- Identification of potent and selective hydantoin inhibitors of aggrecanase-1 and aggrecanase-2 that are efficacious in both chemical and surgical models of osteoarthritis
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A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are zinc metalloproteases commonly referred to as aggrecanase-1 and aggrecanase-2, respectively. These enzymes are involved in the degradation of aggrecan, a key component of cartilage. Inhibitors of these enzymes could be potential osteoarthritis (OA) therapies. A series of hydantoin inhibitors of ADAMTS-4 and ADAMTS-5 were identified from a screening campaign and optimized through structure-based drug design to give hydantoin 13. Hydantoin 13 had excellent selectivity over other zinc metalloproteases such as TACE, MMP2, MMP3, MMP13, and MMP14. The compound also produced efficacy in both a chemically induced and surgical model of OA in rats.
- Durham, Timothy B.,Klimkowski, Valentine J.,Rito, Christopher J.,Marimuthu, Jothirajah,Toth, James L.,Liu, Chin,Durbin, Jim D.,Stout, Stephanie L.,Adams, Lisa,Swearingen, Craig,Lin, Chaohua,Chambers, Mark G.,Thirunavukkarasu, Kannan,Wiley, Michael R.
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Read Online
- α-Nitrosostyrenes as Three-Atom Units for the (3+1) Cyclization Reaction: Facile Access to 2,3-Dihydrodiazete N-Oxides and Their Diversified Synthetic Conversions
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An unprecedented (3+1) cyclization of α-nitrosostyrenes, generated in situ from α-bromooximes, and N-tosyloxycarbamates was developed, which enables the synthesis of a range of structurally unique and hitherto unexplored 2,3-dihydrodiazete N-oxides in mod
- Shen, Li-Wen,Wang, Zhen-Hua,You, Yong,Yuan, Wei-Cheng,Zhao, Jian-Qiang,Zhou, Ming-Qiang
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p. 1094 - 1099
(2022/02/10)
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- Design, synthesis and evaluation of novel 5-phenylthiophene derivatives as potent fungicidal of Candida albicans and antifungal reagents of fluconazole-resistant fungi
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A series of 5-phenylthiophene derivatives with novel structures were designed and synthesized to combat the increasing incidence of susceptible and drug-resistant fungal infections. The antifungal activity of the synthesized compounds was assessed against seven susceptible strains and six fluconazole-resistant strains. It is especially encouraging that compounds 17b and 17f displayed significant antifungal activities against all tested strains. Furthermore, the potent compounds 17b and 17f could prevent the formation of fungi biofilms and 17f displayed satisfactory fungicidal activity. Preliminary mechanistic studies showed that the potent antifungal activity of compound 17f stemmed from inhibition of C. albicans CYP51. In addition, Compounds 17b and 17f were almost nontoxic to mammalian A549, MCF-7, and THLE-2 cells. These results strongly suggested that compounds 17b and 17f are promising as novel antifungal drugs.
- Cheng, Maosheng,Cui, Hengxian,Jiang, Hong,Li, Song,Liu, Lei,Su, Xin,Sun, Yin,Wu, Tianxiao,Yin, Wenbo,Zhang, Yuxin,Zhao, Dongmei,Zhao, Liyu,Zheng, Yang
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- Improving the metabolic stability of antifungal compounds based on a scaffold hopping strategy: Design, synthesis, and structure-activity relationship studies of dihydrooxazole derivatives
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L-amino alcohol derivatives exhibited high antifungal activity, but the metabolic stability of human liver microsomes in vitro was poor, and the half-life of optimal compound 5 was less than 5 min. To improve the metabolic properties of the compounds, the scaffold hopping strategy was adopted and a series of antifungal compounds with a dihydrooxazole scaffold was designed and synthesized. Compounds A33-A38 substituted with 4-phenyl group on dihydrooxazole ring exhibited excellent antifungal activities against C. albicans, C. tropicalis and C. krusei, with MIC values in the range of 0.03–0.25 μg/mL. In addition, the metabolic stability of compounds A33 and A34 in human liver microsomes in vitro was improved significantly, with the half-life greater than 145 min and the half-life of 59.1 min, respectively. Moreover, pharmacokinetic studies in SD rats showed that A33 exhibited favourable pharmacokinetic properties, with a bioavailability of 77.69%, and half-life (intravenous administration) of 9.35 h, indicating that A33 is worthy of further study.
