- Discovery of Anti-TNBC Agents Targeting PTP1B: Total Synthesis, Structure-Activity Relationship, in Vitro and in Vivo Investigations of Jamunones
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Twenty-three natural jamunone analogues along with a series of jamunone-based derivatives were synthesized and evaluated for their inhibitory effects against breast cancer (BC) MDA-MB-231 and MCF-7 cells. The preliminary structure-activity relationship revealed that the length of aliphatic side chain and free phenolic hydroxyl group at the scaffold played a vital role in anti-BC activities and the methyl group on chromanone affected the selectivity of molecules against MDA-MB-231 and MCF-7 cells. Among them, jamunone M (JM) was screened as the most effective anti-triple-negative breast cancer (anti-TNBC) candidate with a high selectivity against BC cells over normal human cells. Mechanistic investigations indicated that JM could induce mitochondria-mediated apoptosis and cause G0/G1 phase arrest in BC cells. Furthermore, JM significantly restrained tumor growth in MDA-MB-231 xenograft mice without apparent toxicity. Interestingly, JM could downregulate phosphatidylinositide 3-kinase (PI3K)/Akt pathway by suppressing protein-tyrosine phosphatase 1B (PTP1B) expression. These findings revealed the potential of JM as an appealing therapeutic drug candidate for TNBC.
- Hu, Caijuan,Li, Guoxun,Mu, Yu,Wu, Wenxi,Cao, Bixuan,Wang, Zixuan,Yu, Hainan,Guan, Peipei,Han, Li,Li, Liya,Huang, Xueshi
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supporting information
p. 6008 - 6020
(2021/05/06)
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- Enantiomeric synthesis of natural alkylglycerols and their antibacterial and antibiofilm activities
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Alkylglycerols (AKGs) are bioactive natural compounds that vary by alkyl chain length and degree of unsaturation, and their absolute configuration is 2S. Three AKGs (5l–5n) were synthesised in enantiomerically pure form, and were characterised for the first time together with 12 other known and naturally occurring AKGs (5a–5k, 5o). Their structures were established using 1H and 13C APT NMR with 2D-NMR, ESI-MS or HRESI-MS and optical rotation data, and they were tested for their antibacterial and antibiofilm activities. AKGs 5a–5m and 5o showed activity against five clinical isolates and P. aeruginosa ATCC 15442, with MIC values in the range of 15–125 μg/mL. In addition, at half of the MIC, most of the AKGs reduced S. aureus biofilm formation in the range of 23%–99% and P. aeruginosa ATCC 15442 biofilm formation in the range of 14%–64%. The antibiofilm activity of the AKGs assessed in this work had not previously been studied.
- Fernández Montoya, Deicy J.,Contreras Jordan, Luis A.,Moreno-Murillo, Bárbara,Silva-Gómez, Edelberto,Mayorga-Wandurraga, Humberto
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supporting information
p. 2544 - 2550
(2019/11/13)
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- Total Synthesis of Nominal ent-Chlorabietol B
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The nominal enantiomer of chlorabietol B was regio- and stereoselectively synthesized from (-)-abietic acid in 13 steps. Key features of the synthesis involved an oxidative [3+2] cycloaddition to install the dihydrobenzofuran moiety and an Aldol reaction, followed by elimination and reduction steps to introduce the long chain with three cis double bonds. However, obvious differences in the NMR spectra of the synthetic and natural samples suggested that the proposed structure of chlorabietol B should be revised carefully.
- Guan, Xingchao,Li, Yulong,Xie, Zhipeng,Xie, Zhixiang,Xu, Zhezhe
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p. 5724 - 5732
(2020/05/19)
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- Copper-catalysed, diboron-mediated: Cis -dideuterated semihydrogenation of alkynes with heavy water
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Methods to incorporate deuterium atoms into organic molecules are valuable for the pharmaceutical industry. Here, we found that diboron reagents can efficiently mediate the transfer of two D atoms from heavy water directly onto alkynes through copper-catalysed cis-selective semihydrogenation. Avoiding the use of costly and flammable D2 gas, this safe and practical process can proceed with excellent chemoselectivity and stereoselectivity. Utilizing the present method as the key step, the formal asymmetric total synthesis of d2-deuterium-labeled cis-combretastatin A4 is demonstrated. Mechanistic studies suggest that monoborylation of alkynes is the key step for this semihydrogenation process.
