyl substituents in the neighboring 4- or 4'-position, to a number of homomeric K+ channels were characterized. All compounds exhibited the highest affinity to Kv1.2. 5,8- Diethoxypsoralen (10d) was found to be an equally potent inhibitor of Kv1.2 and Kv1.3, while lacking the phototoxicity normally inherent in psoralens. The reported compounds represent a novel series of nonpeptide blockers of Shaker-type K+ channels that could be further developed into selective inhibitors of Kv1.2 or Kv1.3.
- Wulff, Heike,Rauer, Heiko,Düring, Tim,Hanselmann, Christine,Ruff, Katharina,Wrisch, Anja,Grissmer, Stephan,H?nsel, Wolfram
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p. 4542 - 4549
(2007/10/03)
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- Modification of polymer surfaces and molecular immobilization by photoreaction
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A method for modifying the surface of a solid polymer wherein the polymer surface is exposed to an aqueous solution containing a two-ring heterocyclic compound that is described in more detail herein. The polymer and the two-ring heterocyclic compound are irradiated with electromagnetic radiation having a wavelength ranging from about 10 nm to about 400 nm to photochemically immobilize the two-ring heterocyclic compound to the polymer.
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- On the Involvement of Singlet Oxygen in the Biosynthesis of Oxygenation Products of the Furocoumarin Imperatorine
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The role of singlet oxygen (1O2) in the photo-oxidation of the furocoumarin imperatorine was investigated in vitro.Irradiation with visible light and sensitization with methylene blue yielded the imperatorine oxidation product isogosferol and the corresponding ketone as main products.The involvement of 1O2 was demonstrated by studying the rate of oxidation under conditions that affect the lifetime of 1O2.Compared to a range of other furocoumarins, imperatorine appeared to be moderately active as a 1O2 generator.The extent of 1O2 production correlated with the skin sensitizing activity.Upon irradiation of imperatorine itself with UVA light (360 nm) no isogosferol formation is observed, probably as a consequence of its photochemical instability.Irradiation with visible light (λ>400 nm) of a chlorophyll chromophore containing sensitizer in the presence of imperatorine, yielded isogosferol and the corresponding ketone product.This demonstrates that in the formation of 1O2 oxidation products of imperatorine in plants naturally occuring sensitizers e.g. chlorophyll and visible light are involved, rather than 1O2 produced by imperatorine or other furocoumarins and UVA light.The protective effect on the chlorophyll sensitized imperatorine oxidation by the 1O2- and chlorophyll triplet quencher β-carotene was demonstrated in a lipophilic solvent. - Key words: Singlet Oxygen, Biosynthesis, Imperatorine, Isogosferol, Photo-oxygenation
- Mol, Nicolaas J. de,Reisch, Johannes,Henegouwen, Gerardus M. J. Bejersb.
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p. 1433 - 1441
(2007/10/02)
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