- Discovery of highly potent tubulin polymerization inhibitors: Design, synthesis, and structure-activity relationships of novel 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidines
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By removing 5-methyl and 6-acetyl groups in our previously reported compound 3, we designed a series of novel 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidine derivatives as potential tubulin polymerization inhibitors. Among them, compound 5e displayed low nanomolar antiproliferative efficacy on HeLa cells which was 166-fold higher than the lead analogue 3. Interestingly, 5e displayed significant selectivity in inhibiting cancer cells over HEK-293 (normal human embryonic kidney cells). In addition, 5e dose-dependently arrested HeLa in G2/M phase through the alterations of the expression levels of p-cdc2 and cyclin B1, and caused HeLa cells apoptosis by regulation of expressions of cleaved PARP. Further evidence demonstrated that 5e effectively inhibited tubulin polymerization and was 3-fold more powerful than positive control CA-4. Moreover, molecular docking analysis indicated that 5e overlapped well with CA-4 in the colchicine-binding site. These studies demonstrated that 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidine skeleton might be used as the leading unit to develop novel tubulin polymerization inhibitors as potential anticancer agents.
- Huo, Xian-Sen,Jian, Xie-Er,Ou-Yang, Jie,Chen, Lin,Yang, Fang,Lv, Dong-Xin,You, Wen-Wei,Rao, Jin-Jun,Zhao, Pei-Liang
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- Rh(III)-Catalyzed Enaminone-Directed C-H Coupling with α-Diazo-α-phosphonoacetate for Reactivity Discovery: Fluoride-Mediated Dephosphonation for C-C Coupling Reactions
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Rh(III)-catalyzed enaminone-directed C-H coupling with α-diazo-α-phosphonoacetate has been used for the identification of fluoride-mediated dephosphonation C-C coupling reactivity for the synthesis of 4-hydroxy-1-naphthoates. Intermolecular C-C coupling of α-phosphonoacetate and benzaldehyde for (E)-selective α,β-unsaturated ester synthesis has also been achieved.
- Song, Chao,Yang, Chen,Zeng, Hua,Zhang, Wenjing,Guo, Shan,Zhu, Jin
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supporting information
p. 3819 - 3823
(2018/07/22)
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- Co(III)-Catalyzed Enaminone-Directed C-H Amidation for Quinolone Synthesis
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We report herein the development of a Co(III)-catalyzed enaminone-directed C-H amidation method for synthetic access to quinolones, an important heterocyclic scaffold for diverse pharmaceutically active structures. The C-H coupling with dioxazolones and subsequent deacylation of an installed amide group allow consecutive C-N coupling generation of quinolones with wide-ranging compatible substituent patterns.
- Shi, Pengfei,Wang, Lili,Chen, Kehao,Wang, Jie,Zhu, Jin
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supporting information
p. 2418 - 2421
(2017/05/12)
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- Enaminones as Synthons for a Directed C?H Functionalization: RhIII-Catalyzed Synthesis of Naphthalenes
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The use of enaminones as effective synthons for a directed C?H functionalization is reported. Proof-of-concept protocols have been developed for the RhIII-catalyzed synthesis of naphthalenes, based on the coupling of enaminones with either alkynes or α-diazo-β-ketoesters. Two inherently reactive functionalities (hydroxy and aldehyde groups) are integrated into the newly formed cyclic framework and a broad range of substituents are tolerated, rendering target products readily available for further elaboration.
- Zhou, Shuguang,Wang, Jinhu,Wang, Lili,Song, Chao,Chen, Kehao,Zhu, Jin
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supporting information
p. 9384 - 9388
(2016/08/05)
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- A novel and efficient synthesis of momelotinib
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An improved route for the synthesis of momelotinib has been developed. A nucleophilic addition reaction between the starting material, 4-morpholinoaniline, and cyanamide gave the 1-(4-morpholinophenyl)guanidine. Simultaneously, methyl 4-acetylbenzoate was converted into methyl (E)-4-[3-(dimethylamino)acryloyl]benzoate in the presence of N,N-dimethylformamide dimethylacetal. The enaminone intermediate was then condensed at elevated temperature in alcoholic alkali with the 1-(morpholinophenyl)guanidine to form the desired pyrimidine, which was hydrolysed to the corresponding acid. This procedure is simple in operation, without noble metal catalyst and suitable for industrial production. Finally, the desired compound momelotinib was acquired by an amidation reaction.
- Sun, Tong,Xu, Jiaojiao,Ji, Min,Wang, Peng
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p. 511 - 513
(2016/08/13)
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- PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
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This document discloses molecules having the following formula ( Formula One ). The molecules disclosed in this document are related to the field of processes to produce molecules that are useful as pesticides (e.g., acaricides, insecticides, molluscicides, and nematicides), such molecules, and processes of using such molecules to control pests.