- Cheng, Maosheng,Su, Xin,Sun, Nannan,Sun, Yin,Tian, Linfeng,Yin, Wenbo,Zhang, Chu,Zhao, Dongmei,Zhao, Liyu,Zhao, Shizhen,Zheng, Yang
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- Copper-catalyzed borylative aminomethylation of C-C double and triple bonds withN,O-acetal
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A copper-catalyzed borylaminomethylation of multiple carbon-carbon bonds withN,O-acetal and bis(pinacolato)diboron has been disclosed that offers efficient and expedient access to γ-amino boronates. The products contain a valuable amine and boronate, whic
- Qiu, Xianfan,Xu, Liugen,Wang, Shuxia,Dai, Ying,Feng, Yunqiu,Gong, Chang,Tao, Chuanzhou
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p. 3279 - 3282
(2021/04/07)
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- Oxidative Deconstruction of Azetidinols to α-Amino Ketones
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A silver-mediated synthesis of α-amino ketones via the oxidative deconstruction of azetidinols has been developed using a readily scalable protocol with isolated yields up to 80percent. The azetidinols are easily synthesized in one step and can act as protecting groups for these pharmaceutically relevant synthons. Furthermore, mechanistic insights are presented and these data have revealed that the transformation is likely to proceed through the β-scission of an alkoxy radical, followed by oxidation and C-N cleavage of the resulting α-amido radical.
- Allen, Lewis A. T.,Natho, Philipp,Parsons, Philip J.,Raclea, Robert-Cristian,White, Andrew J. P.
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p. 9375 - 9385
(2020/08/14)
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- Self-assembly of oxidation-responsive polyethylene glycol-paclitaxel prodrug for cancer chemotherapy
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Amphiphilic drug conjugates can self-assemble into nanovehicles for cancer drug delivery, but the key is to design stable yet intracellular labile drug linkers for drug retention during blood circulation but fast intracellular drug release. The conjugatio
- Dong, Chengyuan,Liu, Fusheng,Shen, Youqing,Xiang, Jiajia,Zhou, Quan,Zhou, Zhuxian
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p. 529 - 539
(2020/03/04)
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- Pd-Catalyzed Decarboxylative Olefination: Stereoselective Synthesis of Polysubstituted Butadienes and Macrocyclic P-glycoprotein Inhibitors
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The efficient and stereoselective synthesis of polysubstituted butadienes, especially the multifunctional butadienes, represents a great challenge in organic synthesis. Herein, we wish to report a distinctive Pd(0) carbene-initiated decarboxylative olefination approach that enables the direct coupling of diazo esters with vinylethylene carbonates (VECs), vinyl oxazolidinones, or vinyl benzoxazinones to afford alcohol-, amine-, or aniline-containing 1,3-dienes in moderate to high yields and with excellent stereoselectivity. This protocol features operational simplicity, mild reaction conditions, a broad substrate scope, and gram-scalability. Notably, a structurally unique allylic Pd(II) intermediate was isolated and characterized. DFT calculation and control experiments demonstrated that a rare Pd(0) carbene intermediate could be involved in this reaction. Moreover, the polysubstituted butadienes as novel building blocks were unprecedentedly assembled into macrocycles, which efficiently inhibited the P-glycoprotein and dramatically reversed multidrug resistance in cancer cells by 190-fold.
- Chen, Xiangyang,Hao, Jiping,Houk, K. N.,Li, Yingzi,Lou, Liguang,Quan, Haitian,Song, Bichao,Wang, Lu,Xia, Yuanzhi,Xie, Peipei,Xu, Zhongliang,Yang, Weibo
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supporting information
p. 9982 - 9992
(2020/06/27)
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- Β - azole - phenylketo derivative and use thereof (by machine translation)
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The invention belongs to the technical field of drug synthesis, provides such as general formula β - azole - phenylketo derivative and its stereoisomers or its pharmaceutically acceptable salt, hydrate, solvate or prodrug and their method of preparation, wherein A, B, R1 , R2 , R3 , X has the definition given in the specification. The invention of the compound provided by the superficial and deep fungus has relatively strong inhibiting activity, with the clinical use of antifungal drug compared, has high activity, low toxicity, antimicrobial spectrum and the like, can be used for preparing the antifungal drug. (by machine translation)
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- Combating fluconazole-resistant fungi with novel β-azole-phenylacetone derivatives
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A series of β-azole-phenylacetone derivatives with novel structures were designed and synthesized to combat the increasing incidence of susceptible fungal infections and drug-resistant fungal infections. The antifungal activity of the synthesized compounds was assessed against five susceptible strains and five fluconazole-resistant strains. Antifungal activity tests showed that most of the compounds exhibited excellent antifungal activities against five pathogenic strains with MIC values in the range of 0.03–1 μg/mL. Compounds with R1 = 3-F substituted and 15o and 15ae exhibited moderate antifungal activities against fluconazole-resistant strains 17# and CaR with MIC values in the range of 1–8 μg/mL. Compounds with R1 = H or 2-F (such as 15a, 15o, 15p) displayed moderate to good antifungal activity against fluconazole-resistant strains 632, 901 and 904 with MIC values in the range of 0.125–4 μg/mL. Notably, 15o and 15ae exhibited antifungal activity against five susceptible strains and five fluconazole-resistant strains. Preliminary mechanistic studies showed that the potent antifungal activity of compound 15ae stemmed from inhibition of C. albicans CYP51. Compounds 15o, 15z and 15ae were nearly nontoxic to mammalian A549 cells.
