2199-51-1Relevant articles and documents
An improved synthesis of sunitinib malate via a solvent-free decarboxylation process
Meng, Ge,Liu, Chunyan,Qin, Shidong,Dong, Mengshu,Wei, Xiaomi,Zheng, Meilin,Qin, Liwen,Wang, Huihui,He, Xiaoshuang,Zhang, Zhiguo
, p. 8941 - 8954 (2015)
To search for an economical and convenient synthesis of sunitinib and its malate salt, optimization of a scalable synthetic route was explored by designing a standard experimental protocol on laboratory scale using commercially available materials including acetyl ethyl acetate, 4-fluoroaniline, and N 1,N 1-diethylethane-1,2-diamine. The optimal conditions were established based on investigating the main reaction steps, including cyclization, hydrolysis, decarboxylation, formylation, and condensation, giving optimized yields for each step of 94.4, 97.6, 98.5, 97.1, 91.0, 86.3, 85.5, 88.2, 99.1, 97.3, and 58.7 %, respectively. The synthesis process of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid as the important intermediate was significantly improved by using solvent-free decarboxylation instead of the traditional process in a high-boiling-point solvent. The subsequent formylation was conducted directly using the dichloromethane solution of the crude product from decarboxylation, leading to an almost quantitative combined yield of these two steps. The overall yields of sunitinib and its salt using the optimal synthesis process were 67.3 and 40.0 % based on acetyl ethyl acetate. The obtained data could be used as reference for future industrialization, especially for avoiding expensive solvents and reducing reaction time.
Antimicrobial and antiproliferative study of chalcone clubbed 2,4-dimethylpyrrole-3-carboxamide derivatives: Synthesis and in vitro evaluation
Bhange, Dattatraya Soma,Jagtap, Sangeeta Vijay,Rasal, Nishant Kisan
, (2021/10/06)
The presented study explores the anticancer potency of a novel series of chalcone clubbed 2,4-dimethyl-1H-pyrrole-3-carboxamide derivatives. In vitro antimicrobial screening concluded that five compounds are potential against Candida albicans having inhibition of growth in the range of 46.38%–73.05% against at the concentration of 32 μg/mL. The antiproliferative screening against 60 cancer cell lines revealed that seven compounds have great potential against the various types of cancer cell lines with inhibition of growth in the range of 41%–71%. The structure–activity relationship study concluded that the hydrazide bond is more significant than the carboxamide bond. In silico study of highly potential derivatives obeys each parameter of Lipinski rule of five and qualified drug-likeness behavior. The presented pyrrole-chalcone template delivered various candidates as anticancer agents, and those could be a potential scaffold to develop the new anticancer drug.
Synthesis, biological evaluation, and in silico study of pyrazoline-conjugated 2,4-dimethyl-1H-pyrrole-3-carboxylic acid derivatives
Rasal, Nishant K.,Sonawane, Rahul B.,Jagtap, Sangeeta V.
, (2020/10/22)
A potential molecular hybridization strategy was used to develop 24 novel pyrazoline-conjugated 2,4-dimethyl-1H-pyrrole-3-carboxylic acid and amide derivatives. The preliminary in vitro antimicrobial assay delivered four potential derivatives with growth inhibition in the range of 50.87–56.60% at the concentration of 32 μg/ml. In the search of an anticancer candidate, all derivatives were screened by NCI-60 at 10 μM concentration, revealing that 12 derivatives were potential agents against the various types of cancer cell lines, with growth inhibition in the range of 50.21–108.37%. The in vitro cytotoxicity assay against the cell line HEK293 (human embryonic kidney cells) and the hemolysis assay of the representative potent compounds propose their potential for a good therapeutic index. In silico studies of the most potent derivatives qualified their significant pharmacokinetic properties with good predicted oral bioavailability and their adherence to Lipinski's rule of five for druglikeness. A molecular docking study against VEGFR-2 with the best-scored conformations reinforced their anticancer potency. The docking study of the most potent compound against VEGFR-2 with the best-scored conformations displayed a binding affinity (?9.5 kcal/mol) comparable with the drug sunitinib (?9.9 kcal/mol) and exhibited that tighter interactions at the active adenosine triphosphate site might be responsible for anticancer potency.