- Han, Xiaowei,Hu, Jiefeng,Chen, Cheng,Yuan, Yu,Shi, Zhuangzhi
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supporting information
p. 6922 - 6925
(2019/06/18)
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- A Supramolecular Strategy for Selective Catalytic Hydrogenation Independent of Remote Chain Length
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Performing selective transformations on complex substrates remains a challenge in synthetic chemistry. These difficulties often arise due to cross-reactivity, particularly in the presence of similar functional groups at multiple sites. Therefore, there is a premium on the ability to perform selective activation of these functional groups. We report here a supramolecular strategy where encapsulation of a hydrogenation catalyst enables selective olefin hydrogenation, even in the presence of multiple sites of unsaturation. While the reaction requires at least one sterically nondemanding alkene substituent, the rate of hydrogenation is not sensitive to the distance between the alkene and the functional group, including a carboxylate, on the other substituent. This observation indicates that only the double bond has to be encapsulated to effect hydrogenation. Going further, we demonstrate that this supramolecular strategy can overcome the inherent allylic alcohol selectivity of the free catalyst, achieving supramolecular catalyst-directed regioselectivity as opposed to directing-group selectivity.
- Bender, Trandon A.,Bergman, Robert G.,Raymond, Kenneth N.,Toste, F. Dean
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supporting information
p. 11806 - 11810
(2019/08/22)
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- NSAID derivatives of omega-3 polyunsaturated acids as gamma secretase modulators
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The present invention relates to the NSAID derivatives of omega-3 fatty acids as gamma secretase modulators and their use in treating Alzheimer's disease, hypertriglyceridemia, and cardiovascular disease by reducing triglycerides, and for use as anti-inflammatory agents.
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Page/Page column 11
(2018/11/30)
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- Tuning the Thermo-Sensitivity of Micellar Systems through a Blending Approach
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This paper reports an original and easy route toward thermosensitive micelles based on a lipidic core and with adjustable cloud point temperatures (TCP) through a simple blending approach between two copolymers of different TCP. The cationic ring-opening polymerization (CROP) of various 2-alkyl-2-oxazoline monomers was first investigated from both mesylated and tosylated lipoinitiators and different lipid-b-poly(2-methyl-2-oxazoline), lipid-b-poly(2-ethyl-2-oxazoline), lipid-b-poly(2-isopropyl-2-oxazoline) and lipid-b-poly((2-ethyl-2-oxazoline)-co-(2-isopropyl-2-oxazoline)) copolymers were synthesized. Blending of lipid-b-p(EtOx) and lipid-b-p(iPrOx) copolymers in various proportions were then prepared and their TCP investigated through UV-visible spectroscopy. Very interesting results were obtained as the blends exhibit a single TCP ranging from 35 to 45 °C. Furthermore, the blends TCP correspond to those of the statistical lipid-b-p((EtOx)-co-(iPrOx)) for the same p(EtOx)/p(iPrOx) content up to 52 wt % of p(EtOx). The blending approach is then an attractive strategy to control the TCP of micellar systems through a simple and easy formulation approach rather than fastidious syntheses.
- El Asmar, Arlette,Gimello, Olinda,Morandi, Ga?lle,Le Cerf, Didier,Lapinte, Vincent,Burel, Fabrice
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p. 4307 - 4315
(2016/07/06)
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- Omefibrates for Treating Dyslipidemia and Cardiovascular Disease
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The present invention relates to the fibric acid derivatives of omega-3 fatty acids and their use in treating Type2 diabetes, obesity, hypertriglyceridemia, cardiovascular diseases, metabolic syndrome, cancer, Alzheimer's disease; and their use for modulating activity of peroxisome proliferator-activated receptors (PPARs).
- -
-
Paragraph 0100 - 0103
(2015/12/23)
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- Statins of Omega-3 Polyunsaturated Acids for Treating Hypercholesterolemia
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The present invention relates to novel statin derivatives of omega-3 fatty acids, and their use in treating hypercholesterolemia, obesity, hypertriglyceridemia, cardiovascular diseases, and metabolic diseases, and Alzheimer's disease.
- -
-
Paragraph 0072-0074
(2015/11/30)
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- ALPHA-SUBSTITUTED OMEGA-3 LIPIDS THAT ARE ACTIVATORS OR MODULATORS OF THE PEROXISOME PROLIFERATORS-ACTIVATED RECEPTOR (PPAR).
