22877-01-6Relevant articles and documents
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)
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 Resorcinol-Based Polycyclic Structures as Tyrosinase Inhibitors for Treatment of Parkinson’s Disease
Li, Qi,Mo, Jun,Xiong, Baichen,Liao, Qinghong,Chen, Ying,Wang, Yuanyuan,Xing, Shuaishuai,He, Siyu,Lyu, Weiping,Zhang, Ning,Sun, Haopeng
, p. 81 - 96 (2021/12/17)
Tyrosinase is involved in the synthesis of neuromelanin in the substantia nigra, which is closely correlated with the pathogenesis of Parkinson’s disease. Herein, we identified S05014 (l-Tyr, IC50 = 6.25 ± 1.43 nM; l-Dopa, IC50 = 0.6
Ring-opening of five-membered heterocycles conjugated 4-isopropylresorcinol scaffold-based benzamides as HSP90 inhibitors suppressing tumor growth in vitro and in vivo
Liu, Yi-Min,Tu, Huang-Ju,Wu, Chueh-Heng,Lai, Mei-Jung,Yu, Shu-Chieh,Chao, Min-Wu,Wu, Yi-Wen,Teng, Che-Ming,Pan, Shiow-Lin,Liou, Jing-Ping
, (2021/05/10)
A series of ring-opened dihydroxybenzamides have been designed and synthesized as heat shock protein 90 inhibitors. One of derivatives, compound 6b ((N-ethyl-2,4-dihydroxy-5-isopropyl-N-(pyridin-3-yl)benzamide)) demonstrated remarkable antiproliferative activity against in human KRAS mutant A549 and EGFR T790 M mutant H1975 lung cancer cell lines with GI50 values of 0.07 and 0.05 μM, respectively. It is also active against in other cancer cell lines, such as colorectal HCT116 (GI50 = 0.09 μM), liver Hep3B (GI50 = 0.20 μM) and breast MDA-MB-231 (GI50 = 0.09 μM), and shows no evidence of toxicity in normal cell line. Compound 6b has an IC50 of 110.18 nM in HSP90α inhibitory activity, slightly better than reference compound 1 (17-AAG, IC50 = 141.62 nM) and achieves the degradation of multiple HSP90 client proteins in a dose- and time-dependent manner and downstream signaling of Akt in a concentration- and time-dependent manner in the human A549 lung cancer cell line. In the Boyden chamber assay, compound 6b can efficiently inhibit the migration of A549 cells when compared to the reference compound 1. It also induce significant activity through the apoptotic pathway. Treatment with 6b showed no vision toxicity (IC50 > 10 μM) on 661w photoreceptor cells as compared to AUY922 (3a) with a 0.04 μM values of IC50 and has no effect in hERG test. In a bidirectional Caco-2 permeability assay, compound 6b was classified as a highly permeable compound which is not a substrate of efflux transporters. In a pharmacokinetic study in rats, 6b showed an F = 17.8% of oral bioavailability. The effect of metabolic stability of compound 6b in human hepatocytes showed a T1/2 of 67.59 min. Compound 6b (50 mg/kg, po, daily) exhibits antitumor activity with a 72% TGD (tumor growth delay) in human A549 lung xenograft. The combination of 6b and afatinib, orally administered, showed tumor growth suppression with 67.5% of TGI in lung H1975 xenograft model. Thus compound 6b is a lead compound for further development of potential agents to treat lung cancer.
A synthesis method of fisetin
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Paragraph 0016; 0051; 0053-0055; 0066; 0068-0070; 0081-0145, (2019/04/10)
The invention provides a method for synthesis of fisetin, solves the fisetin synthetic method only is suitable for the laboratory, and the product yield and content can't problem. The synthetic method comprises the following steps: 1) using 2 - butanone, benzyl chloride, 2, 4 - dihydroxy acetophenone and anhydrous K2 CO3 Generating on the protecting group of the intermediate product; 2) under the protection of nitrogen, in the alkaline environment, the intermediate product and protocatechuic aldehyde condensation reaction, generating 3 ', 4' - dihydroxy - 7 - [...]; 3) the 3 ', 4' - dihydroxy - 7 - [...] reduction generating 3 ', 4', 7 - three hydroxy chalcone; 4) the 3 ', 4', 7 - three hydroxy chalcone is placed on in the alkaline environment of hydroxy, then in toluene sulfonic acid catalysis of a cyclization reaction, generating fisetin. The synthesis method can be used for industrial production; the synthetic method is simple in operation, raw materials are easy, and the production cost is low, and the resulting intermediate product and finally the yield of the product, the higher the purity, has good prospects for development.
RESORCINOL DERIVATIVES FOR THEIR COSMETIC USE
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Page/Page column 20, (2019/04/26)
The invention relates to resorcinol-based compounds of formula (I), to the salts, solvates, optical and/or geometrical isomers thereof, to the use thereof as active agents for depigmenting, lightening and/ or bleaching keratin materials, and/or for preven
M-DIHYDROXYBENZENE DERIVATIVE CRYSTAL AND SALT, AND MANUFACTURING METHOD THEREOF
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, (2019/09/30)
Provided are a crystal and salt of an m-dihydroxybenzene derivative represented by formula (I), a manufacturing method thereof, and an application of the crystal in preparing a pharmaceutical product for treating a HSP90-mediated disease.
3-cyano-2-aminopyridine derivative and preparation method and application thereof
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Paragraph 0056; 0058; 0060, (2019/01/08)
The invention discloses a 3-cyano-2-aminopyridine derivative and a preparation method and an application thereof. The pyridine derivative is as shown in any one of 1) to 5): 1) a name is 2-amino-4-(4-bromophenyl)-6-(4-hydroxyphenyl)cyanopyridine; 2) 2-ami
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
supporting information, 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.
Tyrosinase inhibitor, and preparation method and applications thereof
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Paragraph 0039; 0052; 0053; 0054, (2019/01/06)
The invention belongs to the field of medicine, relates to a tyrosinase inhibitor (I) and a preparation method thereof, and more specifically relates to 2, 4-dihydroxy phenol-pyrazol-aniline structurecompound. It is confirmed by pharmacodynamic tests that
HEAT SHOCK PROTEIN 90 INHIBITORS
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Page/Page column 18; 33; 35, (2018/10/19)
Substituted aromatic compounds of formula (I) shown below: (formula I) The definition of each variable in formula (I) appears in the Specification. Also disclosed is a pharmaceutical composition containing one of the substituted aromatic compounds. Further disclosed is a method of using one of these compounds for treating a medical condition associated with HSP90.
