- A more sustainable isothiocyanate synthesis by amine catalyzed sulfurization of isocyanides with elemental sulfur
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Isothiocyanates (ITCs) are typically prepared using amines and highly toxic reagents such as thiophosgene, its derivatives, or CS2. In this work, an investigation of a multicomponent reaction (MCR) using isocyanides, elemental sulfur and amines revealed that isocyanides can be converted to isothiocyanates using sulfur and catalytic amounts of amine bases, especially DBU (down to 2 mol%). This new catalytic reaction was optimized in terms of sustainability, especially considering benign solvents such as Cyrene or γ-butyrolactone (GBL) under moderate heating (40 °C). Purification by column chromatography was further optimized to generate less waste by maintaining high purity of the product. Thus, E-factors as low as 0.989 were achieved and the versatility of this straightforward procedure was shown by converting 20 different isocyanides under catalytic conditions, while obtaining moderate to high yields (34-95%). This journal is
- Nickisch,Conen,Gabrielsen,Meier
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p. 3134 - 3142
(2021/01/28)
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- Synthesis of N-CF3Alkynamides and Derivatives Enabled by Ni-Catalyzed Alkynylation of N-CF3Carbamoyl Fluorides
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The expansion of chemical space associated with ubiquitous motifs is key to unleash new properties and functions. In this context, alkynamides, prevalent in numerous drugs and materials, represent an untapped resource. We herein report the first synthetic access to N-trifluoromethyl alkynamides. Our strategy relies on a mild and operationally simple Ni-catalyzed coupling of N-CF3 carbamoyl fluorides with alkynyl silanes. The synthesized N-CF3 alkynamides proved to be highly robust and readily functioned as a platform to unlock access to valuable derivatives, such as N-CF3 decorated alkenyl amides, oxindoles, or quinolones, all of which were inaccessible to date.
- Nielsen, Christian D.-T.,Schoenebeck, Franziska,Zivkovic, Filip G.
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supporting information
p. 13029 - 13033
(2021/09/07)
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- Design, synthesis and biological evaluation of novel 2,4-disubstituted quinazoline derivatives targeting H1975 cells via EGFR-PI3K signaling pathway
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In order to find new and highly effective anti-tumor drugs with targeted therapeutic effects, a series of novel 4-aminoquinazoline derivatives containing N-phenylacetamide structure were designed, synthesized and evaluated for antitumor activity against four human cancer cell lines (H1975, PC-3, MDA-MB-231 and MGC-803) using MTT assay. The results showed that the compound 19e had the most potent antiproliferative activity against H1975, PC-3, MDA-MB-231 and MGC-803 cell lines. At the same time, compound 19e could significantly inhibit the colony formation and migration of H1975 cells. Compound 19e also arrested the H1975 cell cycle in the G1 phase and mediated cell apoptosis, promoted the accumulation of ROS in H1975 cells. Furthermore, compound 19e exerted antitumor effect in vitro by reducing the expression of anti-apoptotic protein Bcl-2 and increasing the pro-apoptotic protein Bax and p53. Mechanistically, compound 19e could significantly decreased the phosphorylation of EGFR and its downstream protein PI3K in H1975 cells. Which indicated that compound 19e targeted H1975 cell via interfering with EGFR-PI3K signaling pathway. Molecular docking showed that compound 19e could bind into the active pocket of EGFR. Those work suggested that compound 19e would have remarkable implications for further design of anti-tumor agents.
- Chao, Gao,Dai, Honglin,Ke, Yu,Li, Erdong,Lihong, Shan,Liu, Hongmin,Liu, Limin,Si, Xiaojie,Wang, Zhengjie,Yang, Zhang,Zhang, Luye,Zhang, Qiurong,Zheng, Jiaxin
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- 4-Dimethylaminopyridine-catalyzed synthesis of isothiocyanates from amines and carbon disulfide
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Isothiocyanates were synthesized by reactions between primary amines and CS2 in the presence of 4-dimethylaminopyridine as a catalyst and tert-butyl hydroperoxide as an oxidant. Various aryl, benzyl, alkyl, and hydroxyl amines were transformed into the corresponding isothiocyanates in 41–82% yields.
