Design, synthesis and biological evaluation of a series of CNS penetrant HDAC inhibitors structurally derived from amyloid-β probes

Abstract To develop novel CNS penetrant HDAC inhibitors, a new series of HDAC inhibitors having benzoheterocycle were designed, synthesized, and biologically evaluated. Among the synthesized compounds, benzothiazole derivative 9b exhibited a remarkable anti-proliferative activity (GI50 = 2.01 μM) against SH-SY5Y cancer cell line in a dose and time-dependent manner, better than the reference drug SAHA (GI50 = 2.90 μM). Moreover, compound 9b effectively promoted the accumulation of acetylated Histone H3 and α-tubulin through inhibition of HDAC1 and HDAC6 enzymes, respectively. HDAC enzyme assay also confirmed that compound 9b efficiently inhibited HDAC1 and HDAC6 isoforms with IC50 values of 84.9 nM and 95.9 nM. Furthermore, compound 9b inhibited colony formation capacity of SH-SY5Y cells, which is considered a hallmark of cell carcinogenesis and metastatic potential. The theoretical prediction, in vitro PAMPA-BBB assay, and in vivo brain pharmacokinetic studies confirmed that compound 9b had much higher BBB permeability than SAHA. In silico docking study demonstrated that compound 9b fitted in the substrate binding pocket of HDAC1 and HDAC6. Taken together, compound 9b provided a novel scaffold for developing CNS penetrant HDAC inhibitors and therapeutic potential for CNS-related diseases.

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Photoelectric Dye, NK-5962, as a Potential Drug for Preventing Retinal Neurons from Apoptosis: Pharmacokinetic Studies Based on Review of the Evidence

Life ◽

10.3390/life11060591 ◽

2021 ◽

Vol 11 (6) ◽

pp. 591

Author(s):

Toshihiko Matsuo ◽

Shihui Liu ◽

Tetsuya Uchida ◽

Satomi Onoue ◽

Shinsaku Nakagawa ◽

...

Keyword(s):

Biological Evaluation ◽

Pharmacokinetic Studies ◽

Retinal Neurons ◽

Retinal Cells ◽

Intravitreous Injection ◽

Rcs Rats ◽

Photoelectric Dye ◽

Dark Conditions

NK-5962 is a key component of photoelectric dye-based retinal prosthesis (OUReP). In testing the safety and efficacy, NK-5962 was safe in all tests for the biological evaluation of medical devices (ISO 10993) and effective in preventing retinal cells from death even under dark conditions. The long-term implantation of the photoelectric dye-coupled polyethylene film in the subretinal space of hereditary retinal dystrophic (RCS) rats prevented neurons from apoptosis in the adjacent retinal tissue. The intravitreous injection of NK-5962 in the eyes of RCS rats, indeed, reduced the number of apoptotic cells in the retinal outer nuclear layer irrespective of light or dark conditions. In this study, we reviewed the in vitro and in vivo evidence of neuroprotective effect of NK-5962 and designed pharmacokinetic experiments. The in vitro IC50 of 1.7 μM, based on the protective effect on retinal cells in culture, could explain the in vivo EC50 of 3 μM that is calculated from concentrations of intravitreous injection to prevent retinal neurons from apoptosis. Pharmacokinetics of NK-5962 showed that intravenous administration, but not oral administration, led to the effective concentration in the eye of rats. NK-5962 would be a candidate drug for delaying the deterioration of retinal dystrophy, such as retinitis pigmentosa.

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Germinated and Ungerminated Seeds Extract from TwoLupinusSpecies: Biological Compounds Characterization and In Vitro and In Vivo Evaluations

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/7638542 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Bogdan Andor ◽

Corina Danciu ◽

Ersilia Alexa ◽

Istvan Zupko ◽

Elena Hogea ◽

...

Keyword(s):

Cinnamic Acid ◽

Therapeutic Potential ◽

Lupinus Albus ◽

Biological Evaluation ◽

Lupinus Angustifolius ◽

Cinnamic Acid Derivatives ◽

Natural Agents ◽

Germinated Seeds

In recent years, nutraceuticals attracted a great amount of attention in the biomedical research due to their significant contribution as natural agents for prevention of various health issues. Ethanolic extracts from the ungerminated and germinated seeds ofLupinus albusL. andLupinus angustifoliusL. were analyzed for the content in isoflavones (genistein) and cinnamic acid derivatives. Additionally, the extracts were evaluated for antimicrobial, antiproliferative, and anti-inflammatory properties, using in vitro and in vivo tests. Germination proved to be a method of choice in increasing the amount of genistein and cinnamic acid derivatives in bothLupinus albusL. andLupinus angustifolius L.seeds. Biological evaluation of all vegetal extracts revealed a weak therapeutic potential for both ungerminated and germinated seeds.

