23504-03-2Relevant articles and documents
Design and Synthesis of Hsp90 Inhibitors with B-Raf and PDHK1 Multi-Target Activity
Pinzi, Luca,Foschi, Francesca,Christodoulou, Michael S.,Passarella, Daniele,Rastelli, Giulio
, p. 1177 - 1185 (2021/10/14)
The design of multi-target ligands has become an innovative approach for the identification of effective therapeutic treatments against complex diseases, such as cancer. Recent studies have demonstrated that the combined inhibition of Hsp90 and B-Raf provides synergistic effects against several types of cancers. Moreover, it has been reported that PDHK1, which presents an ATP-binding pocket similar to that of Hsp90, plays an important role in tumor initiation, maintenance and progression, participating also to the senescence process induced by B-Raf oncogenic proteins. Based on these premises, the simultaneous inhibition of these targets may provide several benefits for the treatment of cancer. In this work, we set up a design strategy including the assembly and integration of molecular fragments known to be important for binding to the Hsp90, PDHK1 and B-Raf targets, aided by molecular docking for the selection of a set of compounds potentially able to exert Hsp90-B-Raf-PDHK1 multi-target activities. The designed compounds were synthesized and experimentally validated in vitro. According to the in vitro assays, compounds 4 a, 4 d and 4 e potently inhibited Hsp90 and moderately inhibited the PDHK1 kinase. Finally, molecular dynamics simulations were performed to provide further insights into the structural basis of their multi-target activity.
Kolbe-Schmitt type reaction under ambient conditions mediated by an organic base
Sadamitsu, Yuta,Okumura, Akira,Saito, Kodai,Yamada, Tohru
, p. 9837 - 9840 (2019/08/20)
The combined use of an organic base for resorcinols realized a Kolbe-Schmitt type reaction under ambient conditions. When resorcinols (3-hydroxyphenol derivatives) were treated with DBU under a carbon dioxide atmosphere, nucleophilic addition to carbon dioxide proceeded to afford the corresponding salicylic acid derivatives in high yields.
Synthesis method of 4-isopropylresorcinol
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Paragraph 0018; 0031; 0035-0036; 0040-0041; 0045, (2018/04/01)
The invention discloses a synthesis method of 4-isopropylresorcinol. The method comprises the following steps: group protection, Grignard reaction, hydrodeoxygenation and deprotection. According to the method, a novel protecting group halomethyl methyl ether is adopted for protecting phenolic hydroxy, then the Grignard reaction is performed on 3 milliliters of methylmagnesium chloride or methylmagnesium bromide, hydrogenation is performed under low pressure and normal temperature in the presence of acid, and the protecting group is removed with hydrochloric acid to obtain the 4-isopropylresorcinol. The problem of difficulty in treatment after Witting reaction is solved, the temperature and the pressure of hydrogenation reaction are reduced, the hydrogenation time is shortened, deprotectionis finally implemented under a mild condition, and the whole process is a safe production process capable of implementing industrial production.
Radiosynthesis, biological evaluation and preliminary microPET study of 18F-labeled 5-resorcinolic triazolone derivative based on ganetespib targeting HSP90
Kang, Julie,Young Lee, Jun,Ta?, ?sa,More, Kunal N.,Kim, Hangun,Park, Jeong-Hoon,Chang, Dong-Jo
, p. 3658 - 3664 (2018/10/26)
Heat-shock protein 90 (HSP90) is a molecular chaperone that activates oncogenic transformation in several solid tumors, including lung and breast cancers. Ganetespib, a most promising candidate among several HSP90 inhibitors under clinical trials, has entered Phase III clinical trials for cancer therapy. Despite numerous evidences validating HSP90 as a target of anticancer, there are few studies on PET agents targeting oncogenic HSP90. In this study, we synthesized and biologically evaluated a novel 18F-labeled 5-resorcinolic triazolone derivative (1, [18F]PTP-Ganetespib) based on ganetespib. [18F]PTP-Ganetespib was labeled by click chemistry of Ganetespib-PEG-Alkyne (10) and [18F]PEG-N3 (11) with 37.3 ± 5.11% of radiochemical yield and 99.7 ± 0.09% of radiochemical purity. [18F]PTP-Ganetespib showed proper LogP (0.96 ± 0.06) and good stability in human serum over 97% for 2 h. [18F]PTP-Ganetespib showed high uptakes in breast cancer cells containing triple negative breast cancer (TNBC) MDA-MB-231 and Her2-negative MCF-7 cells, which are target breast cancer cell lines of HSP90 inhibitor, ganetespib, as an anticancer. Blocking of HSP90 by the pretreatment of ganetespib exhibited significantly decreased accumulation of [18F]PTP-Ganetespib in MDA-MB-231 and MCF-7 cells, indicating the specific binding of [18F]PTP-Ganetespib to MDA-MB-231 and MCF-7 cells with high HSP90 expression. In the biodistribution and microPET imaging studies, the initial uptake into tumor was weaker than in other thoracic and abdominal organs, but [18F]PTP-Ganetespib was retained relatively longer in the tumor than other organs. The uptake of [18F]PTP-Ganetespib in tumors was not sufficient for further development as a tumor-specific PET imaging agent by itself, but this preliminary PET imaging study of [18F]PTP-Ganetespib can be basis for developing new PET imaging agents based on HSP90 inhibitor, ganetespib.
