- Drug repurposing and rediscovery: Design, synthesis and preliminary biological evaluation of 1-arylamino-3-aryloxypropan-2-ols as anti-melanoma agents
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Malignant melanoma (MM) presents as the highest morbidity and mortality type in skin cancer. Herein, inspired by the previously reported anti-melanoma effect of propranolol, a widely applied β adrenergic receptor antagonist as cardiovascular drug, we set out to exploit its potential as anti-melanoma therapy based on the drug repurposing strategy. Structural optimization of propranolol yielded 5m, which exhibits dramatically improved potency on human melanoma cell growth (1.98–3.70 μM), compared to propranolol (59.5–75.8 μM). Further investigation demonstrated that 5m could inhibit colony formation of melanoma cell line (completely abolished at 2 μM for 5m, partially inhibited at 50 μM for propranolol), induce cell apoptosis and cell cycle arrest in the G2/M phase (both observed at 1 μM). Preliminary mechanism study indicated that 5m could disrupt the cellular microtubule network, which suggested tubulin as a potential target. Docking study provided a structural insight into the interaction between 5m and tubulin. In summary, our study presents a drug repurposing case that redirects a cardiovascular agent to an anti-melanoma agent.
- Chang, Qi,Long, Jing,Hu, Liqing,Chen, Zhuo,Li, Qianbin,Hu, Gaoyun
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Read Online
- Propranolol Activates the Orphan Nuclear Receptor TLX to Counteract Proliferation and Migration of Glioblastoma Cells
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The ligand-sensing transcription factor tailless homologue (TLX, NR2E1) is an essential regulator of neuronal stem cell homeostasis with appealing therapeutic potential in neurodegenerative diseases and central nervous system tumors. However, knowledge on TLX ligands is scarce, providing an obstacle to target validation and medicinal chemistry. To discover TLX ligands, we have profiled a drug fragment collection for TLX modulation and identified several structurally diverse agonists and inverse agonists of the nuclear receptor. Propranolol evolved as the strongest TLX agonist and promoted TLX-regulated gene expression in human glioblastoma cells. Structure-activity relationship elucidation of propranolol as a TLX ligand yielded a structurally related negative control compound. In functional cellular experiments, we observed an ability of propranolol to counteract glioblastoma cell proliferation and migration, while the negative control had no effect. Our results provide a collection of TLX modulators as initial chemical tools and set of lead compounds and support therapeutic potential of TLX modulation in glioblastoma.
- Faudone, Giuseppe,Bischoff-Kont, Iris,Rachor, Lea,Willems, Sabine,Zhubi, Rezart,Kaiser, Astrid,Chaikuad, Apirat,Knapp, Stefan,Fürst, Robert,Heering, Jan,Merk, Daniel
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Read Online
- One pot synthesis of (±)/(S)-atenolol and (±)/(S)-propranolol by employing polymer supported reagent
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(±)/(S)-Atenolol and (±)/(S)-propranolol were synthesized by using reaction of (±)/(S)-epichlorohydrin with polymer supported phenoxide anion followed by reaction with isopropylamine.
- Damle, Subhash V.,Patil, Prashant N.,Salunkhe, Manikrao M.
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Read Online
- Relationship of nonspecific antiarrhythmic and negative inotropic activity with physicochemical parameters of propranolol analogues
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in an attempt to separate the nonspecific antiarrhythmic activity of propranolol from its negative inotropic effects, analogues containing hydrophilic and lipophylic substituents on the nitrogen and on the naphthyl ring were prepared and tested in an isolated tissue preparation. Though it had been predicted that analogues containing a very hydrophilic group on the nitrogen would have the highest antiarrhythmic/negative inotropic effect ratio, it was found that both effects increased identically when the lipophilicity of either the nitrogen or ring substituent was increased.
- Rauls,Baker
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Read Online
- Synthetic method of propranolol hydrochloride
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The invention belongs to the field of medicines, and particularly relates to a synthetic method of propranolol hydrochloride. The preparation method comprises the following steps: by taking epoxy chloropropane and methyl naphthol as raw materials and acetonitrile as a solvent, firstly reacting in tetramethylammonium hydroxide to obtain an intermediate product, then reacting the intermediate product with isopropylamine in the presence of a metal salt Ni/alpha-Al2O3 catalyst to obtain propranolol, and finally salinizing to obtain the propranolol hydrochloride. The method can significantly improve the yield and purity of the propranolol hydrochloride.
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Paragraph 0014; 0019-0020; 0023-0024; 0027-0035; 0038-0040
(2021/09/04)
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- NAFTOPIDIL MONOHYDROCHLORIDE DIHYDRATE AND USE THEREOF FOR PREPARATION OF NAFTOPIDIL
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PROBLEM TO BE SOLVED: To provide an intermediate that is useful for the preparation of naftopidil (Naftopidil, (2RS)-1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(naphthalene-1-yloxy)propan-2-ol), and a method for preparing naftopidil using the same. SOLUTION: By freeing naftopidil monohydrochloride dihydrate, naftopidil can be obtained in high yield and high purity. In particular, a purity of 99.99% can be achieved without repeating purification operation such as recrystallization multiple times. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2021,JPOandINPIT
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Paragraph 0024-0025
(2021/07/27)
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- Facile microwave-assisted synthesis and antitubercular evaluation of novel aziridine derivatives
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Novel 2-(aryloxymethyl)aziridines and 2-((3-aryl-1-phenylallyloxy)methyl)aziridine derivatives were prepared via ring-opening reaction of epoxides. The synthesized derivatives were characterized by using elemental analysis (EA), FT-IR, 13C NMR, and 1H NMR. The in vitro antitubercular activities of the synthesized compounds were evaluated against Mycobacterium tuberculosis H37Rv (MTB H37Rv) strain using MTT-MABA assay. All the aziridine derivatives exhibited improved persuasive antitubercular activity against MTB H37Rv in comparison with standard drugs. Among the tested compounds, 2-(naphthalene-1-yloxy) methyl aziridine (5b), 2-(naphthalene-2-yloxy)methylaziridine (5c), 2-(m-tolyloxymethyl)aziridine (5e), 2-(3-(4-methoxyphenyl)-1-phenylalloxy)methylaziridine (12b) and 2-(3-(2-chlorophenyl)-1-phenylallyloxy)methylaziridine (12c) revealed promising activity against MTB H37Rv. Specifically, compound 5b and 12 b showed three-times more active (MIC = 0.5 μg/mL) than the standard drugs ethambutol (MIC = 1.56 μg/mL) and ciprofloxacin (MIC = 1.56 μg/mL).