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Targeting Histone Deacetylases: A Novel Approach in Parkinson’s Disease

Parkinson s Disease ◽

10.1155/2015/303294 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 12

Author(s):

Sorabh Sharma ◽

Rajeev Taliyan

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Transcriptional Activation ◽

Histone Deacetylases ◽

Therapeutic Potential ◽

Hdac Inhibitors ◽

Clinical Manifestations ◽

Future Research

The worldwide prevalence of movement disorders is increasing day by day. Parkinson’s disease (PD) is the most common movement disorder. In general, the clinical manifestations of PD result from dysfunction of the basal ganglia. Although the exact underlying mechanisms leading to neural cell death in this disease remains unknown, the genetic causes are often established. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the neurological disease conditions. The acetylation and deacetylation of histone proteins are carried out by opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. In the recent past, studies with HDAC inhibitors result in beneficial effects in bothin vivoandin vitromodels of PD. Various clinical trials have also been initiated to investigate the possible therapeutic potential of HDAC inhibitors in patients suffering from PD. The possible mechanisms assigned for these neuroprotective actions of HDAC inhibitors involve transcriptional activation of neuronal survival genes and maintenance of histone acetylation homeostasis, both of which have been shown to be dysregulated in PD. In this review, the authors have discussed the putative role of HDAC inhibitors in PD and associated abnormalities and suggest new directions for future research in PD.

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NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma

Blood ◽

10.1182/blood-2003-01-0233 ◽

2003 ◽

Vol 102 (7) ◽

pp. 2615-2622 ◽

Cited By ~ 164

Author(s):

Laurence Catley ◽

Ellen Weisberg ◽

Yu-Tzu Tai ◽

Peter Atadja ◽

Stacy Remiszewski ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Histone Deacetylase ◽

Hdac Inhibitors ◽

Myeloma Cell ◽

Parp Cleavage ◽

Significant Activity ◽

Dependent Manner

Abstract Histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in hematologic malignancies. Here we show that NVP-LAQ824, a novel hydroxamic acid derivative, induces apoptosis at physiologically achievable concentrations (median inhibitory concentration [IC50] of 100 nM at 24 hours) in multiple myeloma (MM) cell lines resistant to conventional therapies. MM.1S myeloma cell proliferation was also inhibited when cocultured with bone marrow stromal cells, demonstrating ability to overcome the stimulatory effects of the bone marrow microenvironment. Importantly, NVP-LAQ824 also inhibited patient MM cell growth in a dose- and time-dependent manner. NVP-LAQ824-induced apoptotic signaling includes up-regulation of p21, caspase cascade activation, and poly (adenosine diphosphate [ADP]) ribose (PARP) cleavage. Apoptosis was confirmed with cell cycle analysis and annexin-propidium iodide staining. Interestingly, treatment of MM cells with NVPLAQ824 also led to proteasome inhibition, as determined by reduced proteasome chymotrypsin-like activity and increased levels of cellular polyubiquitin conjugates. Finally, a study using NVP-LAQ824 in a preclinical murine myeloma model provides in vivo relevance to our in vitro studies. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in MM. (Blood. 2003;102:2615-2622)

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The human renin infused rat: use as an in vivo model for the biological evaluation of human renin inhibitors

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y99-068 ◽

1999 ◽

Vol 77 (11) ◽

pp. 886-895 ◽

Cited By ~ 1

Author(s):

Gordon Bolger ◽

Jean-Claude Vigeant ◽

Francine Liard ◽

Bruno Simoneau ◽

Diane Thibeault ◽

...

Keyword(s):

Oral Administration ◽

Pressor Response ◽

Biological Evaluation ◽

In Vivo Model ◽

Dependent Manner ◽

Renin Inhibitors ◽

Human Renin ◽

Dose Dependent

The human renin infused rat model (HRIRM) was used as an in vivo small-animal model for evaluating the efficacy of a collection of inhibitors of human renin. The intravenous infusion of recombinant human renin (2.4 µg·kg-1·min-1) in the ganglion-blocked, nephrectomized rat produced a mean blood pressor response of 47 ± 3 mmHg (1 mmHg = 133.3 Pa), which was reduced by captopril, enalkiren, and losartan in a dose-dependent manner following oral administration, with ED50 values of 0.3 ± 0.1, 2.5 ± 0.9, and 5.2 ± 1.6 mg/kg, respectively. A series of peptidomimetic P2-P3 butanediamide renin inhibitors inhibited purified recombinant human renin in vitro in a concentration-dependent manner, with IC50 values ranging from 0.4 to 20 nM at pH 6.0, with a higher range of IC50 values (0.8-80 nM) observed at pH 7.4. Following i.v. administration of renin inhibitors, the pressor response to infused human renin in the HRIRM was inhibited in a dose-dependent manner, with ED50 values ranging from 4 to 600 µg/kg. The in vivo inhibition of human renin following i.v. administration in the rat correlated significantly better with the in vitro inhibition of human renin at pH 7.4 (r = 0.8) compared with pH 6.0 (r = 0.5). Oral administration of renin inhibitors also resulted in a dose-dependent inhibition of the pressor response to infused human renin, with ED50 values ranging from 0.4 to 6.0 mg/kg and the identification of six renin inhibitors with an oral potency of <1 mg/kg. The ED50 of renin inhibitors for inhibition of angiotensin I formation in vivo was highly correlated (r = 0.9) with the ED50 for inhibition of the pressor response. These results demonstrate the high potency, dose dependence, and availability following oral administration of the butanediamide series of renin inhibitors.Key words: renin-angiotensin system, recombinant human renin, rat, renin inhibitors.

