- Development and preclinical studies of broad-spectrum anti-HIV agent (3′R,4′R)-3-cyanomethyl-4-methyl-3′,4′-di-O-(S) -camphanoyl-(+)-cis-khellactone (3-cyanomethyl-4-methyl-DCK)
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In prior investigation, we discovered that (3′R,4′R)-3- cyanomethyl-4-methyl-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (4, 3-cyanomethyl-4-methyl-DCK) showed promising anti-HIV activity. In these current studies, we developed and optimized successfully a practical 10-step synthesis for scale-up preparation to increase the overall yield of 4 from 7.8% to 32%. Furthermore, compound 4 exhibited broad-spectrum anti-HIV activity against wild-type and drug-resistant viral infection of CD4+ T cell lines as well as peripheral blood mononuclear cells by both laboratory-adapted and primary HIV-1 isolates with distinct subtypes and tropisms. Compound 4 was further subjected to in vitro and in vivo pharmacokinetic studies. These studies indicated that 4 has moderate cell permeability, moderate oral bioavailability, and low systemic clearance. These results suggest that 4 should be developed as a promising anti-HIV agent for development as a clinical trial candidate.
- Xie, Lan,Guo, Huan-Fang,Lu, Hong,Zhuang, Xiao-Mei,Zhang, An-Ming,Wu, Gang,Ruan, Jin-Xiu,Zhou, Ting,Yu, Donglei,Qian, Keduo,Lee, Kuo-Hsiung,Jiang, Shibo
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Read Online
- Synthesis, characterization, and determination of photophysicochemical properties of peripheral and nonperipheral tetra-7-oxy-3,4-dimethylcoumarin substituted zinc, indium phthalocyanines
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The photochemical and photophysical properties of peripheral and nonperipheral zinc and indium phthalocyanines containing 7-oxy-3,4-dimethylcoumarin synthesized were investigated in this study. 7-Hydroxy-3,4-dimethylcoumarin (1) was synthesized via Pechma
- ?zgül Artu?, Gamze,Karap?nar, Begümhan,?zdemir, Mücahit,Bulut, Mustafa
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Read Online
- 2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases
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We have carried out the design, synthesis, and evaluation of a small library of 2-aminobenzoxazole-appended coumarins as novel inhibitors of tumour-related CAs IX and XII. Substituents on C-3 and/or C-4 positions of the coumarin scaffold, and on the benzoxazole moiety, together with the length of the linker connecting both units were modified to obtain useful structure-activity relationships. CA inhibition studies revealed a good selectivity towards tumour-associated CAs IX and XII (K i within the mid-nanomolar range in most of the cases) in comparison with CAs I, II, IV, and VII (K i > 10 μM); CA IX was found to be slightly more sensitive towards structural changes. Docking calculations suggested that the coumarin scaffold might act as a prodrug, binding to the CAs in its hydrolysed form, which is in turn obtained due to the esterase activity of CAs. An increase of the tether length and of the substituents steric hindrance was found to be detrimental to in?vitro antiproliferative activities. Incorporation of a chlorine atom on C-3 of the coumarin moiety achieved the strongest antiproliferative agent, with activities within the low micromolar range for the panel of tumour cell lines tested.
- Fuentes-Aguilar, Alma,Merino-Montiel, Penélope,Montiel-Smith, Sara,Meza-Reyes, Socorro,Vega-Báez, José Luis,Puerta, Adrián,Fernandes, Miguel X.,Padrón, José M.,Petreni, Andrea,Nocentini, Alessio,Supuran, Claudiu T.,López, óscar,Fernández-Bola?os, José G.
