- Design and synthesis of Leukotriene A4 hydrolase inhibitors to alleviate idiopathic pulmonary fibrosis and acute lung injury
-
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.
- 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
-
-
Read Online
- Class i HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 Status
-
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.
- Li, Xiaoyang,Peterson, Yuri K.,Inks, Elizabeth S.,Himes, Richard A.,Li, Jiaying,Zhang, Yingjie,Kong, Xiujie,Chou, C. James
-
-
Read Online
- Novel antiproliferative chimeric compounds with marked histone deacetylase inhibitory activity
-
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.
- 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
-
-
Read Online
- Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia
-
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.
- 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)
-
- Effect of Derivatives of Hydroxamic Acids on Vasculogenic Mimicry
-
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.
- 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)
-
- Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins
-
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.
- 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)
-
- HISTONE DEACETYLASE 6 SELECTIVE INHIBITORS FOR THE TREATMENT OF BONE DISEASE
-
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.
- -
-
Page/Page column 72-73
(2013/03/26)
-
- 6-Deoxyerythronolide B synthase thioesterase-catalyzed macrocyclization is highly stereoselective
-
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.
- Pinto, Atahualpa,Wang, Meng,Horsman, Mark,Boddy, Christopher N.
-
supporting information; experimental part
p. 2278 - 2281
(2012/07/03)
-
- REVERSE AMIDE COMPOUNDS AS PROTEIN DEACETYLASE INHIBITORS AND METHODS OF USE THEREOF
-
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.
- -
-
Page/Page column 76-78
(2011/08/08)
-
- Acylurea connected straight chain hydroxamates as novel histone deacetylase inhibitors: Synthesis, SAR, and in vivo antitumor activity
-
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.
- 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)
-
- Development of a fluorescence polarization based assay for histone deacetylase ligand discovery
-
Histone deacetylases (HDACs) regulate many important physiological processes and the discovery of small molecules that modulate HDAC activity has both academic and clinical relevance. HDAC inhibitors, most notably SAHA, have been pursued as cancer chemotherapeutics but may be useful in treating psychiatric disorders, malaria, and other diseases. Herein, we describe an inexpensive and robust assay, based on fluorescence polarization, for HDAC ligand discovery. The assay is well suited for high-throughput screening and enzyme kinetic studies.
- Mazitschek, Ralph,Patel, Vishal,Wirth, Dyann F.,Clardy, Jon
-
p. 2809 - 2812
(2008/12/22)
-
- Evaluation of azasterols as anti-parasitics
-
In this article, the design and synthesis of some novel azasterols is described, followed by their evaluation against Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum, the causative agents of human African trypanosomiasis, Chagas disease, leishmaniasis, and malaria, respectively. Some of the compounds showed anti-parasitic activity. In particular, a number of compounds appeared to very potently inhibit the growth of the blood stream form T. b. rhodesiense, with one compound giving an IC 50 value of 12 nM. Clear structure activity relationships could be discerned. These compounds represent important leads for further optimization. Azasterols have previously been shown to inhibit sterol biosynthesis in T. cruzi and L. donovani by the inhibition of the enzyme sterol 24-methyltransferase. However, in this case, none of the compounds showed inhibition of the enzyme. Therefore, these compounds have an unknown mode of action.
- Gros, Ludovic,Lorente, Silvia Orenes,Jimenez, Carmen,Yardley, Vanessa,Rattray, Lauren,Wharton, Hayley,Little, Susan,Croft, Simon L.,Ruiz-Perez, Luis M.,Gonzalez-Pacanowska, Dolores,Gilbert, Ian H.
-
p. 6094 - 6103
(2007/10/03)
-
- Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and an EP2 or EP4 selective agonist
-
The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a 2-alkylidene-19-nor-vitamin D derivative and an EP2 or EP4 selective agonist or a pharmaceutically acceptable salt or prodrug thereof. Particularly, the present invention relates to pharmaceutical compositions and methods comprising administering to a patient in need thereof 2-methylene-19-nor-20(S)-1α,25-dihydroxyvitamin D3 and an EP2 or EP4 selective agonist or a pharmaceutically acceptable salt or prodrug thereof.
- -
-
Page/Page column 44
(2010/02/11)
-
- Methods of treatment using an EP2 selective receptor agonist
-
The present invention relates to methods of treating pulmonary hypertension, facilitating joint fusion, facilitating tendon and ligament repair, reducing the occurrence of secondary fracture, treating avascular necrosis, facilitating cartilage repair, facilitating bone healing after limb transplantation, facilitating liver regeneration, facilitating wound healing, reducing the occurrence of gastric ulceration, treating hypertension, facilitating the growth of tooth enamel or finger or toe nails, treating glaucoma, treating ocular hypertension, and repairing damage caused by metastatic bone disease using an EP2 selective receptor agonist.
- -
-
Page/Page column 44
(2010/02/13)
-
- ACYLUREA CONNECTED AND SULFONYLUREA CONNECTED HYDROXAMATES
-
The present invention relates to hydroxamate compounds which are inhibitors of histone deacetylase. More particularly, the present invention relates to acylurea/sulfonylurea containing compounds and methods for their preparation. These compounds may be useful as medicaments for the treatment of proliferative disorders as well as other diseases involving, relating to or associated with enzymes having histone deacetylase activities.
- -
-
Page/Page column 61
(2010/02/11)
-
- Prostaglandin agonists and their use to treat bone disorders
-
This invention relates to prostaglandin agonists, methods of using such prostaglandin agonists, pharmaceutical compositions containing such prostaglandin agonists and kits containing such prostaglandin agonists. The prostaglandin agonists are useful for the treatment of bone disorders including osteoporosis.
- -
-
-
- 2-nitro- and 2,4-dinitrobenzenesulfonamides as protecting groups for primary amines
-
Procedures for the deprotection of the 2-nitro- and 2,4-dinitrobenzenesulfonamides to give the corresponding primary amines were developed. The 2-Nitrobenzenesulfonyl group was effectively removed by HSCH2CH2OH/DBU or PhSH/Cs2/
- Nihei,Kato,Yamane,Palma,Konno
-
p. 1167 - 1169
(2007/10/03)
-
- Enkephalinase inhibitors
-
Mercaptoalkanoyl and acylmercaptoalkanoyl compounds of the formula STR1 wherein n is an integer from one to fifteen possess enkephalinase inhibition activity and are useful as analgesic agents.
- -
-
-
- Synthesis of Nonreducible Bicyclic Analogues of Somatostatin
-
The bis-carba analogues (Ib and Ic) of cyclo-(formula) (Ia) and cyclo-(formula) were prepared by a combination of solid-phase and solution peptide synthesis methods.Tactics involving three types of amino-protecting groups and two types of carboxyl protection were applied.The 20-membered ring portion formed in high yield under standard peptide cyclization conditions, using the azide method.The 16-membered ring portion formed well only with catalysis of the azide acylation reaction by N-hydroxybenzotriazole.The analogues are more resistant to hydrolysis catalyzed by trypsin but do not show increased duration of action for inhibition of growth hormone release relative to the disulfide.Disulfide reduction in vivo does not appear to be the rate-limiting step for inactivation of the sulfur containing bicyclic somatostin analogues.
- Nutt, Ruth F.,Veber, Daniel F.,Saperstein, Richard
-
p. 6539 - 6545
(2007/10/02)
-