17994-94-4Relevant academic research and scientific papers
Design and synthesis of Leukotriene A4 hydrolase inhibitors to alleviate idiopathic pulmonary fibrosis and acute lung injury
Cao, Sheng,Cao, Yuting,Hou, Min,Jiang, Qiuyan,Li, Xiaohe,Lin, Gang,Liu, Xiang,Liu, Xinhua,Lu, Cheng,Mao, Jiahe,Peng, Junya,Qi, Min,Qin, Shuanglin,Song, Yang,Wei, Yujiao,Xie, Maodun,Yang, Cheng,Yang, Guang,Yang, Yuyu,Zhou, Honggang,Zhou, Yunyun
, (2020)
Idiopathic pulmonary fibrosis (IPF) and acute lung injury (ALI) are considered two severe public health issues, attributed to malfunctions of neutrophils. They can cause chronic inflammation and have association with subsequent tissue damages. There have been rare drugs applying to the efficient treatment in clinical practice. Existing research revealed that Leukotriene B4 (LTB4) is the critical endogenous molecule to induce neutrophil inflammatory response. LTB4 blocking biosynthesis is the potential strategy treating IPF and ALI. In the present study, 45 hydroxamic acid derivatives were produced, and compound 26 was screened out as a highly selective Lead compound of Leukotriene A4 Hydrolase (LTA4H), i.e., an enzyme critical to the biosynthesis of LTB4. This compound is capable of relieving neutrophilic inflammation in an IPF mouse model at early stage, as well as mitigating LPS-induced acute lung injury via a mechanism of LTB4 blocking biosynthesis in vivo. Whether this compound acts as the potential lead compound for the treatment of IPF and ALI requires further verification.
Class i HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 Status
Li, Xiaoyang,Peterson, Yuri K.,Inks, Elizabeth S.,Himes, Richard A.,Li, Jiaying,Zhang, Yingjie,Kong, Xiujie,Chou, C. James
, p. 2589 - 2603 (2018)
Previously, we designed and synthesized a series of o-aminobenzamide-based histone deacetylase (HDAC) inhibitors, among which the representative compound 11a exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using 11a as a lead. Representative compound 13b showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2, and 3. The most potent compound 13e exhibited low nanomolar IC50s toward HDAC1, 2, and 3 and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC50 of 13e against MV4-11 cells was 34.7 nM, which is 26 times lower than its parent compound 11a. In vitro responses to 13e vary significantly and interestingly based on cell type: in p53 wild-type MV4-11 cells, 13e induced cell death via apoptosis and G1/S cell cycle arrest, which is likely mediated by a p53-dependent pathway, while in p53-null PC-3 cells, 13e caused G2/M arrest and inhibited cell proliferation without inducing caspase-3-dependent apoptosis.
Novel antiproliferative chimeric compounds with marked histone deacetylase inhibitory activity
Giacomini, Elisa,Nebbioso, Angela,Ciotta, Alfonso,Ianni, Cristina,Falchi, Federico,Roberti, Marinella,Tolomeo, Manlio,Grimaudo, Stefania,Cristina, Antonietta Di,Pipitone, Rosaria Maria,Altucci, Lucia,Recanatini, Maurizio
, p. 973 - 978 (2014)
Given our interest in finding potential antitumor agents and in view of the multifactorial mechanistic nature of cancer, in the present work, taking advantage of the multifunctional ligands approach, new chimeric molecules were designed and synthesized by combining in single chemical entities structural features of SAHA, targeting histone deacetylases (HDACs), with substituted stilbene or terphenyl derivatives previously obtained by us and endowed with antiproliferative and pro-apoptotic activity. The new chimeric derivatives were characterized with respect to their cytotoxic activity and their effects on cell cycle progression on different tumor cell lines, as well as their HDACs inhibition. Among the other, trans-6 showed the most interesting biological profile, as it exhibited a strong pro-apoptotic activity in tumor cell lines in comparison with both of its parent compounds and a marked HDAC inhibition.
Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia
Bukhari, Shazreh,Cabral, Aaron D.,De Araujo, Elvin D.,Gawel, Justyna M.,Gunning, Patrick T.,He, Liying,Johns, Alexandra E.,Manaswiyoungkul, Pimyupa,Nawar, Nabanita,Olaoye, Olasunkanmi O.,Raouf, Yasir S.,Sedighi, Abootaleb,Shouksmith, Andrew E.,Sina, Diana
supporting information, p. 56 - 64 (2020/01/31)
The HDAC inhibitor 4-tert-butyl-N-(4-(hydroxycarbamoyl)phenyl)benzamide (AES-350, 51) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, AES-135, compound 51 demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic window, and more efficient absorption through cellular and lipid membranes. Compound 51 also demonstrated improved oral bioavailability compared to SAHA in mouse models. A broad spectrum of experiments, including FACS, ELISA, and Western blotting, were performed to support our hypothesis that 51 dose-dependently triggers apoptosis in AML cells through HDAC inhibition.