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p. 168 - 177
(2021/12/21)
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- Umbelliferyloxymethyl phosphonate compounds-weakly binding zinc ionophores with neuroprotective properties
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Umbelliferone is a member of the coumarin family of compounds which are known for diverse pharmacological activity including in targets relevant to Alzheimers disease, AD. The toxicity associated with some forms of the amyloid protein, Aβ, and the role of Zn2+ (and other biometals) dyshomeostasis in this, are of great interest in AD and make metal ionophore capability desirable in so called multi target drug ligands MTDLs. A new series of umbelliferyloxymethyl phosphonic acid diethylester compounds (umbelliferyloxymethyl phosphonates) bearing a phosphonate at the 7-position (compounds 1, 3-6), hydrolysis products 2, 2a and 2b from 1 and analogues 7 and 8 of 1 with 7-O to 7-S and 1-O to 1-NH substitutions, are reported. Single crystal X-ray structures of compounds 1, 2 and 2a were determined. In terms of neuroprotective properties, the compounds 1, 2, 3, 4, 5 and 6 at 1 μM concentration, inhibited the toxicity of Aβ1-42 (Aβ42) in both toxic Amyloid Derived Diffusible Ligand (ADDL) and fibrillar (fibril) forms towards rat hippocampal cells. Compound 7 displayed cytotoxicity and 8 failed to inhibit Aβ42 toxicity. Concerning compound-metal ionophore activity (assessed using chemical experiments), despite weak binding to Zn2+ determined from 31P NMR titration of 1 and 2 by ZnCl2, compounds 1, 3, 4, 5 and 6 demonstrated ionophore assisted partition of Zn2+ from water to octanol at micromolar concentrations with efficacy on a par with or better than the chelator MTDL clioquinol (5-chloro-7-iodo-8-hydroxyquinoline). Partition was assessed using furnace Atomic Absorption Spectroscopy (AAS). In further experiments interaction of compound 1 with Zn2+ or it's pathways was inferred by (i) delayed fluorescence response with added Zn2+ in cells treated with FluoZin-3 and (ii) by suppression of Zn2+ promoted aggregation of Aβ42.
- Connole, Laura,Guesne, Sebastien,Kim, Stephanie,Michael-Titus, Adina T.,Motevalli, Majid,Robson, Lesley,Sullivan, Alice
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supporting information
p. 17041 - 17051
(2021/12/10)
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- Design, synthesis, cytotoxicity and mechanism of novel dihydroartemisinin-coumarin hybrids as potential anti-cancer agents
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To develop novel agents with anticancer activities, thirty-four new dihydroartemisinin-coumarin hybrids were designed and synthesized in this study. Those compounds were identified that had great anticancer activity against two cancer cell lines (MDA-MB-231 and HT-29). The structure-activity relationships of the derivatives were also discussed, and the results of docking analysis had shown that carbonic anhydrases IX (CA IX) was very likely to be one of the drug targets of the hybrids. Meanwhile, to clarify the mechanism of the anticancer activity of the hybrids molecule, we did further exploration in the bioactivity of the hybrids. The results had shown that these derivatives obviously inhibited proliferation of HT-29 cell lines, arrested G0/G1 phase of HT-29 cells, suppressed the migration of tumor cells, and induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells. Interestingly, the hybrids also induced the other cell death pathway-ferroptosis.
- Yu, Haonan,Hou, Zhuang,Tian, Ye,Mou, Yanhua,Guo, Chun
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p. 434 - 449
(2018/04/14)
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- Coumarin-dithiocarbamate hybrids as novel multitarget AChE and MAO-B inhibitors against Alzheimer's disease: Design, synthesis and biological evaluation
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A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer's disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC50 values of 0.0068 μM and 0.0089 μM for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114 μM for hAChE; 0.101 μM for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH-SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500 mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold.