- Sarojini, Perumal,Jeyachandran, Malaichamy,Sriram, Dharmarajan,Ranganathan, Palraj,Gandhimathi
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- Synthesis and application of Cu(II) immobilized MCM-41 based solid Lewis acid catalyst for aminolysis reaction under solvent-free condition
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In this paper, a Cu(II) immobilized periodic mesoporous organosilica (PMOs) was synthesized and used as a reusable solid Lewis acid catalyst for the aminolysis of epoxides under solvent-free conditions. An amide-based ligand, L-propylsilyl (1) having a specific binding pocket was prepared and fabricated on mesoporous MCM-41 to produce mesoporous organosilica L-propylsilyl@MCM-41 (2). Further, it has been utilized for anchoring Cu(II) ions under controlled reaction conditions to yield solid Lewis acid catalyst Cu(II)-L-propylsilyl@MCM-41 (3). The synthesized catalyst 3 exhibits significantly higher catalytic activity for aminolysis compared to hitherto known solid Lewis acid catalysts. An extensive range of β-amino alcohols with high regio and stereoselectivity were prepared by using catalyst 3. The catalyst was recovered easily and reused eight times without any loss in its catalytic activity. Furthermore, the synthesis of clinically significant propranolol (β-blocker) from α- naphthyl glycidyl ether was attained successfully using catalyst 3 in a very decent yield.
- Chaudhary, Garima,Gupta, Neha,Singh, Amit Pratap
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- Synthetic method of propranolol hydrochloride (by machine translation)
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To the method, methylnaphthol and epichlorohydrin are subjected to etherification reaction under the action of an alkali condition and a phase transfer catalyst to obtain the key intermediate 3 - (1 - naphthyloxy) -1, 2 - epoxypropane, and then refined to obtain the propranolol hydrochloride crude product which has the advantages of short synthetic route, simple operation and suitableness for industrial production 99.8%. (by machine translation)
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Paragraph 0026-0029
(2020/06/30)
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- Identification of HUHS190, a human naftopidil metabolite, as a novel anti-bladder cancer drug
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We carried out structure-activity relationship study on anti-cancer effects of naftopidil (1) and its metabolites, resulted in identification of 1-(4-hydroxy-2-methoxyphenyl)piperazin-1-yl)-3-(naphthalen-1-yloxy) propan-2-ol (2, HUHS190), a major human metabolite of 1, which exhibited the most selective toxicities between against normal and cancer cells (Table 1). 2 was more hydrophilic compared to 1, was enough to be prepared in high concentration solution of more than 100 μM in saline for an intravesical instillation drug. Moreover, serum concentration of 2 was comparable to that of 1, an oral preparation drug, after oral administration at 32 mg/kg (Fig. 3). Both of 1 and 2 showed broad-spectrum anti-cancer activities in vitro, for example, 1 and 2 showed inhibitory activity IC50 = 21.1 μM and 17.2 μM for DU145, human prostate cancer cells, respectively, and IC50 = 18.5 μM and 10.5 μM for T24 cells, human bladder cancer cells. In this study, we estimated anticancer effects of 2 in a bladder cancer model after intravesical administration similar to clinical cases. A single intravesical administration of 2 exhibited the most potent inhibitory activities among the clinical drugs for bladder cancers, BCG and Pirarubicin, without obvious side effects and toxicity (Fig. 4). Thus, HUHS190 (2) can be effective for patients after post-TURBT therapy of bladder cancer without side effects, unlike the currently available clinical drugs.
- Fukuhara, Hiroshi,Gotoh, Akinobu,Kino, Yukari,Kurioka, Rina,Mabuchi, Miyuki,Matsunaga, Wataru,Nakao, Syuhei,Shimizu, Tadashi,Tanaka, Akito,Yamaguchi, Keiko,Yamamoto, Momoka
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- Facile Synthesis of Propranolol and Novel Derivatives
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Propranolol is one of the first medications of the beta-blocker used for antihypertensive drugs. This study reports the facile route for the synthesis of propranolol and its novel derivatives. Herein, propranolol synthesis proceeded from 1-naphthol and isopropylamine under mild and less toxic conditions. Novel propranolol derivatives were designed by reactions of propranolol with benzoyl chloride, pyridinium chlorochromate, and n-butyl bromide through esterification, oxidation reduction, and alkylation, respectively. The isolation and purity of compounds were conducted using column chromatography and thin-layer chromatography. Mass spectrometry and 1H-NMR spectroscopy were applied to identify new compounds structure. Propranolol derivatives from 2-chlorobenzoyl chloride (compound 3), 2-fluorobenzoyl chloride (compound 5), and especially acetic anhydride (compound 6) manifested high yields and significantly increased water solubility. Six semisynthetic propranolol derivatives promise to improve antioxidative and biological activities.