Design, synthesis and biological activities of pyrrole-3-carboxamide derivatives as EZH2 (enhancer of zeste homologue 2) inhibitors and anticancer agents
Zhou, Qifan,Jia, Lina,Du, Fangyu,Dong, Xiaoyu,Sun, Wanyu,Wang, Lihui,Chen, Guoliang
supporting information, p. 2247 - 2255 (2020/02/20)
Zeste enhancer homolog 2 (EZH2) is highly expressed in various malignant tumors, which could silence tumor suppressor genes via trimethylation of H3K27. Herein was first reported a novel series of pyrrole-3-carboxamide derivatives carrying a pyridone fragment as EZH2 inhibitors. By combining computational modeling, in vitro cellular assays and further rational structure-activity relationship exploration and optimization, compound DM-01 showed powerful inhibition towards EZH2. DM-01 was found to have significant ability to reduce the cellular H3K27me3 level in K562 cells in the Western blot test. Meanwhile, our data showed that knockdown EZH2 in A549 cells resulted in a decrease of cell sensitivity to DM-01 at 50 and 100 μM. DM-01 could also increase the transcription expression of DIRAS3 in a dose-dependent manner, a tumor suppressor in the downstream of EZH2, suggesting it was worth investigating further as a lead compound.
Transition metal-free cyclization of N-boc-N-propargylenamines
Chikayuki, Yuya,Higashiyama, Kimio,Ishikawa, Haruka,Kouno, Yasuaki,Sasaki, Shigeru,Teramoto, Hiroyoshi,Waki, Yoko,Yamauchi, Takayasu,Yonekawa, Shiori
, p. 719 - 746 (2020/07/13)
An efficient method for the synthesis of multi-substituted pyrroles was developed using basic cyclization of readily accessible N-Boc-N-propargylenamines. Despite the basic conditions, cleavage of the N-Boc group occurred easily. The process was rapid and afforded N-H-pyrroles with wide functional group tolerance in high yields.
Preparation method of sunitinib intermediate
-
, (2019/05/04)
The invention discloses a preparation method of a sunitinib intermediate. The method includes the following steps of 1, synthesis of 2, 4-dimethylpyrrole-3, 5-diethyl dicarboxylate, 2, synthesis of 4-ethoxycarbonyl-3, 5-dimethylpyrrole-2-carboxylic acid, 3, synthesis of 2, 4-dimethyl-3-ethyl pyrrole-2-carboxylate, 4, synthesis of 2, 4-dimethyl-5-aldehyde-1H-pyrrole-3-ethyl formate, and 5, synthesis of 2,4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid. The method has the advantages that the raw materials are cheap, the environmental pollution is small, the industrial production is easy to achieve, the processing steps are fewer, the operation is simple, the reaction yield is very high, the mass production of enterprise is facilitated, and application and popularization are facilitated.
Regulating Transition-Metal Catalysis through Interference by Short RNAs
Green, Sydnee A.,Montgomery, Hayden R.,Benton, Tyler R.,Chan, Neil J.,Nelson, Hosea M.
supporting information, p. 16400 - 16404 (2019/08/26)
Herein we report the discovery of a AuI–DNA hybrid catalyst that is compatible with biological media and whose reactivity can be regulated by small complementary nucleic acid sequences. The development of this catalytic system was enabled by the discovery of a novel AuI-mediated base pair. We found that AuI binds DNA containing C-T mismatches. In the AuI–DNA catalyst's latent state, the AuI ion is sequestered by the mismatch such that it is coordinatively saturated, rendering it catalytically inactive. Upon addition of an RNA or DNA strand that is complementary to the latent catalyst's oligonucleotide backbone, catalytic activity is induced, leading to a sevenfold increase in the formation of a fluorescent product, forged through a AuI-catalyzed hydroamination reaction. Further development of this catalytic system will expand not only the chemical space available to synthetic biological systems but also allow for temporal and spatial control of transition-metal catalysis through gene transcription.