- He, Qi,Liu, Jing,Lan, Jin-Shuai,Ding, Jiaoli,Sun, Yongbing,Fang, Yuanying,Jiang, Neng,Yang, Zunhua,Sun, Liyuan,Jin, Yi,Xie, Sai-Sai
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supporting information
p. 512 - 528
(2018/09/29)
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- Synthesis of Novel Anti-inflammatory Psoralen Derivatives?-?Structures?with?Distinct?Anti-Inflammatory?Activities
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As a continuum to our work with coumarins, 12 psoralens were synthesized and evaluated for their anti-inflammatory activity. Psoralens were prepared in three steps; at first, 7-hydroxycoumarins were synthesized by von Pechmann condensation and then converted to 7-(2-oxopropoxy)coumarins. In the final step, a fused furan ring was introduced in an intramolecular ring-formation reaction. Based on a SciFinder search, two out of the 12 synthesized psoralen derivatives (compounds 9 and 12) were found to be novel. The derivatives displayed anti-inflammatory activity by suppressing iNOS and IL-6 expression, but their mechanism of action seemed to be dependent on the substitution. Compound 6 with propyl side chain inhibited NF-κB mediated transcription, while compound 10 with a phenyl substituent down-regulated iNOS expression in a posttranscriptional manner. The results introduce psoralen derivatives as promising anti-inflammatory compounds with potential for treatment of conditions involving iNOS and/or IL-6-mediated adverse responses.
- Timonen, Juri M.,Vuolteenaho, Katriina,Lepp?nen, Tiina,Nieminen, Riina M.,Aulaskari, Paula,J?nis, Janne,Vainiotalo, Pirjo,Moilanen, Eeva
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p. 2590 - 2597
(2018/09/25)
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- Neuroprotective effects of benzyloxy substituted small molecule monoamine oxidase B inhibitors in Parkinson's disease
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The benzyloxy substituted small molecules are well-known highly potent monoamine oxidase B inhibitors, but their therapeutic potential against Parkinson's disease have not been investigated in detail. In this paper, a series of representative benzyloxy substituted derivatives were synthesized and evaluated for MAO-A/B inhibition. In addition, their neuroprotective effects were investigated in 6-OHDA- and rotenone-treated PC12 cells. It was observed that most of the compounds exhibited a marked increase in survival of PC12 cells which treated with the neurotoxins. Among them, 13 exhibited remarkable and balanced neuroprotective potency. The protective effects of 13 against neurotoxins-induced apoptosis were confirmed with flow cytometry and staining methods. Furthermore, 13 also showed good BBB permeability and low toxicity according to in vitro BBB prediction and in vivo acute toxicity test. The results indicated that 13 is an effective and promising candidate to be further developed as disease-modifying drug for Parkinson's disease therapy.
- Wang, Zhimin,Wu, Jiajia,Yang, Xuelian,Cai, Pei,Liu, Qiaohong,Wang, Kelvin D.G.,Kong, Lingyi,Wang, Xiaobing
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supporting information
p. 5929 - 5940
(2016/11/09)
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- Design, synthesis and cytotoxicity of novel dihydroartemisinin-coumarin hybrids via click chemistry
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In order to develop novel chemotherapeutic agents with potent anticancer activities, we designed four series of novel compounds employing hybridization strategy. Twenty novel dihydroartemisinin-coumarin hybrids, 10a-e, 11a-e, 12a-e, 13a-e, were synthesized via click chemistry in this study and their structures were characterized by HRMS and NMR. The cytotoxic activities were measured by MTT assay against three cancer cell lines (HCT-116, MDA-MB-231, and HT-29) under normoxic or anoxic conditions, respectively. The target compounds exhibited moderate activity with IC50 values in the 0.05-125.40 μM range, and these compounds exhibited better activity against HT-29 cell line under anoxic condition. The cytotoxic activities of most compounds under anoxic condition displayed one- to 10-fold greater activity than under normoxic condition. Compounds 10a - e showed better selectivity against the HT-29 cell line than the other two cell lines. These results indicated that our design of CA IX inhibitors does correspond with its action mode to some degree and deserves further investigation.
- Tian, Ye,Liang, Zhen,Xu, Hang,Mou, Yanhua,Guo, Chun
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- p27 PROTEIN INDUCER
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The present invention provides a p27 protein inducing agent comprising a compound represented by general formula (11) below or pharmaceutically acceptable salt thereof as an active ingredient: wherein G 1 , G 2 , G 3 and G 8 are each independently selected from -N= etc., Ring G 6 is selected from divalent aryl etc., A is selected from amino etc., G 4 is selected from oxygen etc., G 5 is selected from oxygen etc., G 7 is selected from -CH 2 - etc., and R 2 is selected from C 1-6 alkyl etc.