- Bach, Long Giang,Le, Van Thuan,Nguyen, Tan Tai,Nguyen, Thi Anh Nga,Nguyen, Thi Thuong,Nguyen, Trinh Duy,Tran, Nguyen Hai Tai,Tran, Vy Anh,Vo, The Ky,Vo, Thu-Thao Thi
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- Continuous flow upgrading of glycerol toward oxiranes and active pharmaceutical ingredients thereof
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A robust continuous flow procedure for the transformation of bio-based glycerol into high value-added oxiranes (epichlorohydrin and glycidol) is presented. The flow procedure features a central hydrochlorination/dechlorination sequence and provides economically and environmentally favorable conditions involving an organocatalyst and aqueous solutions of hydrochloric acid and sodium hydroxide. Pimelic acid (10 mol%) shows an exceptional catalytic activity (>99% conversion of glycerol, a high selectivity toward 1,3-dichloro-2-propanol and 81% cumulated yield toward intermediate chlorohydrins) for the hydrochlorination of glycerol (140 °C) with 36 wt% aqueous HCl. These conditions are validated on a sample of crude bio-based glycerol. The dechlorination step is effective (quantitative conversion based on glycerol) with concentrated aqueous sodium hydroxide (20 °C) and can be directly concatenated to the hydrochlorination step, hence providing a ca. 2:3 separable mixture of glycidol and epichlorohydrin (74% cumulated yield). An in-line membrane separation unit is included downstream, providing usable streams of epichlorohydrin (in MTBE, with an optional concentrator) and glycidol (in water). The scalability of the dechlorination step is then assessed in a commercial pilot-scale continuous flow reactor. Next, bio-based epichlorohydrin is further utilized for the continuous flow preparation of β-amino alcohol active pharmaceutical ingredients including propranolol (hypertension, WHO essential), naftopidil (prostatic hyperplasia) and alprenolol (angina pectoris) within a concatenable two-step procedure using a FDA class 3 solvent (DMSO). This work provides the first example of direct upgrading of bio-based glycerol into high value-added pharmaceuticals under continuous flow conditions.
- Morodo, Romain,Gérardy, Romaric,Petit, Guillaume,Monbaliu, Jean-Christophe M.
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supporting information
p. 4422 - 4433
(2019/08/21)
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- A facile and efficient method for synthesis of β-iodocarboxylates from terminal epoxides
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A facile and efficient method has been developed for synthesis of β-iodocarboxylates in the presences of Ph3P/I2. Starting from epoxides, a series of β-iodocarboxylate compounds can be directly obtained in toluene media with excellent yields. Moreover, the method was successfully applied for the late-stage modification of natural products, such as isosteviol and vincamine derivatives, achieving the corresponding β-iodocarboxylates in good yields.
- Zhu, Ye-Fu,Wei, Bo-Le,Wang, Wen-Qiong,Xuan, Li-Jiang
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supporting information
(2019/11/26)
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- NBS/DMSO-mediated synthesis of (2,3-dihydrobenzo[b] [1,4]oxathiin-3-yl)methanols from aryloxymethylthiiranes
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(2,3-Dihydrobenzo[b][1,4]oxathiin-3-yl)methanols were synthesized via reactions of aryloxymethylthiiranes and N-bromosuccinimide (NBS) in DMSO under microwave irradiation. The reaction mechanism was proposed as an intramolecular aromatic electrophilic substitution of 1-bromo-2-(aryloxymethyl)thiiran-1-iums, generated from aryloxymethylthiiranes and NBS, and the subsequent DMSO nucleophilic ring opening reaction of thiiran-1-iums followed by the water displacement. The current method provides a direct and simple strategy in the efficient preparation of (2,3-dihydrobenzo[b][1,4]oxathiin-3-yl)methanols from readily available aryloxymethylthiiranes.
- Dong, Jun,Xu, Jiaxi
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p. 9037 - 9044
(2018/06/08)
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- Selective Palladium(II)-Catalyzed Carbonylation of Methylene β-C?H Bonds in Aliphatic Amines
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Palladium(II)-catalyzed C?H carbonylation reactions of methylene C?H bonds in secondary aliphatic amines lead to the formation of trans-disubstituted β-lactams in excellent yields and selectivities. The generality of the C?H carbonylation process is aided by the action of xantphos-based ligands and is important in securing good yields for the β-lactam products.
- Cabrera-Pardo, Jaime R.,Trowbridge, Aaron,Nappi, Manuel,Ozaki, Kyohei,Gaunt, Matthew J.
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supporting information
p. 11958 - 11962
(2017/09/20)
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- Solvent-Directed Epoxide Opening with Primary Amines for the Synthesis of β-Amino Alcohols
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An efficient synthesis of β-amino alcohols from a variety of epoxides and primary unbranched amines in the absence of any catalyst in high yields and regioselectivities is reported. A variety of polar mixed solvent systems allow for the selective formation of secondary amino alcohols over tertiary amino alcohols. The reaction scope extends to a wide variety of aromatic and aliphatic substituted epoxides and primary amines bearing complex functionality.
- Lizza, Joseph R.,Moura-Letts, Gustavo
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supporting information
p. 1231 - 1242
(2017/03/11)
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- Autophagy and phospholipidosis pathway assays
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Provided are assays useful for detecting and monitoring autophagy and phospholipidosis, including the progression of lysosomal storage diseases. Drugs and treatments for lysosomal storage diseases can be monitored for effectiveness in lysosomal storage disease conditions. Drug candidates and suspected toxic agents can also be screened for toxicity to cells, tissues and organs. Also provided are methods for distinguishing between phospholipidosis activators and autophagy pathway perturbation agents.
