- Synthesis of difluoromethyl and deuterium-labeled difluoromethyl thioethers from aliphatic electrophiles
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A one-pot difluoromethylthiolation of alkyl electrophiles with thiourea and diethyl bromodifluoromethylphosphonate is described. The transition-metal-free approach, readily available reagents, and mild conditions provide a practical way for the synthesis of difluoromethyl thioethers. By changing the "H" source to the most commonly used "D" sources CD3OD and D2O, this strategy enables efficient synthesis of SCF2D-substituted molecules in good yields with high levels of D incorporation.
- Ding, Tianqi,Jiang, Lvqi,Yi, Wenbin
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p. 3995 - 3998
(2020/04/17)
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- Design, synthesis and biological evaluation of novel N-sulfonylamidine-based derivatives as c-Met inhibitors via Cu-catalyzed three-component reaction
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In our continuing efforts to develop novel c-Met inhibitors as potential anticancer candidates, a series of new N-sulfonylamidine derivatives were designed, synthesized via Cu-catalyzed multicomponent reaction (MCR) as the key step, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, HT-29, MKN-45 and MDA-MB-231). Most of the target compounds showed moderate to significant potency at both the enzyme-based and cell-based assay and possessed selectivity for A549 and HT-29 cancer cell lines. The preliminary SAR studies demonstrated that compound 26af (c-Met IC50 = 2.89 nM) was the most promising compound compared with the positive foretinib, which exhibited the remarkable antiproliferative activities, with IC50 values ranging from 0.28 to 0.72 μM. Mechanistic studies of 26af showed the anticancer activity was closely related to the blocking phosphorylation of c-Met, leading to cell cycle arresting at G2/M phase and apoptosis of A549 cells by a concentration-dependent manner. The promising compound 26af was further identified as a relatively selective inhibitor of c-Met kinase, which also possessed an acceptable safety profile and favorable pharmacokinetic properties in BALB/c mouse. The favorable drug-likeness of 26af suggested that N-sulfonylamidines may be used as a promising scaffold for antitumor drug development. Additionally, the docking study and molecular dynamics simulations of 26af revealed a common mode of interaction with the binding site of c-Met. These positive results indicated that compound 26af is a potential anti-cancer candidate for clinical trials, and deserves further development as a selective c-Met inhibitor.
- Fang, Sen-Biao,Li, Hui-Jing,Nan, Xiang,Wu, Rui,Wu, Yan-Chao,Zhang, Jing,Zhang, Zhi-Zhou
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- Pathway-directed screen for inhibitors of the bacterial cell elongation machinery
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New antibiotics are needed to combat the growing problem of resistant bacterial infections. An attractive avenue toward the discovery of such next-generation therapies is to identify novel inhibitors of clinically validated targets, like cell wall biogenesis. We have therefore developed a pathway-directed whole-cell screen for small molecules that block the activity of the Rod system of Escherichia coli. This conserved multiprotein complex is required for cell elongation and the morphogenesis of rod-shaped bacteria. It is composed of cell wall synthases and membrane proteins of unknown function that are organized by filaments of the actin-like MreB protein. Our screen takes advantage of the conditional essentiality of the Rod system and the ability of the beta-lactam mecillinam (also known as amdinocillin) to cause a toxic malfunctioning of the machinery. Rod system inhibitors can therefore be identified as molecules that promote growth in the presence of mecillinam under conditions permissive for the growth of Rod– cells. A screen of 690,000 compounds identified 1,300 compounds that were active against E. coli. Pathway-directed screening of a majority of this subset of compounds for Rod inhibitors successfully identified eight analogs of the MreB antagonist A22. Further characterization of the A22 analogs identified showed that their antibiotic activity under conditions where the Rod system is essential was strongly correlated with their ability to suppress mecillinam toxicity. This result combined with those from additional biological studies reinforce the notion that A22-like molecules are relatively specific for MreB and suggest that the lipoprotein transport factor LolA is unlikely to be a physiologically relevant target as previously proposed.
- Buss, Jackson A.,Baidin, Vadim,Welsh, Michael A.,Flores-Kim, Josué,Cho, Hongbaek,McKay Wood,Uehara, Tsuyoshi,Walker, Suzanne,Kahne, Daniel,Bernhardta, Thomas G.
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- Optimization of P2Y12 Antagonist Ethyl 6-(4-((Benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283) Led to the Discovery of an Oral Antiplatelet Agent with Improved Druglike Properties
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P2Y12 antagonists are widely used as antiplatelet agents for the prevention and treatment of arterial thrombosis. Based on the scaffold of a known P2Y12 antagonist AZD1283, a series of novel bicyclic pyridine derivatives were designed and synthesized. The cyclization of the ester substituent on the pyridine ring to the ortho-methyl group led to lactone analogues of AZD1283 that showed significantly enhanced metabolic stability in subsequent structure-pharmacokinetic relationship studies. The metabolic stability was further enhanced by adding a 4-methyl substituent to the piperidinyl moiety. Compound 58l displayed potent inhibition of platelet aggregation in vitro as well as antithrombotic efficacy in a rat ferric chloride model. Moreover, 58l showed a safety profile that was superior to what was observed for clopidogrel in a rat tail-bleeding model. These results support the further evaluation of compound 58l as a promising drug candidate.
