- Discovery of quinazoline derivatives as a novel class of potent and in vivo efficacious LSD1 inhibitors by drug repurposing
-
Histone lysine-specific demethylase 1 (LSD1) is an important epigenetic modulator, and is implicated in malignant transformation and tumor pathogenesis in different ways. Therefore, the inhibition of LSD1 provides an attractive therapeutic target for cancer therapy. Based on drug repurposing strategy, we screened our in-house chemical library toward LSD1, and found that the EGFR inhibitor erlotinib, an FDA-approved drug for lung cancer, possessed low potency against LSD1 (IC50 = 35.80 μM). Herein, we report our further medicinal chemistry effort to obtain a highly water-soluble erlotinib analog 5k (>100 mg/mL) with significantly enhanced inhibitory activity against LSD1 (IC50 = 0.69 μM) as well as higher specificity. In MGC-803 cells, 5k suppressed the demethylation of LSD1, indicating its cellular activity against the enzyme. In addition, 5k had a remarkable capacity to inhibit colony formation, suppress migration and induce apoptosis of MGC803 cells. Furthermore, in MGC-803 xenograft mouse model, 5k treatment resulted in significant reduction in tumor size by 81.6% and 96.1% at dosages of 40 and 80 mg/kg/d, respectively. Our findings indicate that erlotinib-based analogs provide a novel structural set of LSD1 inhibitors with potential for further investigation, and may serve as novel candidates for the treatment of LSD1-overexpressing cancers.
- Li, Zhonghua,Li, Zhongrui,Ma, Jinlian,Miao, Jinxin,Qin, Tingting,Yang, Nian,Zhang, Xinhui,Zhang, Zhenqiang,Zhao, Taoqian,Zhao, Xuan
-
-
- Synthesis method of 1-phenyl-5-mercaptotetrazole
-
The invention relates to a synthesis method of 1-phenyl-5-mercaptotetrazole, which comprises the steps of (1) by using sodium anilino dithiocarboxylate and sodium azide as raw materials, water as a reaction solvent and an alkaline solution as a catalyst, carrying out heating reflux reaction, and neutralizing the reaction solution with an acid after the reaction is ended to obtain a 1-phenyl-5-mercaptotetrazole crude product; and (2) recrystallizing the 1-phenyl-5-mercaptotetrazole crude product obtained in the step (1) by using a recrystallization solution to obtain a 1-phenyl-5-mercaptotetrazole finished product, wherein the recrystallization solution is a mixed solution of toluene and water. The 1-phenyl-5-mercaptotetrazole prepared by the method is high in purity, safer in reaction process and suitable for industrial production.
- -
-
Paragraph 0016; 0019-0026
(2020/12/31)
-
- Synthesis of 5-{[(1-Aryl-1H-1,2,3-triazol-4-yl)methyl]sulfanyl}-1-phenyl-1H-tetrazoles
-
Abstract: A series of novel 5-(1,2,3-triazolylmethylsulfanyl)tetrazole derivatives were synthesized by the click reaction from 1-phenyl-5-(prop-2-yn-1-ylsulfanyl)-1H-tetrazole and the corresponding azide. The reaction optimization results showed that higher yields are obtained using CuSO4 and sodium ascorbate in DMF–water (2:1). The product structures were established on the basis of various spectral data, and their evaluation for antimicrobial activity showed moderate to good results compared to standard drugs.
- Kedika, B.,Noole, V. G.,Reddy, C. H. Krishna,Thotla, K.
-
p. 1077 - 1081
(2020/07/25)
-
- Recycling method of 1-phenyl-5-hydroxytetrazole
-
The invention discloses a recycling method of 1-phenyl-5-hydroxytetrazole, and belongs to the technical field of medicinal chemistry. The preparation method comprises the following steps: a byproduct1-phenyl-5-hydroxytetrazole generated in preparation process of a rosuvastatin calcium intermediate is converted into 1-phenyl-5-mercaptotetrazole; and meanwhile, the 1-phenyl-5-mercaptotetrazole is further used for preparing a rosuvastatin calcium intermediate or rosuvastatin calcium. According to the method disclosed by the invention, reasonable recycling of the byproduct 1-phenyl-5-hydroxytetrazole is realized, the raw materials are fully utilized, the production cost of rosuvastatin calcium and the intermediate thereof is reduced, and the emission of three wastes is reduced.