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Paragraph 0783; 3380-3384
(2016/10/08)
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- Multi-target tacrine-coumarin hybrids: Cholinesterase and monoamine oxidase B inhibition properties against Alzheimer's disease
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A series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as multi-target agents against Alzheimer's disease. The biological assays indicated that most of compounds displayed potent inhibitory activity toward AChE and BuChE, and clearly selective inhibition for MAO-B. Among these compounds, 14c exhibited strong inhibitory activity for AChE (IC50 values of 33.63 nM for eeAChE and 16.11 nM for hAChE) and BuChE (IC50 values of 80.72 nM for eqBuChE and 112.72 nM for hBuChE), and the highest inhibitory activity against hMAO-B (IC50 value of 0.24 11/4M). Kinetic and molecular modeling studies revealed that 14c was a mixed-type inhibitor, binding simultaneously to catalytic, peripheral and mid-gorge sites of AChE. It was also a competitive inhibitor, which covered the substrate and entrance cavities of MAO-B. Moreover, 14c could penetrate the CNS and show low cell toxicity. Overall, these results suggested that 14c might be an excellent multi-target agent for AD treatment.
- Xie, Sai-Sai,Wang, Xiaobing,Jiang, Neng,Yu, Wenying,Wang, Kelvin D.G.,Lan, Jin-Shuai,Li, Zhong-Rui,Kong, Ling-Yi
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supporting information
p. 153 - 165
(2015/03/31)
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- Synthesis of osthole derivatives with grignard reagents and their larvicidal activities on mosquitoes
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The structure of osthole has been modified to improve its larvicidal activity against mosquitoes. A new efficient synthesis of osthole derivatives with Grignard reagents has been developed, which employs CuI and LiCl as promoters and covers a broad range of substrates to afford the corresponding products in mild to good yields (up to 83%). Bio-activity evaluation showed that several products exhibited better activities than osthole. CuI and LiCl promoted efficient synthesis of osthole derivatives with Grignard reagents has been developed. Bio-activity evaluation showed that several products exhibited far better larvicidal activities against mosquitoes than osthole.
- Liu, Ming,Liu, Yang,Hua, Xuewen,Wu, Changchun,Zhou, Sha,Wang, Baolei,Li, Zhengming
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supporting information
p. 1353 - 1358
(2016/02/18)
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- BENZOPYRONE DERIVATIVE AND USE THEREOF
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The present invention relates to the field of pharmaceutical chemistry, and in particular, to a benzopyrone derivative and a use thereof. The benzopyrone derivative is compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof. It has been found by experiments that, this type of compounds is useful in prevention or treatment of neuropsychical diseases.
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Paragraph 0025; 0042; 0066
(2014/03/22)
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- BENZOPYRONE DERIVATIVE AND USE THEREOF
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The present invention relates to the field of pharmaceutical chemistry, and in particular, to a benzopyrone derivative and a use thereof. The benzopyrone derivative is compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof. It has been found by experiments that, this type of compounds is useful in prevention or treatment of neuropsychical diseases.
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Paragraph 0066; 0098; 0199
(2014/05/07)
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- Cholinium ionic liquids as cheap and reusable catalysts for the synthesis of coumarins via Pechmann reaction under solvent-free conditions
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A cheap cholinium ionic liquid N,N′-dimethylaminoethanol hydrosulfate ([N112OH][HSO4]) was found to be an efficient and reusable catalyst for the Pechmann condensation under solvent-free conditions. The coumarin products can be simply separated and the ionic liquid catalyst can be recycled and reused for at least six runs without noticeable decrease in the catalytic activity. The UV-vis studies suggested that the increase of the acidity and the introduction of a hydroxyl group to the cation benefit the existence of the keto tautomer of ethyl acetoacetate, which then leads to the excellent performance of [N112OH][HSO4].