Novel RIP1 kinase inhibitor containing pyrrole ring and indoline structure and application thereof
-
Paragraph 0026-0027, (2018/07/30)
The invention relates to a novel RIP1 kinase inhibitor containing a pyrrole ring and an indoline structure and application in preparing drugs for treating inflammation, ischemic diseases and cell injury type diseases.
5-Hydroxy-7-azaindolin-2-one, a novel hybrid of pyridinol and sunitinib: Design, synthesis and cytotoxicity against cancer cells
Shah, Sajita,Lee, Chaemin,Choi, Hyukjae,Gautam, Jaya,Jang, Hyeonjin,Kim, Geum Jin,Lee, Yu-Jeong,Chaudhary, Chhabi Lal,Park, Sang Won,Nam, Tae-Gyu,Kim, Jung-Ae,Jeong, Byeong-Seon
, p. 4829 - 4841 (2016/06/13)
Angiogenesis plays important roles in tumor growth and metastasis. Sunitinib (Sutent) is an antitumor agent targeting receptor tyrosine kinases which are involved in angiogenesis as well as cancer cell growth and survival. Using the pyridin-3-ol scaffold, which was previously reported as an excellent antioxidant and antiangiogenic platform, we have synthesized sunitinib mimics 6 by hybridizing bicyclic pyridinol 4 as a key scaffold and pyrrole-2-carbaldehydes 7 as side chains. Cytotoxicity assays showed that compounds 6 have comparable to better anticancer activity than sunitinib against five different cancer cell lines. In addition, compounds 6 showed even lower levels of cytotoxicity against normal cells, resulting in up to 26-fold better safety windows, than sunitinib. Signaling pathway-associated transcription factor reporter assay and western blot analyses revealed that apoptosis induction in MDA-MB-231 human breast cancer cells by 6F is mainly mediated through the p53 increase and down-regulation of phospho-signal transducer and activator of transcription 3 (STAT3) and its target gene products, cyclin D, Bcl-2, and survivin. The data strongly suggest that our hybrid compounds can provide a novel anticancer scaffold with improved and safer cytotoxicity profiles than sunitinib.
Design and synthesis of new potent PTP1B inhibitors with the skeleton of 2-substituted imino-3-substituted-5-heteroarylidene-1,3-thiazolidine-4-one: Part I
Meng, Ge,Zheng, Meilin,Wang, Mei,Tong, Jing,Ge, Weijuan,Zhang, Jiehe,Zheng, Aqun,Li, Jingya,Gao, Lixin,Li, Jia
, p. 756 - 769 (2016/08/18)
A new series of 2-substituted imino-3-substituted-5- heteroarylidene-1,3-thiazolidine-4-ones as the potent bidentate PTP1B inhibitors were designed and synthesized in this paper. All of the new compounds were characterized and identified by spectra analysis. The biological screening test against PTP1B showed that some of these compounds have the positive inhibitory activity against PTP1B. The activity of the compounds with 5-substituted pyrrole on 5-postion of 1,3-thiazolidine-4-one are more potent than that of those compounds with 5-substituted pyridine group. Compound 14b, 14h and 14i showed IC50values of 8.66?μM, 6.83?μM and 6.09?μM against PTP1B, respectively. Docking analysis of these active compounds with PTP1B showed the possible interaction modes of these biheterocyclic compounds with the active sites of PTP1B. The inhibition tests against oncogenetic CDC25B were also conducted on this set of compounds to evaluate the selectivity and possible anti-neoplastic activity. Compound 14b also showed the lowest IC50of 1.66?μM against CDC25B among all the possible inhibitors, including 14g, 14h, 14i and 15c. Some pharmacological parameters including VolSurf, steric and electric descriptors of all the compounds were calculated to give some hints about the relative relationship with the biological activity. The result of this study might give some light on designing the possible anti-cancer drugs targeting at phosphatases. The most active compound 14i might be used as the lead compound for further structure modification of the new low molecular weight PTP1B inhibitors with the N-containing heterocyclic skeleton.