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Page/Page column 58
(2016/02/26)
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- Chemoenzymatic synthesis of (R)- and (S)-propranolol using an engineered epoxide hydrolase with a high turnover number
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Simultaneous synthesis of the R- and S-enantiomers of biologically active propranolol, a typical β-blocker, was achieved in high optical purity via an epoxide hydrolase-catalyzed resolution of racemic α-naphthyl glycidyl ether (rac-1). A preparative resolution of 100 g/L rac-1 was accomplished with high enantioselectivity (E = 92) using a variant of Bacillus megaterium epoxide hydrolase (BmEHF128T). A biphasic system (isopropyl ether/isooctane/aqueous) was used, in which the product 3-(1′-naphthyloxy)-propane-1,2-diol (2) precipitated instantly, facilitating its separation and increasing the enantiopurity of (R)-2 (>99.5% ee). This enzymatic resolution had a total turnover number of 70,000, affording enantiopure epoxide (S)-1 (>99% ee) and 1,2-diol (R)-2 (>99% ee) in 45.3% and 42.4% yields, respectively. (R)-2 and (S)-1 were subsequently converted to (R)- and (S)-propranolol (3) (>99% ee) in overall yields of 31.4% and 44.8%. To the best of our knowledge, this is the best case for enzymatic resolution of rac-1 using an epoxide hydrolase, giving high space-time yields [136 g L-1 days-1 for (S)-1 and 139 g L-1 days-1 for (R)-2] under mild reaction conditions. It provides a new and eco-friendly route that complements other methods using organometallic catalysts.
- Kong, Xu-Dong,Yu, Hui-Lei,Yang, Sheng,Zhou, Jiahai,Zeng, Bu-Bing,Xu, Jian-He
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p. 275 - 281
(2015/11/02)
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- Synthesis of (S)-(-)-propranolol by using Cs2.5H0.5PW12O40 nanocatalyst as green, eco-friendly, reusable, and recyclable catalyst
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The Cs2.5H0.5PW12O40 nanoparticle catalyst appear to be a new and efficient solid acid catalyst for an economical, environmentally benign synthesis of (S)-(-)-propranolol. Cs2.5H0.5PW12O40 nanocatalyst are used as a new, recyclable and reusable. Synthesis of (S)-(-)-propranolol is carried out in two steps with usual reagents: heteropolyacid, (+)-tartaric acid catalyzed enantioselective synthesis of (S)-(-)-propranolol via kinetic resolution of key intermediate α-naphthyl glycidyl ether with high optical and chemical yield. With this synthesis, we have two products in the first reaction and it is not necessary to purify the crude oil. This by-product is removed in the second step by extraction and yield is satisfactory. The nanocatalyst of Cs2.5H0.5PW12O40 catalyzed the synthesis of propranolol in high yields and good selectivity.
- Gharib, Ali,Jahangir, Manouchehr,Roshani, Mina,Pesyan, Nader Noroozi,Scheeren,Mohadesazadeh, Sara,Lagzian, Shirin
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p. 350 - 355
(2015/02/02)
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- Continuous and convergent access to vicinyl amino alcohols
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Five active pharmaceutical ingredients (APIs) containing the vicinyl amino alcohol moiety were synthesized using a convergent chemical assembly system. The continuous system is composed of four flow reaction modules: biphasic oxidation, Corey-Chaykovsky epoxidation, phenol alkylation, and epoxide aminolysis. Judicious choice of reagents and module order allowed for two classes of β-amino alcohols, aryl and aryloxy, to be synthesized in good (27-69%) overall yields.
- Nobuta, Tomoya,Xiao, Guozhi,Ghislieri, Diego,Gilmore, Kerry,Seeberger, Peter H.
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supporting information
p. 15133 - 15136
(2015/10/12)
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- STORE OVERLOAD-INDUCED CALCIUM RELEASE INHIBITORS AND METHODS FOR PRODUCING AND USING THE SAME
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The present invention provides compounds having store overload-induced Ca2+ release (SOICR) inhibitory activity and methods for producing and using the same. In particular, compounds of the invention is of the formula: R1-X1-L-X2-R2, wherein R1, X1, L, X2, and R2 are those defined herein.
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- Magnetic nano Fe3O4 catalyzed solvent-free stereo- and regioselective a-aminolysis of epoxides by amines; A green method for the synthesis of β-amino alcohols
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We report the use of magnetic nano Fe3O4 as a mild heterogeneous catalyst for the aminolysis of epoxides with amines. The approach constitutes a green method for the formation of a variety of β-amino alcohols with very high stereo- and regioselectivity under solvent-free and ambient reaction conditions. The aminolysis of chiral epoxides with amines gave the corresponding chiral β-amino alcohols with complete inversion of stereochemistry. The magnetic nano Fe3O4 catalyst can be easily recovered and recycled. Georg Thieme Verlag Stuttgart New York.
- Kumar, Amit,Parella, Ramarao,Babu, Srinivasarao Arulananda
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p. 835 - 842
(2014/04/17)
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- A smart library of epoxide hydrolase variants and the top hits for synthesis of (S)-β-blocker precursors
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Microtuning of the enzyme active pocket has led to a smart library of epoxide hydrolase variants with an expanded substrate spectrum covering a series of typical β-blocker precursors. Improved activities of 6- to 430-fold were achieved by redesigning the active site at two predicted hot spots. This study represents a breakthrough in protein engineering of epoxide hydrolases and resulted in enhanced activity toward bulky substrates. Hot pockets: Microtuning of the enzyme active pocket gives a smart library of epoxide hydrolase variants with an expanded substrate spectrum covering a series of typical β-blocker precursors. Improved activities of 6- to 430-fold were achieved by redesigning the active site at two predicted hot spots, and enhanced activity toward bulky substrates was found.
- Kong, Xu-Dong,Ma, Qian,Zhou, Jiahai,Zeng, Bu-Bing,Xu, Jian-He
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supporting information
p. 6641 - 6644
(2014/07/08)
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- Synergistic dual activation catalysis by palladium nanoparticles for epoxide ring opening with phenols
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Synergistic dual activation catalysis has been devised for epoxide phenolysis wherein palladium nanoparticles induce electrophilic activation via coordination with the epoxide oxygen followed by nucleophilic activation through anion-π interaction with the aromatic ring of the phenol, and water (reaction medium) also renders assistance through 'epoxide-phenol' dual activation.
