- Introduction of mercaptoethyl at sorafenib pyridine‐2‐amide motif as a potentially effective chain to further get sorafenib‐PEg‐DGL
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The crystal structure of the sorafenib and B‐RAF complex indicates that the binding cavity occupied by the pyridine‐2‐carboxamide in sorafenib has a large variable space, making it a reasonable modification site. In order to identify novel compounds with anti‐cancer activity, better safety and polar groups for further application, five sorafenib analogs with new pyridine‐2‐amide side chains were designed and synthesized. Preliminary pharmacologic studies showed that these compounds displayed much lower toxicities than that of sorafenib. Among them, compound 10b bearing mercaptoethyl group kept relevant antiproliferation potency compared to sorafenib in Huh7 and Hela cell lines with values of IC50 58.79 and 63.67 μM, respectively. As a small molecule inhibitor targeting protein tyrosine kinases, thiol in compound 10b would be an active group to react with maleimide in a mild condition for forming nanoparticles Sorafenib‐PEG‐DGL, which could be developed as a delivery vehicle to improve the concentration of anti‐tumor therapeutic agents in the target cancer tissue and reduce side effects in the next study.
- Chen, Ying,Kuerbana, Kudelaidi,Wan, Qi,Wang, Ke,Ye, Li,Yu, Zhihui
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- Synthesis and anti-proliferative activity evaluation of sorafenib derivatives with a 3-arylacryloyl hydrazide unit
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A series of sorafenib derivatives with a 3-arylacryloyl hydrazide unit were designed and synthesized, and their anti-proliferative activity against human cancer cell lines (ACHN, HCT116, MDA-MB-231) were evaluated by MTT assay. Most of the synthesized compounds showed superior or similar cytotoxicity against the selected cell lines to the control sorafenib. Among these derivatives, compounds 8a, 8h, 8l, 8m, 11a and 11b showed potent anti-proliferative activity. Compounds 8h and 8m were selected for further evaluation of biological activity against more cancer cell lines. And oral administration of sorafenib analogue 8h at the same dose of sorafenib (30 mg/kg) in the pancreatic cancer Capan2 and Mia-PaCa2 xenograft models in nude mice showed tumour growth inhibition of 60.98 and 54.59 %, respectively, which is similar to the positive control sorafenib.
- Zhang, Lijing,Li, Yan,Wang, Ke,Qin, Aifang,Chen, Xiaoguang,Feng, Zhiqiang
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p. 1733 - 1743
(2015/04/27)
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- Synthesis and in vitro cytotoxic activities of sorafenib derivatives
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A series of novel sorafenib derivatives have been designed and synthesized. The cytotoxic activities of these compounds were tested in three tumor cell lines. Most of the compounds showed potent antiproliferative activity against the tested cell lines with IC50 = 0-20 μmol/L. Some compounds demonstrated competitive antiproliferative activities to sorafenib against all three cancer cell lines. Among them, compound 5g demonstrated significant inhibitory activity against A549, ACHN and MDA-MB-231 cell lines with IC 50 values of 1.29, 1.99, 3.11 μmol/L, respectively.
- Wang, Ke,Li, Yan,Zhang, Li-Jing,Chen, Xiao-Guang,Feng, Zhi-Qiang
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p. 702 - 704
(2014/06/09)
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- METHOD AND PROCESS FOR PREPARATION AND PRODUCTION OF DEUTERATED OMEGA-DIPHENYLUREA
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Methods and processes for preparation and production of deuterated ω-diphenylurea are disclosed. Especially, a kind of deuterated ω-diphenylurea compounds which can inhibit phosphokinase and the preparation method of N-(4-chloro-3-(trifluoromethyl)phenye-N′-(4-(2-(N-d3-methylcarbamoyl)-4-pridinyloxy)phenyl)urea are disclosed. The said deuterated diphenylurea compounds can be used for treating or preventing tumors and relative diseases.
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- RAF KINASE INHIBITORS CONTAINING A ZINC BINDING MOIETY
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The present invention relates to Raf kinase inhibitors containing zinc-binding and their use in the treatment of Raf related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.
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Page/Page column 25
(2008/12/08)
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- DIARYL UREAS AND COMBINATIONS
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The present invention provides methods for treating cancer in humans and other mammals comprising administering a chemotherapeutic agent, such as an interferon, and an aryl urea compound of Formula (I) : B-NH-C(O)-NH-L-M-L1-(Q)1-3 (I). In Formula (I), B and L and are each, independently, optionally substituted phenyl, naphthyl, a 5 or 6 membered monocyclic heteroaryl group, or an 8 to 10 membered bicyclic heteroaryl group; M is a bridging group. Each Q is independently C(O)R4, C(O)OR4 and C(O)NR4R5; and L' is optionally substituted phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl, or a saturated or partially saturated, monocyclic or bicyclic carbocyclic moiety or heterocyclic moiety.
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Page/Page column 50; 60
(2008/06/13)
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- DIARYL UREAS WITH KINASE INHIBITING ACTIVITY
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The present invention provides methods of using aryl ureas to treat diseases and conditions associated with signal transduction pathways comprising at least one of raf, VEGFR, PDGFR, p38 and/or FLT-3. The present invention also provides compositions and methods for identifying conditions and diseases which can be modulated with compounds of the present invention. These methods facilitate the selection of subjects who can be efficiently treated with compounds of the present invention. Additionally, the invention provides methods for monitoring subjects who have been administered a compound of the present invention.
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- OMEGA-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS
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This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.
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Page/Page column 40
(2010/01/31)
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