- Zhang, Yuehua,Zhu, Anlian,Li, Qianqian,Li, Lingjun,Zhao, Yang,Wang, Jianji
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p. 22946 - 22950
(2014/06/24)
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- Ultrasound-assisted one-pot synthesis of substituted coumarins catalyzed by poly(4-vinylpyridinium) hydrogen sulfate as an efficient and reusable solid acid catalyst
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Poly(4-vinylpyridinium) hydrogen sulfate solid acid was found to be efficient catalyst for synthesis of substituted coumarins via Pechmann reaction using ultrasound irradiation at room temperature and neat condition in high yields with short reaction times. This methodology offers momentous improvements over various options for the synthesis of coumarins with regard to yield of products, simplicity in operation and green aspects by avoiding toxic catalysts and solvents. Further, the catalyst can be reused and recovered for several times.
- Khaligh, Nader Ghaffari
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p. 1062 - 1068
(2013/04/24)
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- Succinimide-N-sulfonic acid catalyzed synthesis of bis(indolyl)methane and coumarin derivatives under mild conditions
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A mild and simple procedure is described for the synthesis of bis(indolyl)methane and coumarin derivatives using succinimide-N-sulfonic acid as an efficient, cheap, and reusable catalyst under mild conditions.
- Shirini, Farhad,Khaligh, Nader Ghaffari
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p. 1890 - 1896
(2013/11/19)
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- Introduction of poly(4-vinylpyridinium) perchlorate as a new, efficient, and versatile solid acid catalyst for one-pot synthesis of substituted coumarins under ultrasonic irradiation
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Poly(4-vinylpyridinium) perchlorate, is a supported, recyclable, eco-benign catalyst for synthesis of substituted coumarins via Pechmann reaction using ultrasound irradiation at room temperature and neat condition in high yields with short reaction times. The catalyst was studied by FT-IR, X-ray diffraction, scanning electron microscope, thermo-gravimetric and energy dispersion X-ray analyses. All the products were extensively characterized by 1H NMR, FT-IR, MS and melting point analyses. This methodology offers momentous improvements over various options for the synthesis of coumarins with regard to yield of products, simplicity in operation and green aspects by avoiding toxic catalysts and solvents. Further, the catalyst can be reused and recovered for several times without loss of activity.
- Khaligh, Nader Ghaffari,Shirini, Farhad
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p. 26 - 31,6
(2012/12/11)
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- Synthesis and biological investigation of coumarin piperazine (piperidine) derivatives as potential multireceptor atypical antipsychotics
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The discovery and synthesis of potential and novel antipsychotic coumarin derivatives, associated with potent dopamine D2, D3, and serotonin 5-HT1A and 5-HT2A receptor properties, are the focus of the present article. The most-promising derivative was 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy) -4-methyl-8-chloro-2H-chromen-2-one (17m). This derivative possesses unique pharmacological features, including high affinity for dopamine D2 and D3 and serotonin 5-HT1A and 5-HT2A receptors. Moreover, it possesses low affinity for 5-HT2C and H1 receptors (to reduce the risk of obesity associated with chronic treatment) and hERG channels (to reduce the incidence of torsade des pointes). In animal models, compound 17m inhibited apomorphine-induced climbing behavior, MK-801-induced hyperactivity, and the conditioned avoidance response without observable catalepsy at the highest dose tested. Further, fewer preclinical adverse events were noted with 17m compared with risperidone in assays that measured prolactin secretion and weight gain. Acceptable pharmacokinetic properties were also noted with 17m. Taken together, 17m may constitute a novel class of drugs for the treatment of schizophrenia.
- Chen, Yin,Wang, Songlin,Xu, Xiangqing,Liu, Xin,Yu, Minquan,Zhao, Song,Liu, Shicheng,Qiu, Yinli,Zhang, Tan,Liu, Bi-Feng,Zhang, Guisen
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p. 4671 - 4690
(2013/07/19)
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- Synthesis and anti-inflammatory effects of a series of novel 7-hydroxycoumarin derivatives
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A number of 7-hydroxycoumarins have been synthesised by Pechmann cyclisation using differently substituted resorcinols employing perchloric acid as the condensing agent. All the compounds have been characterised by analytical and spectroscopic methods. The anti-inflammatory properties were tested with LPS-induced inflammation in J774 macrophages. Expression of iNOS and COX-2 was determined by Western blot, NO by nitrite assay and IL-6 by ELISA analyses. Fifteen of the tested 7-hydroxycoumarins also inhibited IL-6 production but none of them had any major inhibitory effect on COX-2 expression.