- Seth, Kapileswar,Roy, Sudipta Raha,Pipaliya, Bhavin V.,Chakraborti, Asit K.
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supporting information
p. 5886 - 5888
(2013/07/25)
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- Nonpeptidic propargylamines as inhibitors of lysine specific demethylase 1 (LSD1) with cellular activity
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Lysine demethylases play an important role in epigenetic regulation and thus in the development of diseases like cancer or neurodegenerative disorders. As the lysine specific demethylase 1 (LSD1/KDM1) has been strongly connected to androgen and estrogen dependent gene expression, it serves as a promising target for the therapy of hormone dependent cancer. Here, we report on the discovery of new small molecule inhibitors of LSD1 containing a propargylamine warhead, starting out from lysine containing substrate analogues. On the basis of these substrate mimicking inhibitors, we were able to increase potency by a combination of similarity-based virtual screening and subsequent synthetic optimization resulting in more druglike LSD1 inhibitors that led to histone hypermethylation in breast cancer cells.
- Schmitt, Martin L.,Hauser, Alexander-Thomas,Carlino, Luca,Pippel, Martin,Schulz-Fincke, Johannes,Metzger, Eric,Willmann, Dominica,Yiu, Teresa,Barton, Michelle,Schüle, Roland,Sippl, Wolfgang,Jung, Manfred
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supporting information
p. 7334 - 7342
(2013/10/21)
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- Novel carvedilol analogues that suppress store-overload-induced Ca 2+ release
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Carvedilol is a uniquely effective drug for the treatment of cardiac arrhythmias in patients with heart failure. This activity is in part because of its ability to inhibit store-overload-induced calcium release (SOICR) through the RyR2 channel. We describe the synthesis, characterization, and bioassay of ca. 100 compounds based on the carvedilol motif to identify features that correlate with and optimize SOICR inhibition. A single-cell bioassay was employed on the basis of the RyR2-R4496C mutant HEK-293 cell line in which calcium release from the endoplasmic reticulum through the defective channel was measured. IC50 values for SOICR inhibition were thus obtained. The compounds investigated contained modifications to the three principal subunits of carvedilol, including the carbazole and catechol moieties, as well as the linker chain containing the β-amino alcohol functionality. The SAR results indicate that significant alterations are tolerated in each of the three subunits.
- Smith, Chris D.,Wang, Aixia,Vembaiyan, Kannan,Zhang, Jingqun,Xie, Cuihong,Zhou, Qiang,Wu, Guogen,Chen, S. R. Wayne,Back, Thomas G.
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p. 8626 - 8655
(2013/12/04)
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- HIGH REFRACTIVE ACRYLATE AND THE METHOD FOR PREPARING THE SAME
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Provided is an acrylate having a high refractive index, which is represented by Chemical Formula (1) or (2), and a method for preparing the same. Since the acrylate has a refractive index, it may be widely applicable to components of display devices such as prism sheet and may be prepared simply, effectively and economically.
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- Synthesis, biological evaluation and mechanistic studies of totarol amino alcohol derivatives as potential antimalarial agents
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Herein we report on the semisynthesis and biological evaluation of β-amino alcohol derivatives of the natural product totarol and other simple aromatic systems. All β-amino alcohol derivatives of totarol exhibited higher antiplasmodial activity than totarol [IC50: 11.69 μM (K1, chloroquine and multi-drug resistant strain), and 11.78 μM (D10, chloroquine sensitive strain)] - 12e was the most active [IC50: 0.63 μM (K1), and 0.61 μM (D10)]. The phenyl and naphthyl β-amino alcohol derivatives were much less active than their corresponding totarol equivalents. The majority of the β-amino alcohol derivatives of totarol were more active against K1 than the D10 strains of Plasmodium falciparum, a trend similar to the inverse relationship observed with the established aryl-amino alcohol antimalarial mefloquine. Selected compounds were shown to affect erythrocyte morphology, inhibit erythrocyte invasion and trigger CQ accumulation.
- Tacon, Claire,Guantai, Eric M.,Smith, Peter J.,Chibale, Kelly
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experimental part
p. 893 - 902
(2012/03/22)
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- An improved method for the conversion of oxiranes to thiiranes and the discrimination of their base peaks in EI-MS
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An efficient method for the conversion of oxiranes to thiiranes by treatment with excess ammonium thiocyanate in aqueous media under reflux or by microwave irradiation is reported. ARKAT-USA, Inc.
- Chen, Hsing-Ming,Chen, Po-Yuan,Wang, Chih-Feng,Tsai, Jui-Chi,Wang, Eng-Chi
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body text
p. 157 - 168
(2012/10/18)
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- An unusual (R)-selective epoxide hydrolase with high activity for facile preparation of enantiopure glycidyl ethers
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A novel epoxide hydrolase (BMEH) with unusual (R)-enantioselectivity and very high activity was cloned from Bacillus megaterium ECU1001. Highest enantioselectivities (E>200) were achieved in the bioresolution of ortho-substituted phenyl glycidyl ethers and para-nitrostyrene oxide. Worthy of note is that the substrate structure remarkably affected the enantioselectivities of the enzyme, as a reversed (S)-enantiopreference was unexpectedly observed for the ortho-nitrophenyl glycidyl ether. As a proof-of-concept, five enantiopure epoxides (>99% ee) were obtained in high yields, and a gram-scale preparation of (S)-ortho-methylphenyl glycidyl ether was then successfully performed within a few hours, indicating that BMEH is an attractive biocatalyst for the efficient preparation of optically active epoxides. Copyright
- Zhao, Jing,Chu, Yan-Yan,Li, Ai-Tao,Ju, Xin,Kong, Xu-Dong,Pan, Jiang,Tang, Yun,Xu, Jian-He
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experimental part
p. 1510 - 1518
(2011/08/03)
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- Analysis of β-amino alcohols as inhibitors of the potential anti-tubercular target N-acetyltransferase
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The synthesis and inhibitory potencies of a novel series of β-amino alcohols, based on the hit-compound 3-[3′-(4″-cyclopent-2?- en-1?-ylphenoxy)-2′-hydroxypropyl]-5,5 dimethylimidazolidine-2,4- dione as specific inhibitors of mycobacterial N-acetyltransferase (NAT) enzymes are reported. Effects of synthesised compounds on growth of Mycobacterium tuberculosis have been determined.