- Kong, Deyu,Xue, Tao,Guo, Bin,Cheng, Jianjun,Liu, Shunyin,Wei, Jianhai,Lu, Zhengyu,Liu, Haoran,Gong, Guoqing,Lan, Tian,Hu, Wenhao,Yang, Yushe
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supporting information
p. 3088 - 3106
(2019/04/01)
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- Tert -Butyl Hypochlorite Mediated Oxidative Chlorination of S -Alkylisothiourea Salts: Synthesis of Sulfonyl Chlorides
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Under neutral conditions, a variety of S-alkylisothiourea salts were smoothly converted into the corresponding sulfonyl chlorides through tert-butyl chlorite mediated oxidative chlorination in good to excellent yields after simple purification. In addition to the environmental and procedural advantages of this method, the neutral conditions potentially make it applicable to substrates that bear acid-sensitive functional groups. For example, the Cbz-protected 2-aminoethanesulfonyl chloride could be synthesized in moderate to good yields under the current neutral conditions, and the acid-sensitive Cbz-protecting group was not affected.
- Qiu, Kui,Wang, Rennan
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p. 3186 - 3190
(2015/10/19)
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- Clean and economic synthesis of alkanesulfonyl chlorides from S-alkyl isothiourea salts via bleach oxidative chlorosulfonation
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A simple procedure for clean and economic synthesis of alkanesulfonyl chlorides via bleach-mediated oxidative chlorosulfonation of S-alkyl isothiourea salts is disclosed. This procedure is environment- and worker-friendly with the advantages of readily accessible materials and reagents, simple and safe operations, easy purification without chromatography, and affords high yields of up to 99%.
- Yang, Zhanhui,Zhou, Bingnan,Xu, Jiaxi
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p. 225 - 229
(2014/03/21)
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- Degradation of MAC13243 and studies of the interaction of resulting thiourea compounds with the lipoprotein targeting chaperone LolA
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The discovery of novel small molecules that function as antibacterial agents or cellular probes of biology is hindered by our limited understanding of bacterial physiology and our ability to assign mechanism of action. We previously employed a chemical genomic strategy to identify a novel small molecule, MAC13243, as a likely inhibitor of the bacterial lipoprotein targeting chaperone, LolA. Here, we report on the degradation of MAC13243 into the active species, S-(4-chlorobenzyl)isothiourea. Analogs of this compound (e.g., A22) have previously been characterized as inhibitors of the bacterial actin-like protein, MreB. Herein, we demonstrate that the antibacterial activity of MAC13243 and the thiourea compounds are similar; these activities are suppressed or sensitized in response to increases or decreases of LolA copy number, respectively. We provide STD NMR data which confirms a physical interaction between LolA and the thiourea degradation product of MAC13243, with a K d of ~150 μM. Taken together, we conclude that the thiourea series of compounds share a similar cellular mechanism that includes interaction with LolA in addition to the well-characterized target MreB.
- Barker, Courtney A.,Allison, Sarah E.,Zlitni, Soumaya,Nguyen, Nick Duc,Das, Rahul,Melacini, Giuseppe,Capretta, Alfredo A.,Brown, Eric D.
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supporting information
p. 2426 - 2431
(2013/05/21)
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- Convenient and environment-friendly synthesis of sulfonyl chlorides from S -alkylisothiourea salts via N-chlorosuccinimide chlorosulfonation
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A convenient, practical, and environmentally friendly method for the synthesis of sulfonyl chlorides has been developed. Structurally diverse sulfonyl chlorides were synthesized in moderate to excellent yields from S-alkylisothiourea salts, which can be easily prepared from readily accessible alkyl halides or mesylates and inexpensive thiourea, via N-chlorosuccinimide chlorosulfonation. In large-scale syntheses, the byproduct succinimide from 'waste water' can be conveniently converted into the starting reagent N-chlorosuccinimide with sodium hypochlorite (bleach) to make the method sustainable. Georg Thieme Verlag Stuttgart, New York.
- Yang, Zhanhui,Xu, Jiaxi
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p. 1675 - 1682
(2013/07/27)
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- Simple synthesis of sulfonyl chlorides from thiol precursors and derivatives by NaClO2-mediated oxidative chlorosulfonation
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A simple method to synthesize diverse sulfonyl chlorides through NaClO 2-mediated oxidative chlorosulfonation of S-alkyl isothiourea salts is presented. The approach features safe operation, environmental friendliness, convenient purification procedures, and delivers high yields of up to 96%. The procedure is also applicable to substrates such as thiols, disulfides, thioacetates, and xanthates. It is a versatile and convenient method for the synthesis of various sulfonyl chlorides from different thiol precursors and derivatives. Georg Thieme Verlag Stuttgart, New York.