- Zhao, Liyu,Sun, Nannan,Tian, Linfeng,Sun, Yin,Chen, Yixuan,Wang, Xinran,Zhao, Shizhen,Su, Xin,Zhao, Dongmei,Cheng, Maosheng
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- Probing the Effects of Heterocyclic Functionality in [(Benzene)Ru(TsDPENR)Cl] Catalysts for Asymmetric Transfer Hydrogenation
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A range of TsDPEN catalysts containing heterocyclic groups on the amine nitrogen atom were prepared and evaluated in the asymmetric transfer hydrogenation of ketones. Bidentate and tridentate ligands demonstrated a mutual exclusivity directly related to their function as catalysts. A broad series of ketones were reduced with these new catalysts, permitting the ready identification of an optimal catalyst for each substrate and revealing the subtle effects that changes to nearby donor groups can exhibit.
- Barrios-Rivera, Jonathan,Xu, Yingjian,Wills, Martin
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supporting information
p. 7223 - 7227
(2019/10/08)
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- Stereoselective Pd-Catalyzed Decarboxylative Allylation: Assembly of Highly Functionalized Allylic Amines Bearing a Quaternary Center
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Here, we report a practical and reliable methodology to direct construction of tri- and tetrasubstituted olefins bearing an allylic amine, with the concomitant construction of the sterically congested quaternary stereocenter through stereoselective pallad
- Shi, Linlin,He, Yingdong,Chang, Yuanyuan,Zheng, Nan,Yang, Zhen,Gong, Jianxian
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supporting information
p. 3077 - 3080
(2019/05/10)
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- Divergent synthesis of N-heterocycles by Pd-catalyzed controllable cyclization of vinylethylene carbonates
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Here, we report a palladium-catalyzed controllable cyclization of vinyl ethylene carbonates that proceeds through formal migration [2+3] and [5+2] cycloadditions, respectively, under mild conditions. The transformation described here affords a series of synthetically versatile 5,7-membered N-heterocycles which are found in natural products and pharmaceuticals with biological and medicinal properties.
- Yang, Yuwen,Yang, Weibo
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supporting information
p. 12182 - 12185
(2018/11/21)
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- Secondary Phosphine Oxides as Multitalented Preligands En Route to the Chemoselective Palladium-Catalyzed Oxidation of Alcohols
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Secondary phosphine oxides O=PHR2 (SPOs) were identified as multitalented preligands for the chemoselective Pd-catalyzed oxidation of alcohols by a hydrogen-abstracting methodology. SPOs were found to promote the hydrogen-abstraction step as well as hydrogen transfer to a Michael acceptor by generating a putative active H?Pd species. The catalytic system operates under neutral conditions and was proven to be compatible with various electrophilic and nucleophilic functionalities within the substrates as well as water- and air-sensitive functional groups.
- Vasseur, Alexandre,Membrat, Romain,Gatineau, David,Tenaglia, Alphonse,Nuel, Didier,Giordano, Laurent
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p. 728 - 732
(2017/03/13)
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- Hit-to-lead evaluation of a novel class of sphingosine 1-phosphate lyase inhibitors
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Inhibition of sphingosine-1-phosphate lyase has recently been proposed as a potential treatment option for inflammatory disorders such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. In this report we describe our hit-to-lead evaluation of the isoxazolecarboxamide 6, a high-throughput screening hit (in vitro IC50 = 1.0 μM, cell IC50 = 1.8 μM), as a novel S1P lyase inhibitor. We were able to establish basic structure-activity relationships around 6 and succeeded in obtaining X-ray structural information which enabled structure-based design. With the discovery of 28, enzyme activity was quickly improved to IC50 = 120 nM and cell potency to IC50 = 230 nM. The main liability in the established isoxazolecarboxamide hit series was determined to be metabolic stability. In particular we identified that future lead-optimization efforts to overcome this problem should focus on blocking the N-dealkylation on the secondary amine.
