- Bifunctional Naphtho[2,3- d][1,2,3]triazole-4,9-dione Compounds Exhibit Antitumor Effects in Vitro and in Vivo by Inhibiting Dihydroorotate Dehydrogenase and Inducing Reactive Oxygen Species Production
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Human dihydroorotate dehydrogenase (hDHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound 3s with a naphtho[2,3-d][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against hDHODH. Further optimization led to compounds 11k and 11l, which inhibited hDHODH activity with IC50 values of 9 and 4.5 nM, respectively. Protein-ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of 11k and 11l with hDHODH. Compounds 11k and 11l significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound 11l displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound 11l with hDHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.
- Zuo, Zeping,Liu, Xiaocong,Qian, Xinying,Zeng, Ting,Sang, Na,Liu, Huan,Zhou, Yue,Tao, Lei,Zhou, Xia,Su, Na,Yu, Yamei,Chen, Qiang,Luo, Youfu,Zhao, Yinglan
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supporting information
p. 7633 - 7652
(2020/08/21)
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- Triazole naphthoquinone connected aromatic (heterocyclic) ring derivative
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The invention belongs to the field of chemical medicine, particularly relates to a micromolecule capable of resisting malignant tumor, acute leukemia and arthritis, multiple sclerosis and immunological rejection and a preparation and application of the mi
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Paragraph 0101; 0102; 0103
(2018/10/01)
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- DERIVATIVES OF 6-SUBSTITUTED TRIAZOLOPYRIDAZINES AS REV-ERB AGONISTS
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The present invention provides novel 6-substituted [1,2,4]triazolo[4,3-b]pyridazines that are agonists of Rev-Erb. These compounds, and pharmaceutical compositions comprising the same, are suitable means for treating any disease wherein the activation of Rev-Erb has therapeutic effects, for instance in inflammatory and circadian rhythm-related disorders or cardiometabolic diseases.
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Page/Page column 45; 70
(2013/04/13)
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- DIARYL UREA DERIVATIVES USEFUL FOR THE TREATMENT OF PROTEIN KINASE DEPENDENT DISEASES
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The invention relates to the use of diaryl urea derivatives in the treatment of protein kinase dependent diseases or for the manufacture of pharmaceutical compositions for use in the treatment of said diseases, methods of use of diaryl urea derivatives in the treatment of said diseases, pharmaceutical preparations comprising diaryl urea derivatives for the treatment of said diseases, diaryl urea derivatives for use in the treatment of said diseases, novel diaryl urea derivatives, pharmaceutical preparations comprising these novel diaryl urea derivatives, processes for the manufacture of the novel diaryl urea derivatives, the use or methods of use of the novel diaryl urea derivatives as mentioned above, and/or these novel diaryl urea derivatives for use in the treatment of the animal or human body.
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- β-methoxy acrylic acid derivatives, method for preparing same, and use of said derivatives as pesticides
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A subject of the invention is the products of formula (I): STR1 in which: R1, R2 and R3, identical or different, represent a linear, branched or cyclic alkyl radical, an alkenyl or alkynyl radical, containing up to 8 carbon atoms, optionally substituted by one or more halogen atoms, an aryl radical optionally substituted by one or more halogen atoms, one or more hydroxyl radicals, one or more linear or branched alkyl radicals, optionally substituted by one or more halogen atoms, one or more O-alkyl or S-alkyl radicals optionally substituted by one or more halogen atoms, X represents a hydrogen atom, a halogen atom, an alkyl, alkenyl, alkynyl, O-alkyl, O-alkenyl, O-alkynyl, S-alkyl, S-alkenyl or S-alkynyl radical, optionally substituted by one or more halogen atoms and containing up to 11 carbon atoms, an aryl radical containing up to 14 carbon atoms, a C N, NO2, NH2, STR2 CO2 alk3 radical, alk1, alk2 and alk3, identical to or different from each other, representing an alkyl radical containing up to 8 carbon atoms, R4 represents one of the values indicated above for X with the exception of hydrogen.
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