- Yang, Zhanhui,Zheng, Yongpeng,Xu, Jiaxi
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supporting information
p. 2165 - 2169
(2013/10/22)
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- INHIBITION OF CELL PROLIFERATION
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The disclosed modulators of Rb:Raf-1 interactions are potent, selective disruptors of Rb:Raf-1 binding, with IC50 values ranging from 80 nM to 500 nM. Further, these compounds are surprisingly effective in inhibiting a wide variety of cancer cells, including osteosarcoma, epithelial lung carcinoma, non small cell lung carcinoma, three different pancreatic cancer cell lines, two different glioblastoma cell lines, metastatic breast cancer, melanoma, and prostate cancer. Moreover, the disclosed compounds effectively disrupt angiogenesis and significantly inhibited tumors in nude mice derived from human epithelial lung carcinoma tumors. Accordingly, the disclosed compounds, pharmaceutical compositions comprising the compounds, methods of inhibiting cell proliferation, methods of treating subjects with cancer, and methods of preparing the disclosed compounds are provided.
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Page/Page column 47; 49; 51; 70
(2008/06/13)
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- A Novel Solution- and Solid-Phase Approach to 2,4,5-Tri- and 2,4,5,6-Tetrasubstituted Pyrimidines and Their Conversion into Condensed Heterocycles
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A novel general synthesis of 2,4,5-tri- and 2,4,5,6-tetrasubstituted pyrimidines 5a-d and 7a, e, f, g by condensation of thiouronium salts of type 3 with (ethoxymethylidene)malononitrile (4) and [bis(methylthio)methylidene]malononitrile (6), respectively, was first established in solution (Scheme 1) and successfully transferred onto solid support by using the polymer-bound thiouronium salt 11 (Scheme 3). Further investigations were directed toward a multidirectional cleavage procedure of the 2-(alkylsulfinyl) intermediates, obtained from the 2-(alkylthio)pyrimidines 7a (Scheme 2) or 12 and 14 (Schemes 3 and 4), with different nucleophiles to form highly substituted pyrimidines. In addition, fused-heterocycle derivatives 22a-h, 24a-c, and 26a-e were generated in good-to-excellent yields by condensation of 7a, e, h with versatile isocyanates and isothiocyanates, with subsequent alkylation (Scheme 5).
- Masquelin, Thierry,Sprenger, Daniel,Baer, Roman,Gerber, Fernand,Mercadal, Yves
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p. 646 - 660
(2007/10/03)
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- Nucleophilic Substitution Reaction of Phenylmethanesulfonyl Halides with Anilines
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Kinetic studies on the nucleophilic substitution reaction of Y-substituted phenylmethanesulfonyl halides with X-substituted anilines in methanol-acetonitrile have been carried out in order to elucidate the reaction mechanism.The phenylmethanesulfonyl fluorides (PSF) had markedly lower rates and smaller magnitudes of ρX and ρY values compared with those for the chlorides (PSC).On the contrary, however, the magnitude of the cross-interaction constant ρXY was greater for PSF than for PSC, so that the degree of bond making in the transition state is actually greater in the reaction of PSF as compared with that for PSC.We have thus demonstrated that extensive charge transfer from a nucleophile to a substrate does not necessarily mean a tight bond in the transition state.Moreover the nonzero ρXY values obtained for both PSC and PSF are taken as evidence in support of a common, associative SN2 mechanism for the two halides.
- Lee, Ikchoon,Kang, Han Keun,Lee, Hai Whang
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p. 7472 - 7477
(2007/10/02)
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- Structure-activity studies on antihyperlipidemic N-benzoylsulfamates, N-benzylsulfamates, and benzylsulfonamides
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A series of aryl substituted N-benzoyl- and N-benzylsulfamic acid sodium salts and benzylsulfonamide sodium salts have been prepared and examined for antihyperlipidemic activity in male CF1 mice at a dose level of 20 mg/kg/d ip for 16 d. These substances were also subjected to toxicological evaluation and chemical stability studies. In general, both series of sulfamates and sulfonamides significantly lowered serum cholesterol and triglyceride levels in mice. The compounds were nonmutagenic, showed no acute toxicity or impaired liver or kidney function in male mice, and were chemically stable both as the monohydrates and in aqueous solution over a pH range of 3.5-7.4. While both series of sulfamates and sulfonamides lowered serum cholesterol and triglyceride levels, the sulfamates were relatively more potent with regard to decreasing cholesterol levels, while the sulfonamides were more effective in lowering serum triglyceride levels in mice.
- Wyrick,Hall,Dubey
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p. 374 - 377
(2007/10/02)
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