- Timonen, Juri M.,Nieminen, Riina M.,Sareila, Outi,Goulas, Antonis,Moilanen, Lauri J.,Haukka, Matti,Vainiotalo, Pirjo,Moilanen, Eeva,Aulaskari, Paula H.
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supporting information; experimental part
p. 3845 - 3850
(2011/11/13)
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- Synthesis and bioactivity of novel coumarin derivatives containing (E)-methyl 2-(methoxyimino)-2-phenylacetates
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Ten coumarin derivatives containing (E)-methyl 2-(methoxyimino)-2- phenylacetate were synthesized and bioassayed. The compounds were identified by IR, 1H NMR and elemental analyses. The test results indicated that compound 5j (R1 is methyl and R2 is n-C6H 13) was the optimal structure in this paper with good fungicidal activity against CDM (85%) at 6.25 mg/L concentration.
- Guan, Ai Ying,Liu, Chang Ling,Li, Zhi Nian,Zhang, Ming Xing
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scheme or table
p. 663 - 666
(2012/01/13)
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- p27 PROTEIN INDUCER
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The present invention provides a p27 protein inducing agent comprising a compound represented by general formula (11) below or pharmaceutically acceptable salt thereof as an active ingredient: wherein G1, G2, G3 and G8 are each independently selected from -N= etc., Ring G6 is selected from divalent aryl etc., A is selected from amino etc., G4 is selected from oxygen etc., G5 is selected from oxygen etc., G7 is selected from -CH2- etc., and R2 is selected from C1-6 alkyl etc.
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- Coumarins as novel 17β-hydroxysteroid dehydrogenase type 3 inhibitors for potential treatment of prostate cancer
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The synthesis and SAR studies of 3- and 4-substituted 7-hydroxycoumarins as novel 17β-HSD3 inhibitors are discussed. The most potent compounds from this series exhibited low nanomolar inhibitory activity with acceptable selectivity versus other 17β-HSD isoenzymes and nuclear receptors.
- Harada, Koichiro,Kubo, Hideki,Tomigahara, Yoshitaka,Nishioka, Kazuhiko,Takahashi, Junya,Momose, Mio,Inoue, Shinichi,Kojima, Atsuyuki
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scheme or table
p. 272 - 275
(2010/04/06)
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- BENZOPYRONE COMPOUNDS, PREPARATION METHOD AND USE THEREOF
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The invention relates to pesticide and bactericide, specifically to the benzopyrone compounds and its preparation method and use thereof. The benzopyrone compounds of the invention having general formula (I): The present invention, having good pesticide activity and broad bactericide activity, applied for controlling various pests in plants such as army worm, diamond backmoth and aphid, carmine spider mite, two-spotted spider mite, ladybeetle, mites and mosquito larvae. Various disease in plants can be controlled by the invention and that of grape downy mildew, rice sheath and culm blight, rice blast, tomato early blight, tomato late blight ,wheat leaf rust, wheat leaf blotch, wheat powdery mildew, cucumber powdery mildew, cucumber downy mildew, cucumber grey mold and so on.
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Page/Page column 19
(2008/06/13)
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- A solvent-free synthesis of coumarins using a Wells-Dawson heteropolyacid as catalyst
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Seventeen examples are resolved, most of them in good to excellent yields, using the cheap WD catalyst. Substituted coumarins are synthesized from phenols and β-ketoesters by the Pechmann reaction, using a Wells-Dawson heteropolyacid (H6P2W18O62? 24H2O) as catalyst by a solvent-free procedure. This one requires low reaction times, 130°C temperature and as little as 1 mol % of Wells-Dawson acid, obtaining good to excellent yields of coumarins. The catalyst showed to be reusable with no differences in the yields. The results are compared with those of the reactions performed in toluene solution. The presented synthetic procedure is a convenient, clean and fast alternative for synthesizing 4-substituted coumarins (17 examples).