- Rong, Hao-Jie,Chen, Tao,Xu, Ze-Gang,Su, Tian-Duo,Shang, Yu,Wang, Yong-Qiang,Yang, Cui-Feng
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- N-Trifluoromethyl Hydrazines, Indoles and Their Derivatives
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Reported herein is the first efficient strategy to synthesize a broad range of unsymmetrical N-CF3 hydrazines, which served as platform to unlock numerous currently inaccessible derivatives, such as tri- and tetra-substituted N-CF3 hydrazines, hydrazones, sulfonyl hydrazines, and valuable N-CF3 indoles. These compounds proved to be remarkably robust, being compatible with acids, bases, and a wide range of synthetic manipulations. The feasibility of RN(CF3)-NH2 to function as a directing group in C?H functionalization is also showcased.
- Bouayad-Gervais, Samir,Scattolin, Thomas,Schoenebeck, Franziska
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supporting information
p. 11908 - 11912
(2020/05/18)
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- Synthesis and bioevaluation of N,4-diaryl-1,3-thiazole-2-amines as tubulin inhibitors with potent antiproliferative activity
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A series of N,4-diaryl-1,3-thiazole-2-amines containing three aromatic rings with an amino linker were designed and synthesized as tubulin inhibitors and evaluated for their antiproliferative activity in three human cancer cell lines. Most of the target compounds displayed moderate antiproliferative activity, and N-(2,4-dimethoxyphenyl)-4-(4-methoxyphenyl)-1,3-thiazol-2-amine (10s) was determined to be the most potent compound. Tubulin polymerization and immunostaining experiments revealed that 10s potently inhibited tubulin polymerization and disrupted tubulin microtubule dynamics in a manner similar to CA-4. Moreover, 10s effectively induced SGC-7901 cell cycle arrest at the G2/M phase in both concentrationand time-dependent manners. The molecular docking results revealed that 10s could bind to the colchicine binding site of tubulin.
- Sun, Maolin,Xu, Qile,Xu, Jingwen,Wu, Yue,Wang, Yueting,Zuo, Daiying,Guan, Qi,Bao, Kai,Wang, Jian,Wu, Yingliang,Zhang, Weige
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- Pyrazolopyrimidines: Potent Inhibitors Targeting the Capsid of Rhino- and Enteroviruses
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There are currently no drugs available for the treatment of enterovirus (EV)-induced acute and chronic diseases such as the common cold, meningitis, encephalitis, pneumonia, and myocarditis with or without consecutive dilated cardiomyopathy. Here, we report the discovery and characterization of pyrazolopyrimidines, a well-tolerated and potent class of novel EV inhibitors. The compounds inhibit the replication of a broad spectrum of EV in vitro with IC50 values between 0.04 and 0.64 μM for viruses resistant to pleconaril, a known capsid-binding inhibitor, without affecting cytochrome P450 enzyme activity. Using virological and genetics methods, the viral capsid was identified as the target of the most promising, orally bioavailable compound 3-(4-trifluoromethylphenyl)amino-6-phenylpyrazolo[3,4-d]pyrimidine-4-amine (OBR-5-340). Its prophylactic as well as therapeutic application was proved for coxsackievirus B3-induced chronic myocarditis in mice. The favorable pharmacokinetic, toxicological, and pharmacodynamics profile in mice renders OBR-5-340 a highly promising drug candidate, and the regulatory nonclinical program is ongoing. Curing the common cold! A cluster of pyrazolopyrimidines with potent broad-spectrum activity against enteroviruses was discovered. Extensive structure-property relationship analyses led to the identification of 3-(4-trifluoromethyl-phenyl)amino-6-phenylpyrazolo[3,4-d]pyrimidine-4-amine, shown to be a blocker of the viral capsid protein, as a lead compound for drug development with favorable physicochemical, pharmacokinetic, and toxicological properties.
- Makarov, Vadim A.,Braun, Heike,Richter, Martina,Riabova, Olga B.,Kirchmair, Johannes,Kazakova, Elena S.,Seidel, Nora,Wutzler, Peter,Schmidtke, Michaela
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supporting information
p. 1629 - 1634
(2015/10/06)
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- Design, synthesis and in vitro evaluation of novel ursolic acid derivatives as potential anticancer agents
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A series of novel ursolic acid (UA) derivatives modified at the C-3 and the C-28 positions were designed and synthesized in an attempt to develop potential antitumor agents. The in vitro cytotoxicity were evaluated against five cancer cell lines (MGC-803, HCT-116, T24, HepG2 and A549 cell lines) and a normal cell (HL-7702) by MTT assay. The screening results indicated that some of these target compounds displayed moderate to high levels of antiproliferative activities compared with ursolic acid and 5-fluorouracil (5-FU), and exhibited much lower cytotoxicity than 5-FU, indicating that the targeted compounds had selective and significant effect on the cell lines. The induction of apoptosis and affects on the cell cycle distribution of compound 6r were investigated by acridine orange/ethidium bromide staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining and flow cytometry, which revealed that the antitumor activity of 6r was possibly achieved through the induction of cell apoptosis by G1 cell-cycle arrest. Western blot and qRT-PCR (quantitative real-time PCR) experiments demonstrated that compound 6r may induce apoptosis through both of intrinsic and extrinsic apoptosis pathway.