- -
-
-
- 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives as inhibitors of full-length RORγt
-
Retinoid-related orphan receptor gamma-t (RORγt) belongs to the nuclear receptor superfamily that takes vital roles in the development and maturation of T-helper 17 cell (Th17) and lymph-node genesis. Because Th17 cells have been proved to be major effectors in human autoimmune and inflammatory diseases, the agonists and antagonists of RORγt have been discovered as promising leads for the therapeutics of these diseases. Most of the current studies of RORγt inhibitors have been focused on ligand binding domain (LBD) of RORγt because the structure and binding pockets of LBD have been elucidated and studied in detail. Recent research elucidated that the hinge domain (HD) of RORγt was significantly involved in the SUMOylation of RORγt and thus specifically affecting T cell development but not lymph-node genesis. These discoveries highlighted the potential of HD of RORγt as the target of RORγt inhibitors that could specifically inhibit Th17-related activities without affecting lymph-node genesis. In this study, we utilized a screening system with full-length RORγt including DBD, HD and LBD to evaluate the activities of a synthesized library of tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives. We identified a potent lead compound (28) that effectively inhibited Th17 cell differentiation. Docking and structure–activity relationship (SAR) studies showed that compound 28 may not bind in the binding pocket as most of the known inhibitors, but may bind in the pocket closed to Gln223 and Leu244 in HD. Our studies showed evidence that the HD of RORγt could afford a binding pocket for Th17 specific inhibitors and this domain should be further studied to discover potent and specific RORγt inhibitors.
- Lao, Chuyu,Zhou, Xiaoqing,Chen, Huanpeng,Wei, Fengjiao,Huang, Zhaofeng,Bai, Chuan
-
-
- Non-catalyzed addition of heterocyclic thiols and 5-substituted-1H-tetrazoles to vinyl ethers
-
The alkylation of 1-substituted 1H-tetrazole-5-thiols and 4-substituted 4 H-1,2,4-triazole-3-thiols with alkyl halides or sulfonates lead to the formation of S-alkylated products regardless of the substituent on the heterocycle. In this work, we found that substituted 1H-tetrazole-5-thiols and 4 H-1,2,4-triazole-3-thiols readily reacted with vinyl ethers in the absence of a catalyst to exclusively form N-substituted 1H-tetrazole-5(4H)-thiones and 1H-1,2,4-triazole-5(4H)-thiones, respectively. Furthermore, the reactions of 5-substituted-1H-tetrazoles with vinyl ethers under the same conditions selectively yielded 2,5-disubstitued tetrazoles.
- Melnikova, Iuliia,Roh, Jaroslav,Kune?, Ji?í,Artamonova, Tatiana,Zevatskii, Yuri,Myznikov, Leonid
-
supporting information
p. 3842 - 3845
(2017/09/15)
-
- Mechanism of the zinc-catalyzed addition of azide ion to unsaturated compounds: Synthesis of 5-substituted 1Н-tetrazoles from nitriles and of 1-substituted 1Н-tetrazole-5-thiols from isothiocyanates
-
The mechanism of the formation of 5-substituted 1H-tetrazoles from organic nitriles and thiocyanates in the presence of NaN3 and ZnCl2 in aliphatic alcohols was studied. The results of this study allowed efficient methods of synthesis of substituted tetrazoles from nitriles, thiocyanates, and isothiocyanates to be proposed.
- Myznikov,Vorona,Artamonova,Zevatskii, Yu. E.
