- 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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- Sorafenib sulfydryl derivative and application thereof
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The invention belongs to the field of medicine, and relates to a sorafenib sulfhydryl derivative and application thereof, in particular to a sorafenib sulfhydryl derivative and application thereof in preparation of an anti-tumor drug targeted delivery carrier. The structure of the sorafenib sulfhydryl derivative is shown as the following formula, a sulfhydryl functional group is introduced into pyridine-2-formamide of an anti-tumor small-molecule targeted drug sorafenib, and sorafenib can be coupled to free amino of polypeptide through proper linker molecules by utilizing the sulfhydryl functional group, so that a sorafenib polypeptide conjugate is constructed, the conjugate can give play to the targeting effect and tumor inhibition effect of sorafenib at the same time, and can be used as a targeting delivery carrier of antitumor drugs.
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- 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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- A process for the preparation of SUO draw non-Buddhist nun-toluene-sulfonic acid (by machine translation)
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The invention discloses a method for the preparation of SUO draw non-Buddhist nun-toluene-sulfonic acid. The method is as follows: P-amino-phenol and 4?Polybromide?2?Cyano pyridine the reaction is performed in the presence of sodium hydroxide, then is acidified to obtain 4?(4?Aminophenoxy)?2?(Formic acid) pyridine; the substitution after the reaction, thionyl chloride, in the presence of potassium carbonate, the reaction is carried out with methyl amine, to obtain the 4?(4?Aminophenoxy)?2?(Methyl carbamoyl) pyridine; then with compound 4?Chlorotrifluoromethylbenzene?3?Phenylisocyanate (trifluoromethyl) after direct condensation, with toluene-P-sulfonic acid salifying-toluene-sulfonic acid SUO draw non-Buddhist nun. The preparation method adopts a 4?Polybromide?2?Cyano pyridine as the starting raw materials for preparing the 4?(4?Aminophenoxy)?2?(Methyl carbamoyl) pyridine, the follow-up at the same time simplifying the step of reacting, simple steps of the reaction, the yield of the product is high. (by machine translation)
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Paragraph 0034; 0035
(2016/10/17)
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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 22; 25
(2008/12/08)
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