- Dinges, Jurgen,Harris, Christopher M.,Wallace, Grier A.,Argiriadi, Maria A.,Queeney, Kara L.,Perron, Denise C.,Dominguez, Eric,Kebede, Tegest,Desino, Kelly E.,Patel, Hetal,Vasudevan, Anil
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p. 2297 - 2302
(2016/04/20)
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- Practical enzymatic desymmetrization of 2-(ethoxycarbonyl)propane-1,3-diyl dihexanoate and model cyclization for the A-D ring system of lysergic acid
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Porcine pancreas lipase-catalyzed hydrolysis of symmetrical 2-(ethoxycarbonyl)propane-1,3-diyl dihexanoate, under the modified conditions of the Seebach protocol, afforded a desymmetrized monohexanoate in 40-51% yield with 91-94% ee, even in a gram-scale reaction. The absolute configuration of a half-hydrolyzed (-)-product was determined to be (R) by conversion to a known 2-methylpropane-1,3-diol derivative. Samarium iodide-induced radical cyclization of 2-oxo-3-phenylethylamine with a C4 unit on the N-atom, derived from the racemic monohexanoate, afforded a 3-phenylpiperidine derivative as a model construction of the A-D ring system of lysergic acid.
- Miyata, Sachiho,Kumamoto, Takuya,Ishikawa, Tsutomu
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p. 1420 - 1438
(2008/02/08)
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- AGENT FOR TREATMENT OF SOLID TUMOR
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A therapeutic and/or prophylactic agent for a solid tumor, which comprises a thiadiazoline derivative represented by the general formula (I), or a pharmaceutically acceptable salt thereof: [wherein, n represents an integer of 1 to 3, R1 represe
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Page/Page column 43
(2008/06/13)
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- AGENT FOR TREATMENT OF HEMATOPOIETIC TUMOR
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A therapeutic and/or prophylactic agent for a hematopoietic tumor, which comprises a thiadiazoline derivative represented by the general formula (I), or a pharmaceutically acceptable salt thereof: [wherein, n represents an integer of 1 to 3, R1
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Page/Page column 37
(2010/11/29)
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- THIADIAZOLINE DERIVATIVES
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An antitumor agent comprising a thiadiazoline derivative represented by the general formula (I), or a pharmacologically acceptable salt thereof as an active ingredient: (wherein Z represents a sulfur atom and the like, R1 represents substituted or unsubstituted lower alkynyl and the like, R2 represents a hydrogen atom and the like, R3 represents substituted or unsubstituted lower alkyl and the like, and R4 represents substituted or unsubstituted aryl and the like), and the like are provided.
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Page/Page column 37
(2010/11/08)
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- COMPOUND HAVING TGF-BETA INHIBITORY ACTIVITY AND PHARMACEUTICAL COMPOSITION CONTAINING SAME
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The present invention provides compounds of formula (I) or compounds of formula (II) and pharmaceutically acceptable salts or solvates thereof. An objective of the present invention is to provide compounds having TGF2 inhibitory activity.
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Page/Page column 72
(2010/11/24)
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- M-STAGE KINESIN INHIBITOR
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A mitotic kinesin Eg5 inhibitor which comprises a thiadiazoline derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient: [wherein R1 represents a hydrogen atom and the like, R2 represents a hydrogen atom, -C(=W)R6 (wherein W represents an oxygen atom or a sulfur atom, and R6 represents substituted or unsubstituted lower alkyl and the like) and the like, R3 represents -C(=Z)R19 (wherein Z represents an oxygen atom or a sulfur atom, and R19 represents substituted or unsubstituted lower alkyl and the like) and the like, R4 represents substituted or unsubstituted lower alkyl and the like, and R5 represents substituted or unsubstituted aryl and the like] and the like are provided.
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Page/Page column 51
(2010/11/08)
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- Synthesis of pyrido[2,3-d]pyridazines and pyrazino[2,3-d]-pyridazines-novel classes of GABAA receptor benzodiazepine binding site ligands
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Novel syntheses of 2,3,8-trisubstituted pyrido[2,3-d]pyridazines and 2,3,5-trisubstituted pyrazino[2,3-d]pyridazines are described. Two complementary routes to pyrido[2,3-d]pyridazines were developed, the first of which began by constructing the pyridine
- Mitchinson, Andrew,Blackaby, Wesley P.,Bourrain, Sylvie,Carling, Robert W.,Lewis, Richard T.