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Synthesis and Biological Evaluation of Some Pyrazole Derivatives, Containing (Thio) Semicarbazide, as Dual Anti-Inflammatory Antimicrobial Agents

Letters in Drug Design & Discovery ◽

10.2174/1570180816666190325163117 ◽

2019 ◽

Vol 16 (9) ◽

pp. 1020-1030

Author(s):

Zhaochang Liang ◽

Yuping Huang ◽

Shiben Wang ◽

Xianqing Deng

Keyword(s):

Antiinflammatory Activity ◽

Antimicrobial Activities ◽

Biological Evaluation ◽

Dilution Method ◽

Pyrazole Derivatives ◽

Reference Drug ◽

Tnf Α ◽

Anti Inflammatory

Background: Several series of pyrazole derivatives containing (thio) semicarbazide (4a-4h, 5a-5l, 6a-6f, 7a-7c) were designed and synthesized to screen dual inflammatory and antimicrobial activities. Methods: The products were characterized by1H NMR, 13C NMR and HRMS. In vitro LPS-induced TNF-α model and in vivo xylene-induced ear-edema model were used to evaluate their antiinflammatory activity. Their in vitro antimicrobial activities were evaluated using a serial dilution method against several gram-positive strains, gram-negative strains and a fungi strain. Results: Bioassays indicated that most of the compounds markedly inhibited the expression of TNF- α at the concentration of 20 µg/mL Compounds 5i, 6b, and 7b had comparable in vivo antiinflammatory activity to the reference drug dexamethasone at the dose of 50 mg/kg. In addition, several compounds showed antimicrobial activity against different strains, and compounds 5g and 5h exhibited potent inhibitory activities with the MIC value of 8 µg/mL against the Streptococcus pneumoniae CMCC 31968 and Staphylococcus aureus CMCC 25923, respectively. Compound 7b, which exhibited both anti-inflammatory and antimicrobial activities, should be studied as it is or after derivatization. Conclusion: It can be concluded that pyrazoles, with (thio)-semicarbazone moieties, have the potential to be developed into new anti-inflammatory agents.

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Growth Hormone-Releasing Hormone in Lung Physiology and Pulmonary Disease

Cells ◽

10.3390/cells9102331 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2331

Author(s):

Chongxu Zhang ◽

Tengjiao Cui ◽

Renzhi Cai ◽

Medhi Wangpaichitr ◽

Mehdi Mirsaeidi ◽

...

Keyword(s):

Growth Hormone ◽

Therapeutic Potential ◽

Dependent Manner ◽

Growth Hormone Releasing Hormone ◽

Releasing Hormone ◽

Lung Physiology ◽

Extracellular Signal ◽

P21 Activated Kinase

Growth hormone-releasing hormone (GHRH) is secreted primarily from the hypothalamus, but other tissues, including the lungs, produce it locally. GHRH stimulates the release and secretion of growth hormone (GH) by the pituitary and regulates the production of GH and hepatic insulin-like growth factor-1 (IGF-1). Pituitary-type GHRH-receptors (GHRH-R) are expressed in human lungs, indicating that GHRH or GH could participate in lung development, growth, and repair. GHRH-R antagonists (i.e., synthetic peptides), which we have tested in various models, exert growth-inhibitory effects in lung cancer cells in vitro and in vivo in addition to having anti-inflammatory, anti-oxidative, and pro-apoptotic effects. One antagonist of the GHRH-R used in recent studies reviewed here, MIA-602, lessens both inflammation and fibrosis in a mouse model of bleomycin lung injury. GHRH and its peptide agonists regulate the proliferation of fibroblasts through the modulation of extracellular signal-regulated kinase (ERK) and Akt pathways. In addition to downregulating GH and IGF-1, GHRH-R antagonist MIA-602 inhibits signaling pathways relevant to inflammation, including p21-activated kinase 1-signal transducer and activator of transcription 3/nuclear factor-kappa B (PAK1-STAT3/NF-κB and ERK). MIA-602 induces fibroblast apoptosis in a dose-dependent manner, which is an effect that is likely important in antifibrotic actions. Taken together, the novel data reviewed here show that GHRH is an important peptide that participates in lung homeostasis, inflammation, wound healing, and cancer; and GHRH-R antagonists may have therapeutic potential in lung diseases.

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Biological Evaluation ofPupalia lappaceafor Antidiabetic, Antiadipogenic, and Hypolipidemic Activity BothIn VitroandIn Vivo

Scientifica ◽

10.1155/2016/1062430 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Vivek Kumar ◽

Parag Jain ◽

Kalpana Rathore ◽

Zabeer Ahmed

Keyword(s):

Cell Line ◽

Reference Group ◽

Lipid Level ◽

Biological Evaluation ◽

Diabetic Rats ◽

Hypolipidemic Activity ