- Identification, Synthesis, and Biological Evaluations of Potent Inhibitors Targeting Type i Protein Arginine Methyltransferases
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CARM1 (coactivator-associated arginine methyltransferase 1), which belongs to type I PRMTs (protein arginine methyltransferases), is a potential therapeutic target for treatment of multiple cancers. In this study, we first identified several hit compounds against CARM1 by structure-based virtual screening (IC50 = 35.51 ± 6.68 to 68.70 ± 8.12 μM) and then carried out chemical structural optimizations, leading to six compounds with significantly improved activities targeting CARM1 (IC50 = 18 ± 2 to 107 ± 6 nM). As a compound with an ethylenediamino motif, the most potent inhibitor, ZL-28-6, also exhibited potent inhibition against other type I PRMTs. Compared to the type I PRMT inhibitor from our previous work (DCPR049_12), ZL-28-6 showed increased potency against CARM1 and decreased activity against other type I PRMTs. Moreover, ZL-28-6 showed better antiproliferation activities toward a series of solid tumor cells than DCPR049_12, indicating its broad spectrum of anticancer activity. In addition, cellular thermal shift and Western blot assays validated that ZL-28-6 could target CARM1 in cells. Taken together, the inhibitor we identified could serve as a potent probe for studying CARM1's biological functions and shed light on the future design of novel CARM1 inhibitors with stronger activities and selectivities.
- Li, Xiao,Zhang, Lun,Xu, Jing,Liu, Chenyu,Zhang, Xiaojian,Abdelmoneim, Amr Abbas,Zhang, Qian,Ke, Jiaqi,Zhang, Yingnan,Wang, Lei,Yang, Fan,Luo, Cheng,Jin, Jia,Ye, Fei
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p. 692 - 702
(2022/02/09)
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- PRMTI Type methyltransferase inhibition active compound as well as preparation and application thereof
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The invention relates to a compound with PRMT I-type methyltransferase inhibition activity and preparation and application thereof, wherein the compound has the structure shown I. The compound of the formula I has a good inhibition effect on PRMT I-type m
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Paragraph 0014
(2021/11/03)
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- Design, synthesis and biological evaluation of benzamide derivatives as novel NTCP inhibitors that induce apoptosis in HepG2 cells
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Sodium taurocholate cotransport polypeptide (NTCP) plays an important role in the development of hepatitis and acts as a switch to allow hepatitis virus to enter hepatic cells. As the entry receptor protein of hepatitis virus, NTCP is also an effective ta
- Zhao, Shuangmei,Zhen, Yongqi,Fu, Leilei,Gao, Feng,Zhou, Xianli,Huang, Shuai,Zhang, Lan
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supporting information
(2019/08/20)
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- Potassium tert-Butoxide-Mediated Condensation Cascade Reaction: Transition Metal-Free Synthesis of Multisubstituted Aryl Indoles and Benzofurans
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An efficient and facile method to synthesize valuable disubstituted 2-aryl indoles and benzofurans in good yields has been demonstrated, based on a tert-butoxide-mediated condensation reaction involving a vinyl sulfoxide intermediate. Products are obtained from N- or O-benzyl benzaldehydes using dimethyl sulfoxide as a carbon source. The methodology features a wide functional group tolerance and transition metal-free environment. Preliminary mechanistic studies suggest that the reaction involves a tandem aldol reaction/Michael addition/dehydrosulfenylation/isomerization sequence through an ionic protocol.
- Yang, Pengfei,Xu, Weiyan,Wang, Rongchao,Zhang, Min,Xie, Chunsong,Zeng, Xiaofei,Wang, Min
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supporting information
p. 3658 - 3662
(2019/05/17)
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- Hydride transfer reactions of 5-(2-alkohybenzylidene) barbituric acids: Synthesis of 2,4,6-trioxoperhydropyrimidine-5-spiro-3′-chromanes
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The thermal cyclization of 5-(2-phenoxymethylphenyl-methylene)barbituric acid and its derivatives affords 2,4,6-trioxoperhydropyrimidine-5-spiro-3′-chromanes. The reactions require no catalysts and proceed at temperatures from 118 to 240?°C depending on the substrate activity. These cyclization reactions are analogous to T-reactions of tertiary amines involving the hydride transfer.
- Krasnov, Konstantin A.,Dorovatovskii, Pavel V.,Zubavichus, Yan V.,Timofeeva, Tatiana V.,Khrustalev, Victor N.
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p. 542 - 549
(2017/01/12)
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- Synthesis and anticancer activity of benzyloxybenzaldehyde derivatives against HL-60 cells
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A series of benzyloxybenzaldehyde derivatives were prepared and tested against the HL-60 cell line for anticancer activity. Preliminary structure-activity relationships were established. It was discovered that 2-(benzyloxy)benzaldehyde (17), 2-(benzyloxy)-4-methoxybenzaldehyde (26), 2-(benzyloxy)-5-methoxybenzaldehyde (27), 2-(benzyloxy)-5-chlorobenzaldehyde (28), 2-[(3-methoxybenzyl)oxy]benzaldehyde (29), 2-[(2-chlorobenzyl)oxy] benzaldehyde (30), and 2-[(4-chlorobenzyl)oxy]benzaldehyde (31) exhibited significant activity at 1-10 μM. Among them, compound 29 was the most potent one. The morphological assessment and DNA fragmentation analysis indicated that these compounds arrested cell cycle progression at G2/M phase and induced cell apoptosis. They resulted in the loss of mitochondrial membrane potential after 12 h of treatment.
- Lin, Chin-Fen,Yang, Jai-Sing,Chang, Chiung-Yun,Kuo, Sheng-Chu,Lee, Miau-Rong,Huang, Li-Jiau
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p. 1537 - 1544
(2007/10/03)
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- Synthesis of heterocycles with MF/Al2O3 base-systems: 2-arylbenzofuranes and 2,3-diarylisoquinolin-1(2H)-ones
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2-Benzyloxybenzaldehydes, -acetophenones and -benzophenones substituted in the benzyl part with electron-withdrawing groups, cyclize easily to 2-arylbenzofuranes by using a standardized KF- or CsF-Al2O3 base system. An efficient one-pot synthesis for 2,3-diarylisoquinolin-1(2H)-ones is possible by reacting a variety of arene carbaldehyde anils with phthalides under the same reaction conditions.
- Hellwinkel,Goke
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p. 1135 - 1141
(2007/10/02)
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