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p. 2257 - 2260
(2007/10/03)
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- Electrophilic amination of enolates with oxaziridines: Effects of oxaziridine structure and reaction conditions
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A range of N-alkoxycarbonyl- and N-carboxamido-oxaziridines has been prepared to test the effects of oxaziridine structure on yields of enolate amination product. Side-products arising from reaction of aldehyde-derived oxaziridines with base were identified, while a ketone-derived oxaziridine afforded moderate yields of amination product with stabilised carbanions.
- Armstrong, Alan,Edmonds, Ian D.,Swarbrick, Martin E.,Treweeke, Nigel R.
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p. 8423 - 8442
(2007/10/03)
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- A new family of small molecules to probe the reactivation of mutant p53
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Cells that express mutant p53 derived from cancers are selectively killed by a new class of small organic molecules. The protein p53 is recognized as one of the most important guardians in the body that prevents tumor development. Mutant forms of p53 are
- Myers, Michael C.,Wang, JinLing,Iera, Jaclyn A.,Bang, Jeong-Kyu,Saito, Shin'ichi,Hara, Toshiaki,Zambetti, Gerard P.,Appella, Daniel H.
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p. 6152 - 6153
(2007/10/03)
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- COMPOUNDS AND RELATED METHODS FOR MUTANT p53 REACTIVATION
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Ketoamine compounds and related methods for reactivation of tumor suppressor protein p53.
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Page/Page column 15; 16
(2008/06/13)
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- Synthetic applicability and in situ recycling of a B-methoxy oxazaborolidine catalyst derived from cis-1-amino-indan-2-ol
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A procedure is described that greatly simplifies the use of an oxazaborolidine catalyst derived from (1R,2S) cis-1-amino-indan-2-ol. This B-OMe catalyst has been employed in the asymmetric reduction of a number of structurally diverse prochiral ketones, in particular the reduction of α-amino acetophenone and its derivatives. A method for reducing the effective catalyst loading by "in situ recycling" is also presented.
- Gilmore, Nathan J.,Jones, Simon,Muldowney, Mark P.
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p. 2805 - 2808
(2007/10/03)
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- Process for the preparation of optically active amino alcohols
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Process for preparing optically active β-amino alcohols represented by a general formula (2): Ra—C*H(OH)—C*H(Rb)—Rc wherein Ra and Rc are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, Rb is one member select
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- Improved syntheses of α-BOC-aminoketones from α-BOC-amino-Weinreb amides using a pre-deprotonation protocol
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A general procedure was developed to prepare α-BOC-aminoketones in good yields from α-BOC-amino Weinreb amides containing an exchangeable amino proton. By first deprotonating this amino group using 1 equiv. of a simple alkyl Grignard base, only a stoichio
- Liu, Jinchu,Ikemoto, Norihiro,Petrillo, Daniel,Armstrong III, Joseph D.
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p. 8223 - 8226
(2007/10/03)
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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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- Process for producing threo-3-amino-2-hydroxybutanoyl-aminoacetic acids, as well as novel intermediated therefor and process for producing them
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A process for producing threo-3-amino-2-hydroxybutanoylaminoacetic acids comprises the steps of allowing to react a starting compound represented by the general formula: STR1 wherein R1 represents a naphthyl or a group of the formula: STR2 in which R6 and R7 represent individually hydrogen, halogen, amino or a protected amino, hydroxy or a protected hydroxy, a lower alkoxy or a lower alkyl and R2 represents a protected amino, with a starting compound represented by the general formula: STR3 wherein R3 represents hydrogen or an ester residue, to obtain threo-3-protected amino-2-hydroxy-4-oxobutanoic acid or its ester represented by the general formula: STR4 wherein R1, R2 and R3 have the same meanings as above, and then reducing the same into threo-3-protected amino-2-hydroxybutanoic acid or its ester represented by the general formula: STR5 wherein R1, R2 and R3 have the same meanings as above, and further converting the above compound into 3-amino-2-hydroxybutanoic acid represented by the general formula: STR6 wherein R2 ' represents amino or a protected amino, thereafter condensing the same, in a conventional manner for forming a peptide coupling, with a compound represented by the general formula: STR7 wherein R4 represents an alkyl having 3-4 carbon atom or 3-guanidinopropyl, while previously protecting as required those groups not relevant to the reaction, and removing the protecting groups for the functional groups to produce threo-3-amino-2-hydroxybutanoylaminoacetic acids represented by the general formula: STR8 wherein R1 and R4 have the same meanings as above. This invention also provides the compounds represented by the general formula (III) as novel intermediates for the above aimed compounds and a process for producing the intermediates.
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