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Page/Page column 50; 51
(2014/02/15)
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- PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
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This document discloses molecules having the following formula ("Formula One") The molecules disclosed in this document are related to the field of processes to produce molecules that are useful as pesticides (e.g., acaricides, insecticides, molluscicides, and nematicides), such molecules, and processes of using such molecules to control pests.
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Page/Page column 49; 50
(2013/03/26)
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- FUSED HETEROARYL MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-KB ACTIVITY AND USE THEREOF
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Novel non-steroidal compounds are provided which are useful in treating diseases or disorders associated with modulation of the glucocorticoid receptor, AP-1, and/or NF-κB activity, including metabolic and inflammatory and immune diseases or disorders, ha
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Page/Page column 70-71
(2009/10/09)
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- Chemical Compounds
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There is provided compounds of Formula (I) and salts, solvates, and physiologically functional derivatives thereof: wherein R1 is hydrogen or C1-6alkyl; n is 1, 2, 3 or 4; R2 is aryl, optionally substituted by one or two groups selected from the group consisting of halogen, hydroxy, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkanoyl, haloC1-4alkyl, haloC1-4alkoxy, aryl, aryloxy, C1-4alkoxycarbonyl, C1-4alkylsulfonyl and a group R3R4NSO2 (wherein R3 and R4 are independently hydrogen or C1-4alkyl) and a 5- or 6-membered heteroaryl group; or n is 0 and R1 and R2, together with the nitrogen atom to which they are joined, form a 5- or 6-membered monocyclic heterocyclic ring or a 9- or 10-membered bicyclic heterocyclic ring wherein at least the ring which contains the nitrogen atom to which R1 and R2 are joined is non-aromatic, and wherein the 5- or 6-membered monocyclic heterocyclic ring or the 9- or 10-membered bicyclic heterocyclic ring is optionally substituted by one or two groups selected from the group consisting of halogen, hydroxy, cyano, oxo, C1-4alkyl, C1-4alkanoyl, C1-4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, aryl, aryloxy and C1-4alkoxycarbonyl; and X is indazolyl, pyrazolyl or a group: wherein G is CH or N; and Y1 and Y2 are independently hydrogen, halogen and a group NR5R6 (wherein R5 and R6 are independently hydrogen, C1-6alkyl or C2-6alkenyl).
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Page/Page column 15-16
(2008/12/08)
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- Inhibitors of acyl-coA:cholesterol O-acyltransferase. 2. Identification and structure-activity relationships of a novel series of N-alkyl-N- (heteroaryl-substituted benzyl)-N'-arylureas
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A series of N-alkyl-N-(heteroaryl-substituted benzyl)-N'-arylurea and related derivatives represented by 2 and 3 have been prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyltransferase in vitro and to lower plasma cholesterol levels in cholesterol-fed rats in vivo. Among these novel compounds, the type 3 series was superior. A pyrazol-3-yl group on the N-benzyl group of this trisubstituted urea (i.e. 3, Ar1 = pyrazol-3- yl) was identified as a heteroaromatic ring providing a good profile of biological activity. As a result of optimization of the combination with the N-alkyl group (R) and N-aryl group (At3), compound 3aq (FR186054) was identified as a new, orally efficacious ACAT inhibitor, which exhibited potent in vitro ACAT inhibitory activity (rabbit intestinal microsomes IC50 = 99 nM) and excellent hypocholesterolemic effects in cholesterol-fed rats, irrespective of administration mode (ED50 = 0.046 mg/kg dosed via the diet, ED50 = 0.44 mg/kg administered by gavage in PEG400 vehicle). Moreover, a toxicological study revealed compound 3aq to be nontoxic to the adrenal glands of dogs when tested at a single dose of 10 mg/kg po.
- Tanaka, Akira,Terasawa, Takeshi,Hagihara, Hiroyuki,Sakuma, Yuri,Ishibe, Noriko,Sawada, Masae,Takasugi, Hisashi,Tanaka, Hirokazu
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p. 2390 - 2410
(2007/10/03)
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- Palladium-Promoted Transformation of β-Amino Ketones to Enaminones
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The reaction of β-amino ketones with bis(acetonitrile)dichloropalladium(II) in the presence of triethylamine gives the corresponding enaminones regioselectively.The cyclic β-amino ketones can be converted into the corresponding exocyclic enaminones.The enaminones thus obtained are versatile synthetic intermediates.The reaction of (E)-enaminones with organocuprates gave the corresponding (E)-α,β-unsaturated ketones.
- Murahashi, Shun-Ichi,Mitsue, Yo,Tsumiyama, Tatsuo
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p. 3285 - 3290
(2007/10/02)
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