- Romanelli,Bennardi,Ruiz,Baronetti,Thomas,Autino
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p. 8935 - 8939
(2007/10/03)
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- Discovery and structure-activity relationship of coumarin derivatives as TNF-α inhibitors
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The discovery and structure-activity relationship of a novel series of coumarin-based TNF-α inhibitors is described. Starting from the initial lead 1a, various derivatives were prepared surrounding the coumarin core structure to optimize the in vitro inhibitory activity of TNF-α production by human peripheral blood mononuclear cells (hPBMC), stimulated by bacterial lipopolysaccharide (LPS). Selected compounds also demonstrated in vivo inhibition of TNF-α production in rats.
- Cheng, Jie-Fei,Chen, Mi,Wallace, David,Tith, Sovouthy,Arrhenius, Thomas,Kashiwagi, Hirotaka,Ono, Yoshiyuki,Ishikawa, Akira,Sato, Haruhiko,Kozono, Toshiro,Sato, Hediki,Nadzan, Alex M.
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p. 2411 - 2415
(2007/10/03)
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- Synthesis of coumarin by Yb(OTf)3 catalyzed Pechmann reaction under the solvent-free conditions
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Yb(OTf)3 is used as an alternative to conventional acid catalysts in the Pechmann condensation reaction of phenols with β-keto esters leading to the formation of coumarin derivatives. This new method has the advantage of high yields, solvent-free conditions, short reaction times and reusability of the catalyst with no loss of yield. Ytterbium triflate catalyzed Pechmann reaction applied to synthesis of coumarin derivatives is simple and environmentally friendly process.
- Wang, Limin,Xia, Jianjun,Tian, He,Qian, Changtao,Ma, Yun
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p. 2097 - 2099
(2007/10/03)
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- Anti-AIDS agents. 42. Synthesis and anti-HIV activity of disubstituted (3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis- khellactone analogues
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A series of disubstituted 3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogues (1-10) were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. 5-Methoxy-4-methyl DCK (8) was the most promising compound with an EC50 value of 7.21 × 10-6 μM and a therapeutic index of >2.08 × 10,7 which were much better than those of lead compound DCK in the same assay. Another six disubstituted DCK analogues (1-5 and 7) were more potent than AZT but less active than DCK. Conformational analysis suggested that resonance of the coumarin system is an essential structural feature for potent anti-HIV activity. Steric compression of C(4) and C(5) substituents of the coumarin moiety can reduce the overall planarity and thus resonance of the coumarin nucleus, resulting in a decrease or lack of anti-HIV activity.
- Xie,Takeuchi,Cosentino,McPhail,Lee
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p. 664 - 671
(2007/10/03)
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- Synthesis of coumarins catalyzed by eco-friendly W/ZrO2 solid acid catalyst
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Synthesis of substituted coumarins via reactions of resorcinol and substituted resorcinol with ethyl acetoacetate and ethyl α-methylacetoacetate (Pechmann reaction) are reported, in which the production of environmentally harmful waste streams is minimized by the use of a novel solid acid catalyst.
- Reddy,Reddy,Giridhar
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p. 3603 - 3607
(2007/10/03)
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- Phenylpiperazine derivatives with strong affinity for 5HT(1A), D(2A) and D3 receptors
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Four 7-[3-(4-phenyl-1-piperazinyl)propoxy]coumarins were synthesized. The affinities of these compounds for DA (D(2A), D3) and 5HT(1A) receptors were evaluated for their ability to displace [3H]-raclopride and [3H]-8- OH-DPAT respectively from their specific binding sites. The affinities of the target compounds were all in the nanomolar range and followed the order 5- HT(1A) > D2 > D3.