Heat shock protein inhibitor and preparation method and application thereof
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, (2016/10/09)
The present invention discloses a heat shock protein inhibitor and a preparation method and an application thereof, and belongs to the technical field of medicinal chemistry. The heat shock protein inhibitor has the structure features of a formula I. The compound can inhibit activity of the heat shock protein 90, and then can be used for preparing anti-tumor drugs.
Phenyl 1, 2 - isoxazole or phenyl 1, 2 - pyrazole compound and use thereof (by machine translation)
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, (2017/01/19)
The invention discloses the following formula of phenyl 1, 2 - different oxazole or 1, 2 - pyrazole compounds with use. Through the biological activity tests show that, the compound inhibiting heat shock protein 90 activity. Therefore, the invention phenyl 1, 2 - different oxazole or 1, 2 - pyrazole compounds can be used as a heat shock protein 90 inhibitor for the treatment of cancer. (by machine translation)
Synthesis and biological evaluation of 3,5-disubstituted-4-alkynylisoxozales as a novel class of HSP90 inhibitors
Sun, Jian,Lin, Cai,Qin, Xiaochu,Dong, Xiaoping,Tu, Zhengchao,Tang, Fei,Chen, Chaonan,Zhang, Jiancun
, p. 3129 - 3134 (2015/07/08)
Abstract A series of 3,5-disubstitute-4-alkynylisoxazole derivatives were designed and synthesized through palladium(II)-copper(I) catalyzed Sonogashira cross-coupling reaction of an alkynyl moiety and an isoxazole scaffold as novel HSP90 inhibitors. The resultant compounds displayed moderate to potent binding affinity to HSP90 proteins, and also demonstrated good cell growth inhibitory activity against various cancer cell lines (A549, K562, MCF-7, DU145 and Hela). Some compounds (18d, 18e, 19a, 19d, 20c and 20q) show similar or better binding affinity towards HSP90α and HSP90β comparing to NVP-AUY922. In addition, compounds 18e, 19a and 20q exhibited potent inhibitory activity against various human cancer cell lines.
Hybrids of the benzofuran core from natural products and the 2,4-dihydroxy-5-isopropylbenzene fragment as potent Hsp90 inhibitors: Design, synthesis and bioevaluation
Jia, Jian-Min,Liu, Fang,Xu, Xiao-Li,Guo, Xiao-Ke,Jiang, Fen,Huang, Hao-Zhe,Pan, Yang,Cherfaoui, Bahidja,Sun, Hao-Peng,You, Qi-Dong
, p. 495 - 502 (2014/10/15)
Several chemical fragments have been confirmed as highly efficient cores for the design of Hsp90 inhibitors. Molecular hybridization of potent fragments has been widely used as a rational drug discovery strategy. In this study, a novel class of hybrids of benzofuran, a privileged core from natural products, and 2,4-dihydroxy-5-isopropyl phenyl, an efficient fragment in Hsp90 inhibitors, were designed and synthesized. Subsequent evaluation confirmed they inhibited cell proliferation and regulated the level of client proteins through Hsp90 inhibition. Some of the hybrids can serve as leads to obtain novel chemotypes of Hsp90 inhibitors. The methods reported here may expand the range of known structural types accommodated by the ATP binding site of Hsp90.
Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors
Chen, Danqi,Shen, Aijun,Li, Jian,Shi, Feng,Chen, Wuyan,Ren, Jing,Liu, Hongchun,Xu, Yechun,Wang, Xin,Yang, Xinying,Sun, Yiming,Yang, Min,He, Jianhua,Wang, Yueqin,Zhang, Liping,Huang, Min,Geng, Meiyu,Xiong, Bing,Shen, Jingkang
, p. 765 - 781 (2014/12/11)
HSP90 is ubiquitously overexpressed in a broad spectrum of human cancers and has been recognized as an attractive target for cancer treatment. Here, we described the fragment screening, synthesis and structure-activity relationship studies of small molecule inhibitors with 4,5-diarylisoxazole scaffold targeting HSP90. Among them, the compound N-(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-morpholinopiperidin-1-yl)methyl)phenyl)isoxazol-5-yl)cyclopropanecarboxamide (108) showed high affinity for binding to HSP90 (FP binding assay, IC50 Combining double low line 0.030 μM) and inhibited the proliferation of various human cancer cell lines with averaging GI50 about 88 nM. Compound 108 exhibited its functional inhibition of HSP90 by depleting key signaling pathways and concomitantly elevating of HSP70 and HSP27 in U-87MG cells. Further in vivo studies showed that compound 108 strongly suppressed the tumor growth of human glioblastoma xenograft model U-87MG with T/C Combining double low line 18.35% at 50 mg/kg q3w/2.5w. Moreover, compound 108 also exhibited good pharmacokinetic properties. Together, our study implicates that compound 108 is a promising candidate of HSP90 inhibitor and is currently advanced to preclinical study.
METHOD OF SYNTHESIZING SUBSTITUTED 2-ALKYL PHENOLS
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Page/Page column 25, (2012/03/26)
Methods of synthesizing 4-alkyl resorcinols and other substituted phenol compounds, according to formula (IV): or salts thereof, are disclosed, wherein the variables are defined herein.
