- Efficient Synthesis and Bioevaluation of Novel Dual Tubulin/Histone Deacetylase 3 Inhibitors as Potential Anticancer Agents
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Novel dual HDAC3/tubulin inhibitors were designed and efficiently synthesized by combining the pharmacophores of SMART (tubulin inhibitor) and MS-275 (HDAC inhibitor), among which compound 15cwas found to be the most potent and balanced HDAC3/tubulin dual inhibitor with high HDAC3 activity (IC50= 30 nM) and selectivity (SI > 1000) as well as excellent antiproliferative potency against various cancer cell lines, including an HDAC-resistant gastric cancer cell line (YCC3/7) with IC50values in the range of 30-144 nM. Compound 15cinhibited B16-F10 cancer cell migration and colony formation. In addition, 15cdemonstrated significantin vivoantitumor efficacy in a B16-F10 melanoma tumor model with a better TGI (70.00%, 10 mg/kg) than that of the combination of MS-275 and SMART. Finally, 15cpresented a safe cardiotoxicity profile and did not cause nephro-/hepatotoxicity. Collectively, this work shows that compound 15crepresents a novel tubulin/HDAC3 dual-targeting agent deserving further investigation as a potential anticancer agent.
- Chen, Jianjun,Chen, Jingxuan,Huang, Junli,Li, Ling,Liu, Jin,Peng, Xiaopeng,Ren, Yichang,Sun, Zhiqiang
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p. 8447 - 8473
(2021/06/28)
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- 3H-1,2,4-Dithiazol-3-one compounds as novel potential affordable antitubercular agents
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Small molecules with oxathiazol-2-one moiety were recently reported as potent inhibitors of Mycobacterium bovis var. bacilli Calmette-Guérin (BCG), among which HT1171 was the most potent and selective proteasome inhibitor. Herein we synthesized a series of novel compounds by bioisosteric replacement of the oxathiazol-2-one ring with 3H-1,2,4-dithiazol-3-one, and also fifteen 1,3,4-oxathiazol-2-one molecules in order for potency comparison and structure-activity relationship elucidation since their antibacterial effects on the virulent strains were not evaluated before. All the compounds were assessed for antitubercular activities on the virulent H37Rv strain by a serial dilution method. Among the tested compounds, 3H-1,2,4-dithiazol-3-one compound 4n was found to be the most active with a lowest MIC90 value of 1 μg/mL. Furthermore, the cytotoxicities of all the compounds against normal human liver cell line L02 were determined by an MTT method. Compound 4n displayed a lower inhibitory ratio than HT1171 at the concentration of 100 μM, indicating its better safety profile.
- Yang, Jianzhong,Pi, Weiyi,Xiong, Li,Ang, Wei,Yang, Tao,He, Jun,Liu, Yuanyuan,Chang, Ying,Ye, Weiwei,Wang, Zhenling,Luo, Youfu,Wei, Yuquan
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supporting information
p. 1424 - 1427
(2013/03/14)
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- Arylthioamides as H2S donors: L-cysteine-activated releasing properties and vascular effects in vitro and in vivo
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A small library of arylthioamides 1-12 was easily synthesized, and their H2S-releasing properties were evaluated both in the absence or in the presence of an organic thiol such as l-cysteine. A number of arylthioamides (1-3 and 7) showed a slow and l-cysteine-dependent H2S-releasing mechanism, similar to that exhibited by the reference slow H2S- releasing agents, such as diallyl disulfide (DADS) and the phosphinodithioate derivative GYY 4137. Compound 1 strongly abolished the noradrenaline-induced vasoconstriction in isolated rat aortic rings and hyperpolarized the membranes of human vascular smooth muscle cells in a concentration-dependent fashion. Finally, a significant reduction of the systolic blood pressure of anesthetized normotensive rats was observed after its oral administration. Altogether these results highlighted the potential of arylthioamides 1-3 and 7 as H 2S-donors for basic studies, and for the rational design/development of promising pharmacotherapeutic agents to treat cardiovascular diseases.
- Martelli, Alma,Testai, Lara,Citi, Valentina,Marino, Alice,Pugliesi, Isabella,Barresi, Elisabetta,Nesi, Giulia,Rapposelli, Simona,Taliani, Sabrina,Da Settimo, Federico,Breschi, Maria C.,Calderone, Vincenzo
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supporting information
p. 904 - 908
(2013/10/22)
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- Practical routes to the triarylsulfonyl chloride intermediate of a β3 adrenergic receptor agonist
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A β3 adrenergic receptor agonist was prepared on a multi-kilogram scale in high yield and purity via a convergent synthesis. A key intermediate in this synthesis was an arylthiazolylbenzenesulfonyl chloride. The triaryl segment of this sulfonyl chloride was assembled at the thiazole ring via coupling of α-haloketone and thiobenzamide precursors (Hantzsch synthesis). Three strategies for introducing the para-sulfonyl chloride moiety were developed and evaluated. The sulfonation/chlorination and diazotization/chlorosulfonylation routes were found the most efficient.
- Ikemoto, Norihiro,Liu, Jinchu,Brands, Karel M.J.,McNamara, James M.,Reider, Paul J.
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p. 1317 - 1325
(2007/10/03)
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