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Omega-3 lipid compounds of the general formula (I): wherein R1 and R2 are the same or different and may be selected from a group of substitu- ents consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an al- kynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, a car- boxy group, an alkylsulfmyl group, an alkylsulfonyl group, an amino group, and an alkylamino group; - X represents a carboxylic acid or a derivative thereof, a carboxylate, a carboxylic anhydride or a carboxamide; and - Y is a C16 to C22 alkene with two or more double bonds, having E and/or Z configuration, are disclosed. Also disclosed are pharmaceutical compositions and lipid compositions comprising such compounds, and to such compounds for use as medicaments in particular for the treatment of cardiovascular and metabolic diseases.
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Page/Page column 64
(2008/12/05)
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- Facile and efficient syntheses of (3Z,6Z,9Z)-3,6,9-nonadecatriene and homologues: Pheromone and attractant components of lepidoptera
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Facile and efficient chemical syntheses of (3Z,6Z,9Z)-3,6,9-nonadecatriene and homologues from commercially available α-linolenic acid [(9Z,12Z,15Z)-9,12,15-octadecatrienoic acid] are reported. These straight-chain homoconjugated trienes are common sex pheromone and attractant components for many lepidopterous insect pests. The metal-catalyzed cross-coupling reactions between (9Z,12Z,15Z)-9,12,15-octadecatrienyl triflate and the appropriate Grignard reagents proceed very rapidly under notable mild conditions using Li2CuCl4 as catalyst in diethyl ether, and the resulting (3Z,6Z,9Z)-3,6,9-trienes with retention of geometrical configuration were in >92% isolated yield.
- Wang, Shifa,Zhang, Aijun
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p. 6929 - 6932
(2008/09/17)
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- New N-arachidonoylserotonin analogues with potential "dual" mechanism of action against pain
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N-Arachidonoylserotonin (AA-5-HT, 1a) is an inhibitor of fatty acid amide hydrolase (FAAH) that acts also as an antagonist of transient receptor potential vanilloid-type 1 (TRPV1) channels and is analgesic in rodents. We modified the chemical structure of 1a with the aim of developing "hybrid" FAAH/TRPV1 blockers more potent than the parent compound or obtaining analogues with single activity at either of the two targets to study the mechanism of the analgesic action of 1a. Thirty-eight AA-5-HT analogues, containing a serotonin "head" bound to a variety of lipophilic moieties via amide, urea, or carbamate functionalities, were synthesized. Unlike 1a, most of the new compounds possessed activity at only one of the two considered targets. The amides 1b and 1c of α- and γ-linolenic acid, however, showed "hybrid" activity similar to 1a. The carbamate 3f (OMDM106), although unable to antagonize TRPV1 receptors, was the most potent FAAH inhibitor in this study (IC50 = 0.5 μM). Compounds 3f and 1m (OMDM129), which exhibited activity at only FAAH or TRPV1, respectively, were 10-fold less potent than 1a at preventing formalin-induced hyperalgesia in mice.
- Ortar, Giorgio,Cascio, Maria Grazia,De Petrocellis, Luciano,Morera, Enrico,Rossi, Francesca,Schiano-Moriello, Aniello,Nalli, Marianna,De Novellis, Vito,Woodward, David F.,Maione, Sabatino,Di Marzo, Vincenzo
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p. 6554 - 6569
(2008/09/17)
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- Use of the anti-oxidant butylated hydroxytoluene in situ for the synthesis of readily oxidized compounds: Application to the synthesis of the moth pheromone (Z,Z,Z)-3,6,9-nonadecatriene
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The triene (Z,Z,Z)-3,6,9-nonadecatriene was synthesized in three steps from methyl linolenate. The key to the synthesis was the use of the anti-oxidant butylated hydroxytoluene in situ to provide protection of the unstable triene from autoxidation during reaction workup. This simple modification resulted in an increase in the yield from 20 to 85% over three steps. CSIRO 2007.
- Davies, Noel W.,Meredith, Graham,Molesworth, Peter P.,Smith, Jason A.