- Fullam, Elizabeth,Abuhammad, Areej,Wilson, David L.,Anderton, Matthew C.,Davies, Steve G.,Russell, Angela J.,Sim, Edith
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supporting information; experimental part
p. 1185 - 1190
(2011/04/16)
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- Synthesis and characterization of high-affinity 4,4-difluoro-4-bora-3a,4a- diaza-s-indacene-labeled fluorescent ligands for human β-adrenoceptors
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The growing practice of exploiting noninvasive fluorescence-based techniques to study G protein-coupled receptor pharmacology at the single cell and single molecule level demands the availability of high-quality fluorescent ligands. To this end, this study evaluated a new series of red-emitting ligands for the human β-adrenoceptor family. Upon the basis of the orthosteric ligands propranolol, alprenolol, and pindolol, the synthesized linker-modified congeners were coupled to the commercially available fluorophore BODIPY 630/650-X. This yielded high-affinity β-adrenoceptor fluorescent ligands for both the propranolol and alprenolol derivatives; however, the pindolol-based products displayed lower affinity. A fluorescent diethylene glycol linked propranolol derivative (18a) had the highest affinity (log KD of -9.53 and -8.46 as an antagonist of functional β2- and β1-mediated responses, respectively). Imaging studies with this compound further confirmed that it can be employed to selectively label the human β2-adrenoceptor in single living cells, with receptor-associated binding prevented by preincubation with the nonfluorescent β2-selective antagonist 3-(isopropylamino)-1-[(7- methyl-4-indanyl)oxy]butan-2-ol (ICI 118551) (J. Cardiovasc. Pharmacol.1983, 5, 430-437.)
- Baker, Jillian G.,Adams, Luke A.,Salchow, Karolina,Mistry, Shailesh N.,Middleton, Richard J.,Hill, Stephen J.,Kellam, Barrie
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scheme or table
p. 6874 - 6887
(2011/12/15)
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- Synthesis of novel aryloxy propanoyl thiadiazoles as potential antihypertensive agents
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2-Amino-5-aryl/alkyl-1,3,4-thiadiazoles 3a-e were synthesized from aliphatic and aromatic acids and thiosemicarbazide. These 2-amino-5-aryl/alkyl- 1,3,4-thiadiazoles 3a-e were condensed with 2-(naphthalenyloxymethyl) oxirane 4a-b to prepare some naphthalenyloxy-propanol amine derivatives 5a-j. These compounds were synthesized as potential antihypertensive agents.
- Samel, Amarish B.,Pai, Nandini R.
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experimental part
p. 1327 - 1330
(2011/10/07)
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- Synthesis of aryloxyacetaldehydes and N-(aryloxyethyl)cyclohexanamine hydrochloroides
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Oxidation of 2-(aryloxymethyl)oxiranes with periodic acid gave a series of aryloxyacetaldehydes which reacted with cyclohexylamine in THF, and subsequent reduction of Schiff bases thus obtained with sodium tetrahydridoborate resulted in the formation of the corresponding secondary amines which were isolated and characterized as hydrochlorides.
- Shapenova,Belyatskii,Panicheva
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experimental part
p. 1017 - 1020
(2010/10/21)
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- SUBSTITUTED BETA-PHENYL-ALPHA-HYDROXY PROPANOIC ACID, SYNTHESIS METHOD AND USE THEREOF
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The present invention relates to a compound of the formula (I), wherein R1, R2 and R3 are each independently selected from H, OH, F, Cl, Br, methoxy and ethoxy; or alternatively, R1 and R2 together form -OCH2O-, R3 is selected from H, OH, methoxy, ethoxy and halogens; R4 is OH or acyloxy; R5 is cycloalkoxyl, amino and substituted amino, and when R5 is selected from amino, at least one of R1, R2 and R3 is not H. The present invention further relates to a process for synthesizing a compound of the formula (I), and use of the compound of the formula (I) in the manufacture of a medicament for the prevention or treatment of cardiovascular or cerebrovascular diseases.
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Page/Page column 11
(2009/02/10)
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- Zinc(II) perchlorate hexahydrate catalyzed opening of epoxide ring by amines: Applications to synthesis of (RS)/(R)-propranolols and (RS)/(R)/(S)-naftopidils
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(Figure Presented) Commercially available zinc(II) Perchlorate hexahydrate [Zn(ClO4)2·6H2O] was found to be a new and highly efficient catalyst for opening of epoxide rings by amines affording 2-amino alcohols in high yields under solvent-free conditions and with excellent chemo-, regio-, and stereoselectivities. For unsymmetrical epoxides, the regioselectivity was influenced by the electronic and steric factors associated with the epoxides and the amines. A complementarity in the regioselectivity was observed during the reaction of styrene oxide with aromatic and aliphatic amines: aromatic amines provided amino alcohols from nucleophilic attack at the benzylic carbon as major products whereas aliphatic amines resulted in formation of the amino alcohols through reaction at the terminal carbon atom of the epoxide ring as the major/sole products. Reaction of aniline with various glycidic ethers gave the amino alcohols by regioselective nucleophilic attack at the terminal carbon atom of the epoxide ring as the only/major product. Zinc(II) Perchlorate hexahydrate was found to be the best catalyst compared to other metal Perchlorates. The counteranion modulated the catalytic property of the various Zn(II) compounds that followed the order Zn(ClO4) 2·6H2O Zn(BF4)2 ~ Zn(OTf)2 ZnI2 > ZnBr2 > ZnCl2 > Zn(OAc)2 > Zn(CO3)2 in parallelism with the acidic strength of the corresponding protic acids (except for TfOH). The applicability of the methodology was demonstrated by the synthesis of cardiovascular drugs propranolol and naftopidil as racemates and optically active enantiomers.