- Hua, Shi-Xian,Huang, Ri-Zhen,Ye, Man-Yi,Pan, Ying-Ming,Yao, Gui-Yang,Zhang, Ye,Wang, Heng-Shan
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p. 435 - 452
(2015/04/14)
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- Diversity-orientated synthesis of 3,5-bis(arylamino)pyrazoles
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The synthesis of differentially-substituted 3,5-bis(arylamino)pyrazoles has not yet been documented. During our investigation, we managed to develop a novel, entirely combinatorial synthesis of 3,5-bis(arylamino)pyrazoles relying on a simple one-pot two-step operation.
- Degorce, Sébastien,Jung, Frédéric H.,Harris, Craig S.,Koza, Patrice,Lecoq, Jonathan,Stevenin, Arnaud
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supporting information; experimental part
p. 6719 - 6722
(2012/01/05)
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- A new efficient synthesis of isothiocyanates from amines using di-tert-butyl dicarbonate
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Alkyl and aryl amines are converted smoothly to the corresponding isothiocyanates via the dithiocarbamates in good to excellent yields using di-tert-butyl dicarbonate (Boc2O) and 1-3 mol % of DMAP or DABCO as catalyst. As most of the byproducts are volatile, the work-up involves simple evaporation of the reaction mixture.
- Munch, Henrik,Hansen, Jon S.,Pittelkow, Michael,Christensen, J?rn B.,Boas, Ulrik
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p. 3117 - 3119
(2008/09/20)
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- Substituted urea/thiourea derived from fluoxetine as potent appetite suppressants
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A series of urea and thiourea analogues of fluoxetine (5-17) were synthesized and evaluated for their anorexigenic and antidepressant activities. The related conformationally restrained analogues (20-23) were also prepared for structure-activity relationship (SAR) studies. Many of these derivatives (5, 6, 8, 10, 12, 13, 16, and 23) exhibited significant anorexigenic activity and interestingly were devoid of antidepressant activity, thus emerging as a promising tool for further research work.
- Bhandari, Kalpana,Srinivas, Nagarapu,Sharma, Lata,Srivastava, Shipra,Nath, Amar,Nath, Chandishwar
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p. 103 - 113
(2008/12/22)
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- Synthesis of thiophene-2-carboxamidines containing 2-aminothiazoles and their biological evaluation as urokinase inhibitors
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The serine protease urokinase (uPa) has been implicated in the progression of both breast and prostate cancer. Utilizing structure based design, the synthesis of a series of substituted 4-[2-amino-1,3-thiazolyl]-thiophene-2-carboxamidines is described. Further optimization of this series by substitution of the terminal amine yielded urokinase inhibitors with excellent activities.
- Wilson, Kenneth J.,Illig, Carl R.,Subasinghe, Nalin,Hoffman, James B.,Jonathan Rudolph,Soll, Richard,Molloy, Christopher J.,Bone, Roger,Green, David,Randall, Troy,Zhang, Marie,Lewandowski, Frank A.,Zhou, Zhao,Sharp, Celia,Maguire, Diane,Grasberger, Bruce,DesJarlais, Renee L.,Spurlino, John
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p. 915 - 918
(2007/10/03)
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- PIPERAZINYL DERIVATIVES AND METHODS OF TREATING CENTRAL NERVOUS SYSTEM AILMENTS RELATING TO THE 5-HT2 RECEPTOR SYSTEM
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Piperazinyl derivatives of the general formula I STR1 wherein R. sup.1 represents substituted phenyl, 1-or 2-diazanaphthyl, azadiazanaphtyl or diazanaphtyl groups; n is 1, 2, 3 or 4; X is--O--or STR2 wherein R. sup.2 is hydrogen, C 1-6-alkyl or C 3-8-cycloalkyl; Y is =O or =S or =NZ wherein Z is hydrogen, C. sub. 1-6-alkyl or--CN and R 3 is selected from a group consisting of various structures have been found to exhibit high affinity for various receptor subtypes including the 5-HT 2 receptor, the 5-HT 1A receptor, the alpha 1 receptor the dopamine receptor or a combination of these and may therefore be useful for treating CNS system, cardiovascular system and gastrointestinal disorders.
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