-
p. 731 - 738
(2017/05/29)
-
- Improved efficiency of CdS quantum dot sensitized solar cell with an organic redox couple and a polymer counter electrode
-
Quantum dot sensitized solar cells (QDSSCs) based on an organic thiolate/disulfide redox couple (C7H5N4S-/C14H10N8S2or C2H3N4S-/C4H6N8S2) and a polymer counter electrode [poly (3, 4-ethylenedioxythiophene), PEDOT] were fabricated and their photovoltaic performance were investigated. In CdS QDSSC, the organic C7H5N4S-/C14H10N8S2electrolyte shows better performance than the polysulfide electrolyte, and the PEDOT counter electrode exhibits higher efficiency than that of the Pt counter electrode and the CoS counter electrode. An efficiency of 1.53% was achieved in this QDSSC. The influences of the morphology and the deposition charge of the PEDOT counter electrodes on the cell performance were also studied. Furthermore, it was found that the C7H5N4S-/C14H10N8S2redox couple outperformed the C2H3N4S-/C4H6N8S2redox couple due to reduced electron recombination.
- Shu, Ting,Li, Xiong,Ku, Zhi-Liang,Wang, Shi,Wu, Shi,Jin, Xiao-Hong,Hu, Chun-Di
-
p. 700 - 704
(2014/12/11)
-
- Reactions of dimethyl 2-chloroethynylphosphonate with 1-substituted 5-oxo-1H-1,2,3,4-tetrazoles
-
Addition of 1-substituted tetrazol-5-ones to dimethyl 2-chloroethynylphosphonate occurred regioselectively to form new geminally substituted bis(4-R-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)ethenylphosphonates with 65- 92% yield.
- Mel'nikova,Myznikov,Dogadina,Svintsitskaya
-
p. 2160 - 2166
(2015/02/02)
-
- Efficient dye-sensitized solar cells with potential-tunable organic sulfide mediators and graphene-modified carbon counter electrodes
-
A new class of organic sulfide mediators with programmable redox properties is designed via density functional theory calculations and synthesized for efficient dye-sensitized solar cells (DSCs). Photophysical and electrochemical properties of these mediators derived from systematical functionalization of the framework with electron donating and withdrawing groups (MeO, Me, H, Cl, CF3, and NO2) are investigated. With this new class of organic mediators, the redox potential can be fine-tuned over a 170 mV range, overlapping the conventional I-/I3-couple. Due to the suitable interplay of physical properties and electrochemical characteristics of the mediator involving electron-donating MeO group, the DSCs based on this mediator behave excellently in various kinetic processes such as dye regeneration, electron recombination, and mass transport. Thus, the MeO derivative of the mediator is identified as having the best performance of this series of redox shuttles. As inferred from electrochemical impedance spectroscopy and cyclic voltammetry measurements, the addition of graphene into the normal carbon counter electrode material dramatically improves the apparent catalytic activity of the counter electrode towards the MeO derivative of mediator, resulting in N719 based DSCs showing a promising conversion efficiency of 6.53% under 100 mW·cm-2 simulated sunlight illumination. Copyright
- Li, Xiong,Liu, Linfeng,Liu, Guanghui,Rong, Yaoguang,Yang, Ying,Wang, Heng,Ku, Zhiliang,Xu, Mi,Zhong, Cheng,Han, Hongwei
-
p. 3344 - 3352
(2013/07/26)
-
- A facile one-pot synthesis of 1-substituted tetrazole-5-thiones and 1-substituted 5-alkyl(aryl)sulfanyltetrazoles from organic isothiocyanates
-
Treatments of organic isothiocyanates (R-NCS) with NaN3 in the presence of pyridine in water at room temperature gave corresponding various organic tetrazole-thiones, [S=CN4(R)] (R = alkyl or aryl). Isolated products are obtained as white or yellow solids in good yields (76-97%). The molecular structure by X-ray diffraction study for one of products shows the proposed formation. In addition, one-pot synthesis of 1- substituted 5-alkyl(or aryl)sulfanyltetrazoles has been demonstrated. Addition of alkyl or aryl halides into the mixture of organic isothiocyanates, NaN3, and pyridine in water at room temperature exclusively formed 1- substituted 5-alkyl(or aryl)sulfanyltetrazoles (S-derivatives) in high yields.