- Shivani,Pujala, Brahmam,Chakraborti, Asit K.
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p. 3713 - 3722
(2008/02/05)
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- Synthesis of some novel thioxanthenone-fused azacrown ethers, and their use as new catalysts in the efficient, mild, and regioselective conversion of epoxides to β-hydroxy thiocyanates with ammonium thiocyanate
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The regioselective ring-opening reactions of some epoxides with ammonium thiocyanate in the presence of a series of new 9H-thioxanthen-9-one-fused azacrown ethers, i.e., 7-11 (Scheme 1), and also of dibenzo[18]crown-6 (12), Kryptofix 22 (13), and benzo[15]crown-5 (14) were studied (Tables 1 and 2). The epoxides were subjected to cleavage by NH4SCN in the presence of these catalysts under mild conditions in various aprotic solvents. Reagents and conditions were identified for the synthesis of individual β-hydroxy thiocyanates in high yield and with more than 90% regioselectivity. The results can be discussed in terms of a four-step mechanism (Scheme 2): 1) formation of a complex between catalyst and NH4SCN, 2) release of SCN- from the complex, 3) reaction of the released SCN- at the sterically less hindered site of the epoxide, and 4) regeneration of the catalyst. The major advantages of this method are the high regioselectivity, the simple regeneration of the catalyst, the reuse of it through several cycles without a decrease of activity, and the ease of workup of the reaction mixtures.
- Sharghi, Hashem,Beni, Alireza Salimi,Khalifeh, Reza
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p. 1373 - 1385
(2008/02/07)
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- Improvement and simplification of synthesis of 3-aryloxy-1,2-epoxypropanes using solvent-free conditions and microwave irradiations. Relation with medium effects and reaction mechanism
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Some 3-aryloxy-1,2-epoxypropanes, interesting as potential synthons in β-adrenergic receptor antagonists preparation, were obtained in excellent yields (65-96% within 2-17 min) by microwave activation (monomode system) using solid-liquid solvent-free phase transfer catalysis (PTC). The best results for the O-alkylation of some phenols with epichlorohydrin were obtained using TBAB and NaOH/K2CO3 (1:4 mol/mol) as phase transfer catalyst and more acceptable basic system, respectively. These new procedure is compared with classical methods. Significant specific microwave effect (non-purely thermal) was evidenced in all cases. They were discussed in terms of reaction medium and mechanism, taking into account the variations in polarity of the systems.
- Pchelka, Beata K.,Loupy, Andre,Petit, Alain
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p. 10968 - 10979
(2007/10/03)
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- New propranolol analogues: Binding and chiral discrimination by cellobiohydrolase Cel7A
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Novel propranolol analogues have been designed and synthesised and their enantioselective binding to the cellulose degrading enzyme, Cel7A, has been evaluated. Affinity and enantioselectivity have been determined by capillary electrophoresis experiments. Ligands with significantly improved affinity and selectivity have been obtained and an analysis of the results has led to insights concerning the relation between the changes in ligand structure and selectivity as well as affinity to the protein. The Royal Society of Chemistry 2006.
- Fagerstroem, Alexandra,Nilsson, Mikael,Berg, Ulf,Isaksson, Roland
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p. 3067 - 3076
(2008/02/12)
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- Synthesis and evaluation of uterine relaxant activity for a novel series of substituted p-hydroxyphenylethanolamines
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Novel racemic 1-(4-hydroxyphenyl)-2-[3-(substituted phenoxy)-2-hydroxy-1-propyl]aminopropan-1-ol hydrochlorides (9a-h) were synthesized by condensing racemic 1-(p-hydroxyphenyl)-2-aminopropan-1-ol hydrochloride (6) with substituted aryloxymethyloxiranes (8a-h) in DMF in presence of anhydrous potassium carbonate and then reacting with dry hydrogen chloride gas. They were evaluated for uterine relaxant activity in vitro on isolated rat uterus and in vivo in pregnant rats. Their cAMP releasing potential was studied using rat uterus tissue homogenates by cAMP [3H] assay and cardiac stimulant potential was evaluated in dog. All compounds exhibited potent uterine relaxant activity in vitro and produced a significant delay in the onset of labour in pregnant rats; their cAMP releasing potential was higher than isoxsuprine hydrochloride except for 9b and 9c. Finally insignificant cardiac stimulant potential was noted for these compounds when compared to isoxsuprine hydrochloride.
- Viswanathan,Chaudhari
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p. 6581 - 6585
(2007/10/03)
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- Hydrolytic kinetic resolution of α-naphthyl glycidyl ether: A practical access to highly enantioselective β-adrenergic blocking agents
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Kinetic resolution of (±)-naphthyl glycidyl ether using 0.5 mol% (R,R)-salen Co(III)OAc and water (0.55 equiv) provided enantiomerically pure naphthyl glycidyl ether and 1-naphthylglycerol derivatives with high enantiomeric excess. Application of this approach to highly enantioenriched (S)-naftopidil and (S)-propranolol is described. Georg Thieme Verlag Stuttgart.
- Subhas Bose,Narsimha Reddy,Chavhan, Sanjay W.
