- Identification and optimization of biphenyl derivatives as novel tubulin inhibitors targeting colchicine-binding site overcoming multidrug resistance
-
Microtubule targeting agents (MTAs) are among the most successful chemotherapeutic drugs, but their efficacy is often limited by the development of multidrug resistance (MDR). Therefore, the development of novel MTAs with the ability to overcome MDR is urgently needed. In this contribution, through modification of the unsymmetric biaryl compounds, we discovered a novel compound dxy-1-175 with potent anti-proliferative activity against cancer cells. Mechanistic study revealed that dxy-1-175 inhibited tubulin polymerization by interacting with the colchicine-binding site of tubulin, which caused cell cycle arrest at G2/M phase. Based on the predicted binding model of dxy-1-175 with tubulin, a series of new 4-benzoylbiphenyl analogues were designed and synthesized. Among them, the hydrochloride compound 12e with improved solubility and good stability in human liver microsome, exhibited the most potent anti-proliferative activity with IC50 value in the low nanomolar range, and markedly inhibited the growth of breast cancer 4T1 xenograft in vivo. Notably, 12e effectively overcame P-gp-mediated MDR and our preliminary data suggested that 12e may not be a substrate of P-glycoprotein (P-gp). Taken together, our study reveals a novel MTA 12e targeting the colchicine-binding site with potent anticancer activity and the ability to circumvent MDR.
- Cheng, Bao,Zhu, Guirong,Meng, Linghua,Wu, Guolin,Chen, Qin,Ma, Shengming
-
-
- COMPOUNDS
-
A compound of formula (I), or a pharmaceutical salt thereof.
- -
-
Page/Page column 277
(2020/01/11)
-
- meta-Nitration of Arenes Bearing ortho/para Directing Group(s) Using C?H Borylation
-
Herein, we report the meta-nitration of arenes bearing ortho/para directing group(s) using the iridium-catalyzed C?H borylation reaction followed by a newly developed copper(II)-catalyzed transformation of the crude aryl pinacol boronate esters into the corresponding nitroarenes in a one-pot fashion. This protocol allows the synthesis of meta-nitrated arenes that are tedious to prepare or require multistep synthesis using the existing methods. The reaction tolerates a wide array of ortho/para-directing groups, such as ?F, ?Cl, ?Br, ?CH3, ?Et, ?iPr ?OCH3, and ?OCF3. It also provides regioselective access to the nitro derivatives of π-electron-deficient heterocycles, such as pyridine and quinoline derivatives. The application of this method is demonstrated in the late-stage modification of complex molecules and also in the gram-scale preparation of an intermediate en route to the FDA-approved drug Nilotinib. Finally, we have shown that the nitro product obtained by this strategy can also be directly converted to the aniline or hindered amine through Baran's amination protocol.
- Li, Xuejing,Deng, Xingwang,Coyne, Anthony G.,Srinivasan, Rajavel
-
supporting information
p. 8018 - 8023
(2019/05/29)
-
- Microwave-assisted, Ir-catalyzed aromatic C-H borylation
-
One-step conversions of 1,3-disubstituted benzenes to aryl boronates and 2,6-disubstituted pyridines to heteroaryl boronates are described. Microwave heating was used for all reactions. [(COD)Ir(μ-OMe)]2 and 4,4′-di-tert-butyl-2,2′-bipyridine w
- Zeqing, Li,Zhibin, Liang,Yuqiang, Wang,Pei, Yu
-
p. 1917 - 1926
(2013/06/05)
-
- (HETERO)ARYL CYCLOPROPYLAMINE COMPOUNDS AS LSD1 INHIBITORS
-
The invention relates to (hetero)aryl cyclopropylamine compounds, including particularly the compounds of formula (I) as described and defined herein, and their use in therapy, including, e.g., in the treatment or prevention of cancer, a neurological disease or condition, or a viral infection.
- -
-
Page/Page column 151
(2013/05/09)
-
- Discovery of a series of potent arylthiadiazole H3 antagonists
-
A series of 2-piperidinopiperidine-5-arylthiadiazoles was synthesized and subjected to a structure-activity relationship (SAR) investigation. The potency of this series was improved to the single digit nanomolar range. The key analogs were shown to be free of P450 issues, and they also maintained good ex vivo activity and brain penetration.
- Xiao, Dong,Palani, Anandan,Sofolarides, Michael,Huang, Ying,Aslanian, Robert,Vaccaro, Henry,Hong, Liwu,McKittrick, Brian,West Jr., Robert E.,Williams, Shirley M.,Wu, Ren-Long,Hwa, Joyce,Sondey, Christopher,Lachowicz, Jean
-
scheme or table
p. 861 - 864
(2011/03/18)
-
- NOVEL 2-AMINO-5, 5-DIARYL-IMIDAZOL-4-ONES
-
This invention relates to novel compounds having the structural formula (I) below: and to their pharmaceutically acceptable salt, compositions and methods of use. These novel compounds provide a treatment or prophylaxis of cognitive impairment, Alzheimer Disease, neurodegeneration and dementia.
- -
-
Page/Page column 117-118
(2008/12/06)
-