- Han, Sam Yong,Lee, Je Woo,Kim, Hee-Jung,Kim, Yong-Joo,Lee, Soon W.,Gyoung, Young Soo
-
experimental part
p. 55 - 59
(2012/03/09)
-
- Cytostatic tetrazole-butenolide conjugates: Linking tetrazole and butenolide rings via stille coupling and biological activity of the target substances
-
A series of tetrazoles linked to the butenolide core via benzene rings were prepared by the Stille coupling reaction of α-(tributylstannyl) butenolides and 5-(alkylsulfanyl)-1-(4-iodophenyl)tetrazoles, and the compounds were tested for antifungal and cytostatic activity. Interesting antifungal activities against the filamentous strain Absidia corymbifera, and cytostatic activities against leukemic cells HL-60 and CCRF-CEM were found. The cytostatic activity requires the presence of both the butenolide ring and the alkylsulfanyl group bound to tetrazole ring. In addition, the feasibility of Pd-coupling reactions with 5-iodotetrazoles was evaluated.
- Balsanek, Vojtech,Tichotova, Lucie,Kunes, Jiri,Spulak, Marcel,Pour, Milan,Votruba, Ivan,Buchta, Vladimir
-
scheme or table
p. 1161 - 1178
(2010/04/28)
-
- THIOREDOXIN AND THIOREDOXIN REDUCTASE INHIBITORS
-
The present invention relates to sulfone derivatives and to their use as modulators of the thioredoxin/thioredoxin reductase redox system, including for the treatment and/or prevention of pathophysiological conditions mediated by thioredoxin/thioredoxin reductase, such as cancer, HIV/ AIDS, Alzheimer's disease, rheumatoid arthritis, and skin disorders. Also provided are pharmaceutical compositions comprising the inventive sulfones.
- -
-
Page/Page column 58; 13/22; 14/22
(2008/06/13)
-
- Some reactions and spectroscopic studies of tris(pentafluorophenyl) arsenic and -antimony(III and V) derivatives
-
The reactions of tris(pentafluorophenyl)arsenic(III) with iodine monochloride, iodine monoazide, and dithiocyanogen yielded corresponding oxidative-addition products of the type (C6F5) 3As(V)XY (X=I, Y=Cl, N3; X=Y=NCS). The elemental sulphur also added oxidatively with tris(pentafluorophenyl)arsenic(III) yielding tris(pentafluorophenyl)arsine(V) sulphide. Some displacement reactions were also carried out to synthesize mixed pseudohalide derivatives of the type (C6F5)3 M(N3)NCS (M=As and Sb) and their insertion reactions were studied with phenyl isothiocyanate which yielded the corresponding 1,2-cycloaddition products, i.e. tetrazole-5-thiones. The compounds were characterized by elemental analysis, molar conductance, UV, IR and 19F NMR spectroscopic studies.
- Shukla, Sanjeev K.,Ranjan, Ashok,Saxena
-
p. 165 - 170
(2007/10/03)
-
- Synthesis of unsymmetrical sulfides derived from tetrazole-5-thiols
-
A series of unsymmetrical sulfides derived from I-substituted tetrazole-5-thiols was prepared by fusion of the corresponding 1-R-tetrazole-5-thiol sodium salt with 1-R′-5-halotetrazole. The structure was confirmed by 1H NMR and 13C NMR spectra. The target compounds were prepared in 50-80% yields.
- Hrabalek,Pus,Baranek,Kunes,Palat
-
p. 183 - 189
(2007/10/03)
-
- Synthesis and biological properties of new 1β-methylcarbapenems having tetrazolothioether moiety
-
The synthesis and biological activities of a series of new 1β-methylcarbapenems 1a-1 having tetrazolothioether moiety at C-5 position of pyrrolidine were described. Among these compounds, 1c showed the most potent antibacterial activity and advanced pharmacokinetics compared with imipenem and meropenem. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Shin, Kye Jung,Koo, Ki Dong,Yoo, Kyung Ho,Kim, Dong Chan,Kim, Dong Jin,Park, Sang Woo
-
p. 1421 - 1425
(2007/10/03)
-
- Kinetics and Mechanism of the Alkaline Release of Phenyl(mercapto)tetrazoles from α-Oximes
-
Compounds such as α-phenyl(mercapto)tetrazole (PMT) oxime (9) undergo rapid elimination of the PMT anion in base via a nitrosoene intermediate.Solution kinetics and HPLC analysis of reaction products are consistent with the mechanism shown in Scheme 2.For open chain oximes such as 4, substitution α to the oxime increases the rate of release of PMT and is attributed to the relief of strain when a crowded reactant is converted to a less-crowded product.For cyclic oximes, the six-membered ring compounds are more reactive than the corresponding five-membered compounds.A linear isokinetic relationship between the entropy and enthalpy of activation was found with β = 346 +/- 51 K.Entropies of activation were found to range from -7 to +24 c.u. (1 c.u. = 4.184 J mol-1 K-1) and support the proposed mechanism.