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p. 2345 - 2348
(2007/10/03)
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- Complete assignments of 1H and 13C NMR data for ten phenylpiperazine derivatives
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Ten phenylpiperazine derivatives were designed and synthesized. The first complete assignments of 1H and 13C NMR chemical shifts for these phenylpiperazine derivatives were achieved by means of 1D and 2D NMR techniques, including 1H-1H COSY, HSQC and HMBC spectra. Copyright
- Xiao, Zhihui,Yuan, Mu,Zhang, Si,Wu, Jun,Qi, Shuhua,Li, Qingxin
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p. 869 - 872
(2007/10/03)
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- The first enantiomerically pure synthesis of (S)- And (R)-naftopidil utilizing hydrolytic kinetic resolution of (±)-(α-Naphthyl) glycidyl ether
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Hydrolytic Kinetic Resolution (HKR) of (±)-(α-Naphthyl) glycidyl ether with (R,R)-salen Co(III) OAc complex provided enatiomerically pure (S)-naphthyl glycidyl ether and (R)-1-naphthyl glycerol; opening of the corresponding pure terminal epoxide with 1-(2-methoxyphenyl)piperizine gave the enantiomerically pure (S)- and (R)-Naftopidil.
- Kothakonda, Kiran Kumar,Bose, D. Subhas
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p. 1212 - 1213
(2007/10/03)
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- Azolidines as beta-3 adrenergic receptor agonists
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This invention provides compounds of Formula I having the structure wherein, A, X, Y, Z, W, R1, R2, R3, R4, R5, and R6 are as defined hereinbefore or a pharmaceutically acceptable salt thereof, which are useful in treating or inhibiting metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
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- Enantioselective synthesis of β-hydroxy amines and aziridines using asymmetric transfer hydrogenation of α-amino ketones
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Enantioselective transfer hydrogenation of α-amino ketones is an effective method for the asymmetric synthesis of β-hydroxy amines and aziridines.
- Kawamoto,Wills
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p. 1916 - 1928
(2007/10/03)
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- Resolution of racemic 1-azido-3-aryloxy-2-propanols by lipase-catalyzed enantioselective acetylation
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Kinetic resolution of racemic 1-azido-3-aryloxy-2-propanols 1a-g was performed using supported lipase of Candida antarctica-B (Novozym() SP 435) in toluene at 4°C with isopropenyl acetate as the acyl donor to afford the optically active (S)-alcohols 2a-g and their corresponding (R)-acetates 3a-g with E values from 56 to 72. Copyright (C) 2000 Elsevier Science Ltd.
- Pchelka, Beata Krystyna,Loupy, Andre,Plenkiewicz, Jan,Blanco, Luis
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p. 2719 - 2732
(2007/10/03)
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- Method of using calcilytic compounds
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The present invention features calcilytic compounds. "Calcilytic compounds" refer to compounds able to inhibit calcium receptor activity. Also described are the use of calcilytic compounds to inhibit calcium receptor activity and/or achieve a beneficial effect in a patient; and techniques which can be used to obtain additional calcilytic compounds.
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- Process for the preparation of 3-amino-2-hydroxy-1-propyl ethers
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PCT No. PCT/JP97/03220 Sec. 371 Date Apr. 28, 1999 Sec. 102(e) Date Apr. 28, 1999 PCT Filed Sep. 12, 1997 PCT Pub. No. WO98/12171 PCT Pub. Date Mar. 26, 1998A process for preparation of 3-amino-2-hydroxy-1-propyl ether of the formula wherein R1 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic ring, R2 and R3 are the same or different hydrogen atom, a substituted or unsubstituted alkyl, or may form a ring together with an adjacent nitrogen atom, which ring may be interrupted with nitrogen atom, oxygen atom or sulfur atom, which is characterized in reacting an epoxy compound of the formula wherein X is halogen, in the presence of a fluoride salt, with an alcohol and then reacting an amine. According to the above method, an intermediates for synthesis of medicines is obtained in good yield and highly optical purity.
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- Process for preparation of glycidyl ether
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PCT No. PCT/JP97/03221 Sec. 371 Date Apr. 29, 1999 Sec. 102(e) Date Apr. 29, 1999 PCT Filed Sep. 12, 1997 PCT Pub. No. WO98/12186 PCT Pub. Date Mar. 26, 1998A process for preparation of a glycidyl ether which is characrelized in reacting an epoxy compound of the formula wherein X is halogen or sulfonyloxy in the presence of a fluoride salt, with an alcohol. According to the above method, glycigyl ethers or their optically active compounds important as intermediates for synthesis of medicines are easily obtained in good yield and especially the optically active compounds are obtained with highly optical purity.
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- 4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists
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PCT No. PCT/US96/20872 Sec. 371 Date Sep. 16, 1998 Sec. 102(e) Date Sep. 16, 1998 PCT Filed Dec. 20, 1996 PCT Pub. No. WO97/23216 PCT Pub. Date Jul. 3, 1997Novel 4-substituted piperidine analogs, pharmaceutical compositions containing the same and the method of using 4-substituted piperidine analogs are selective active antagonists of N-methyl-D-aspartate (NMDA) receptor subtypes for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, psychosis, anxiety, migraine headaches, glaucoma, CMV retinitis, aminoglycoside antibiotics-induced hearing loss, convulsions, chronic pain, opioid tolerance or withdrawal, urinary incontinence or neurodegenerative disorders, such as lathyrism, Alzheimer's Disease, Parkinsonism and Huntington's Disease are described.
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- Synthesis of 3-O-aryl esters of (R,S)-9-(2,3-dihydroxypropyl)adenine and its pyrimidine analogs as new potential inhibitors of S-adenosyl-L-homocysteine hydrolase
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With the aim of searching for new antiviral agents of the acyclonucleoside type, 3-O-aryl esters of (R,S)-9-(2,3-dihydroxypropyl)adenine and its pyrimidine analogs have been synthesized. Alkylation of adenine and cytosine by aryl glycidyl ethers in the presence of potassium carbonate affords 46-76% yields of the corresponding N9- and N1-substituted derivatives. The interaction of aryl glycidyl ethers with trimethylsilyl derivatives of uracil and thymine also results in 41-57% yields of N1-monosubstituted products with identical acyclic chain structure. 1999 KluwerAcademic/Plenum.
- Ozerov,Novikov,Brel'
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