- Teran, Carmen,Santana, Lourdes,Uriarte, Eugenio,Fall, Yagamare,Unelius, Lena,Tolf, Bo-Ragnar
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p. 3567 - 3570
(2007/10/03)
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- Steroidal and nonsteroidal sulfamates as potent inhibitors of steroid sulfatase
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Synthetic routes to potent steroidal and nonsteroidal sulfamate-based active site-directed inhibitors of the enzyme steroid sulfatase, a topical target in the treatment of postmenopausal women with hormone-dependent breast cancer, are described. Novel compounds were examined for estrone sulfatase (E1-STS) inhibition in intact MCF-7 breast cancer cells and placental microsomes. Reaction of the sodium salt of estrone with sulfamoyl chloride gave estrone 3-O-sulfamate (EMATE, 2) which inhibits E1-STS activity potently (>99% at 0.1 mM in intact MCF-7 cells, IC50 = 65 pM) in a time- and concentration-dependent manner, suggesting that EMATE is an active site- directed inhibitor. EMATE is also active in vivo orally. 5,6,7,8- Tetrahydronaphthalene 2-O-sulfamate(7) and its N-methylated derivatives (8 and 9) were synthesized, and 7 inhibits the E1-STS activity in intact MCF-7 cells by 79% at 10 μM. 4-Methylcoumarin 7-O-sulfamate (COUMATE) and its derivatives (14, 16, and 18) wee prepared to extend this series of nonsteroidal inhibitors, and COUMATE educes the E1-STS activity in placental microsomes by >90% at 10 μM. Although the orally active COUMATE is less potent than EMATE as an active site-directed inhibitor, it has the important advantage of being nonestrogenic. Analogues (20, 22, 24, 26, 27, 31, 33, 39, and 44) of COUMATE were synthesized to study its structure-activity relationships, and sulfamates of tetralones (46 and 48) and indanones (49, 51, and 53) wee also prepared. While most of these compounds were found to inhibit E1-STS activity less effectively than COUMATE, one analogue, 3,4- dimethylcoumarin 3-O-sulfamate (24), was found to be some 12-fold more potent than COUMATE as an E1-STS inhibitor in intact MCF-7 cells (IC50 = 30 nM for 24, cf. 380 mM for COUMATE). Hence, highly potent sulfamate-based inhibitors of steroid sulfatase, such as EMATE, COUMATE, and 24, possess therapeutic potential and will allow the importance of estrogen formation in breast tumors via the E1-STS pathway to be assessed. A pharmacophore for active site-directed sulfatase inhibition is proposed.
- Woo, L. W. Lawrence,Howarth, Nicola M.,Purohit, Atul,Hejaz, Hatem A. M.,Reed, Michael J.,Potter, Barry V. L.
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p. 1068 - 1083
(2007/10/03)
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- Synthesis and characterization of new methylpsoralens as potential photochemotherapeutic agents
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Three new psoralens with methyl groups on carbons involved in their reactive double bonds (compounds 9-11 in Scheme 1) were synthesized from the corresponding 7-hydroxycoumarins by cyclization of acetonyl derivatives of the latter in an alkaline medium. In preliminary tests, the new methyl-substituted psoralens exhibited considerable interaction in the dark with DNA, good photoreactivity against the macromolecule, and also interesting antiproliferative activity.
- Antonello,Zagotto,Mobilio,Marzano,Gia,Uriarte
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p. 277 - 280
(2007/10/02)
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- Chemical synthesis of picumast dihydrochloride
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The chemical synthesis of the antiallergic substance picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) is described.
- Witte
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p. 1309 - 1309
(2007/10/02)
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- Synthesis of 7-Ethoxy-3,4-dimethylcoumarin and 5-Methoxy-4-methylcoumarin
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The structures proposed for two new naturally occuring coumarins as 7-ethoxy-3,4-dimethylcoumarin (1a) and 5-methoxy-4-methylcoumarin (2) (isolated from Edgeworthia gardneri) have been confirmed by their syntheses.
- Ahluwalia, V. K.,Mehta, Vimal D.,Khanduri, C. H.
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