- Boggs, Roger A.,Hasan, Fariza B.,Mahoney, J. Barry,Mehta, Avi C.,Palumbo, Catherine M. K.,et al.
-
p. 1271 - 1277
(2007/10/02)
-
- Novel reactions of S,S'-bis(1-phenyl-1H-tetrazol-5-yl) dithiocarbonate
-
S,S'-Bis(1-phenyl-1H-5-yl) dithiocarbonate (1) was synthesized in good yield from 1-phenyl-5-mercapto-5H-tetrazole (2) and trichloromethyl chloroformate (TCF).The structure of 1 was confirmed by using X-ray crystal analysis.The reagent (1) could be applied to the formation of amides, Friedel-Crafts type reactions, isothiocyanate syntheses, and carbonyl group insertion reactions.Keywords - S,S'-bis(1-phenyl-1H-tetrazol-5-yl) dithiocarbonate; X-ray crystal analysis; amide; isothiocyanate; Friedel-Crafts reaction; carbonyl group insertion reaction.
- Takeda, Kazuyoshi,Tsuboyama, Kanoko,Takayanagi, Hiroaki,Shirokami, Rie,Takeura, Masumi,Ogura, Haruo
-
p. 2334 - 2337
(2007/10/02)
-
- N-METHYL-2-DIMETHYLAMINOACETOHYDROXAMIC ACID AS A NEW REAGENT FOR THE SELECTICE CLEVEAGE OF ACTIVE ESTERS UNDER NEUTRAL CONDITIONS
-
A new reagent, N-methyl-2-dimethylaminoacetohydroxamic acid 3 was developed for the selective cleavage of active esters under neutral conditions.The kinetic studies and the applications of 3 are described.
- Ono, Mitsunori,Itoh, Isamu
-
p. 207 - 210
(2007/10/02)
-
- Cycloaddition Reactions of Phenylmetallic Azides with Unsaturated Substrates
-
1,2-Cycloaddition reactions of RNCS (R = Ph, p-BrPh, o-CH3Ph and p-CH3Ph) and CS2 with (Ph)nMN3 (n = 3 for M = Sn and Pb; n = 4 for M = P, As and Sb) give mostly organometal substituted tetrazoles.A tentative mechanism for the formation of cyclic products has been suggested.The products have been characterised by conductance measurements, and ultraviolet and infrared data.
- Bhattacharya, S. N.,Saxena, A. K.,Raj, Prem
-
p. 141 - 143
(2007/10/02)
-
- Product and preparation of 1H-tetrazole-5-thiol derivatives
-
The process for preparation of and the intermediate compounds such as 1H-tetrazole-5-thiol having the formula STR1 wherein R1 is alkyl, aminoalkyl, acylaminoalkyl, aryl, alkoxycarbonylaminoalkyl, halogen-substituted aryl or alkylamino-substituted aryl and R2 is hydrogen or arakyl, preferably benzyl. The compound is produced by reacting a substituted thiosemicarbazide with an aralkyl chloride, subjecting the resultant compound to diazotization, and reacting the resultant compound with a Friedel Crafts catalyst. Optionally, this may be further hydrolyzed when R1 is aminoalkyl and/or converted to conventional salts.
- -
-
-
- Meso-ionic se- and s-containing tetrazoles
-
This invention relates to meso-ionic tetrazole compounds of the formula: STR1 wherein X- is -S- or -Se- which are useful as photographic additives and to an intermediate useful in the preparation thereof having the formula: STR2
- -
-
-