Effect of Derivatives of Hydroxamic Acids on Vasculogenic Mimicry
Balaev, A. N.,Khachatryan, D. S.,Khochenkov, D. A.,Khochenkova, Yu. A.,Kolotaev, A. V.,Machkova, Yu. S.,Ohmanovich, K. A.,Osipov, V. N.,Vartanian, A. A.
, p. 252 - 263 (2020/05/04)
Abstract—: Vasculogenic mimicry, the formation of vascular channels lined with tumor cells of a highly malignant phenotype, is currently considered as an additional system of blood supply of the tumor. Experimental studies in vivo have repeatedly demonstrated that vascular channels form in the areas of a tumor with a low density of blood vessels. It is supposed that the formation of a network of these channels inside the tumor maintains homeostasis and prevents early necrosis within it. In this work, bifunctional compounds based on a combination of quinazoline and hydroxamic acid in one molecule were examined for the ability to inhibit the migration of tumor cells and vasculogenic mimicry.
Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins
Lu, Yuzhi,Wu, Shuangchan,Yue, Yuan,He, Si,Li, Jun,Tang, Jun,Wang, Wei,Zhou, Hai-Bing
supporting information, p. 1185 - 1190 (2016/12/18)
A series of gossypol Schiff bases that were derived from unnatural linear amino acid methyl esters were identified and found to be much more potent than gossypol and ABT-199 in terms of anticancer activity. This is the first example of gossypol Schiff bases with increased activity. The investigation of the Schiff base side chain of gossypol revealed that the unique anticancer effect was achieved by the introduction of hydrophobic ester groups. The optimized products showed low micromolar pan antitumor activities against NCI-60 tumor cell lines, which is promising for further drug development. Studies on the preliminary mechanism of action for their cellular activities was also carried out with antiapoptotic protein (Bcl-2 and Mcl-1) inhibition FP assays. The molecular modeling analysis demonstrated a possible binding mode for these compounds with Bcl-2, which could explain the binding affinity of the novel gossypol Schiff bases with these proteins.
HISTONE DEACETYLASE 6 SELECTIVE INHIBITORS FOR THE TREATMENT OF BONE DISEASE
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, (2013/03/26)
This invention relates to methods for treating bone disease associated with osteoclast activation using HDAC6 selective inhibitors, e.g., small molecule inhibitors such as reverse amide compounds.
6-Deoxyerythronolide B synthase thioesterase-catalyzed macrocyclization is highly stereoselective
Pinto, Atahualpa,Wang, Meng,Horsman, Mark,Boddy, Christopher N.
supporting information; experimental part, p. 2278 - 2281 (2012/07/03)
Macrocyclic polyketide natural products are an indispensable source of therapeutic agents. The final stage of their biosynthesis, macrocyclization, is catalyzed regio- and stereoselectively by a thioesterase. A panel of substrates were synthesized to test their specificity for macrocyclization by the erythromycin polyketide synthase TE (DEBS TE) in vitro. It was shown that DEBS TE is highly stereospecific, successfully macrocyclizing a 14-member ring substrate with an R configured O-nucleophile, and highly regioselective, generating exclusively the 14-member lactone over the 12-member lactone.
REVERSE AMIDE COMPOUNDS AS PROTEIN DEACETYLASE INHIBITORS AND METHODS OF USE THEREOF
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, (2011/08/08)
The present invention relates to novel "reverse amide" compounds comprising a zinc chelator group, and the use of such compounds in the inhibition of HDAC6 and in the treatment of various diseases, disorders or conditions related to HDAC6.
Acylurea connected straight chain hydroxamates as novel histone deacetylase inhibitors: Synthesis, SAR, and in vivo antitumor activity
Wang, Haishan,Lim, Ze-Yi,Zhou, Yan,Ng, Melvin,Lu, Ting,Lee, Ken,Sangthongpitag, Kanda,Goh, Kee Chuan,Wang, Xukun,Wu, Xiaofeng,Khng, Hwee Hoon,Goh, Siok Kun,Ong, Wai Chung,Bonday, Zahid,Sun, Eric T.
scheme or table, p. 3314 - 3321 (2010/08/06)
Thirty-six novel acylurea connected straight chain hydroxamates were designed and synthesized. Structure-activity relationships (SAR) were established for the length of linear chain linker and substitutions on the benzoylurea group. Compounds 5g, 5i, 5n, and 19 showed 10-20-fold enhanced HDAC1 potency compared to SAHA. In general, the cellular potency pIC50 (COLO205) correlates with enzymatic potency pIC50 (HDAC1). Compound 5b (SB207), a structurally simple and close analogue to SAHA, is more potent against HDAC1 and HDAC6 compared to the latter. As a representative example of this series, good in vitro enzymatic and cellular potency plus an excellent pharmacokinetic profile has translated into better efficacy than SAHA in both prostate cancer (PC3) and colon cancer (HCT116) xenograft models.