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p. 848 - 849
(2008/03/12)
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- Chemical C2-elongation of polyunsaturated fatty acids
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Three fatty acids were synthesized from commercially available α-linolenic, stearidonic and eicosapentaenoic acids by C2-elongation using a four step preparative technique. The parent fatty acid methyl esters were reduced to alcohols with LiAlH4, converted to bromides by treatment with triphenylphosphine dibromide, coupled with a lithiated C2-elongation block - 2,4,4-trimethyl-2-oxazoline - to form the corresponding 2,2-dimethyloxazolines of C2-elongated fatty acids, and finally, converted to the target polyunsaturated fatty acids by acidic alcoholysis. Yields of more than 60% were achieved on a gram scale. The resulting 11Z,14Z,17Z-eicosatrienoic, 8Z,11Z,14Z,17Z-eicosatetraenoic and 7Z,10Z,13Z,16Z,19Z-docosapentaenoic acids were obtained as colorless oils with >98% purity and could be used for biochemical investigations without additional purification. The elongated fatty acids were free of byproducts that could result from Z-E isomerization or migration of double bonds.
- Kuklev, Dmitry V.,Smith, William L.
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p. 172 - 177
(2007/10/03)
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- Synthesis of a tetronic acid library focused on inhibitors of tyrosine and dual-specificity protein phosphatases and its evaluation regarding VHR and Cdc25B inhibition
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Selective inhibitors of protein tyrosine phosphatases (PTPs) and dual-specificity phosphatases (DSPs) are expected to be useful tools for clarifying the biological functions of the PTPs themselves and also to be candidates for novel therapeutics. We planned a library approach for the identification of PTP/DSP inhibitors in which 3-acyltetronic acid is used as a "core" phosphate mimic. A series of novel tetronic acid derivatives were synthesized and evaluated as inhibitors of the dual-specificity protein phosphatases VHR and cdc25B. Several compounds are found to be potent inhibitors of cdc25B, which is a key enzyme for cell-cycle progression. The promising results described herein strongly indicated that this tetronic acid library is potent as a library focused on the PTP/DSP-selective inhibitor.
- Sodeoka,Sampe,Kojima,Baba,Usui,Ueda,Osada
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p. 3216 - 3222
(2007/10/03)
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- Sex pheromone of tomato fruit borer, Neoleucinodes elegantalis
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Five candidate pheromone components were identified by analyzing pheromone gland extracts by gas chromatography (GC), coupled GC-electro-antennographic detection (EAD), and coupled GC-mass spectrometry (MS): (E)-11-hexadecenol(E11-16: OH), (Z)-11-hexadecenol(Z11-16: OH), (E)-11-hexadecenal, (E)-11-hexadecenyl acetate, and (Z)-3,(Z)-6,(Z)-9-tricosatriene (Z3,Z6,Z9-23: Hy). In electroantennogram (EAG) recordings, synthetic E11-16: OH elicited stronger antennal responses at low doses than other candidate pheromone components. Field tests demonstrated that synthetic E11-16: OH as a trap bait was effective in attracting males, whereas addition of Z11-16: OH inhibited the males' response. Z3,Z6,Z9-23 : Hy strongly enhanced attractiveness of E11-16: OH, but was not attractive by itself. A pheromone blend with synergistic behavioral activity of an alcohol (E11- 16: OH) and hydrocarbon (Z3,Z6,Z9-23: Hy) component is most unusual in the Lepidoptera. The synthetic two-component pheromone is approximately 60 times more attractive than the female-produced blend and might facilitate the control of this pest.
- Cabrera, Aivle,Eiras, Alvaro E.,Gries, Gerhard,Gries, Regine,Urdaneta, Neudo,Miras, Beatriz,Badji, Cesar,Jaffe, Klaus
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p. 2097 - 2107
(2007/10/03)
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- Synthesis of novel n-Alktrienyltrichlorosilane -versatile reagent and precursor for organic monolayer formation
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Preparation of (Z,Z,Z)-9,12,15-octadecatrienyltrichlorosilane (2) by the reaction of the corresponding Grignard reagent with SiCl4 is described. The novel compound of the type RSiX3, useful for various organometallic applications and with the ability to form close-packed ordered monolayers chemically bonded to the surface, was thoroughly characterized by spectral analysis.
- Markovic, Rade,Holzschueh, Eugen
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p. 423 - 426
(2007/10/03)
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- Fluorescein esters and ethers and the preparation thereof
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Fluorescein esters and ethers including the dioleyl derivative of fluorescein are disclosed. These compounds have the useful property of being fluorescent under the influence of the proper frequency of electromagnetic irradiation. Further, dioleyl fluorescein is readily incorporated into low-density lipoproteins which can then become part of the cell matter; the compounds retain their fluorescent properties during this procedure. The fluorescence allows cells to be identified and separated. The fluorescein esters and ethers are prepared from fluorescein and the novel reagent O-alkenyl-N,N'-dialkylisourea.
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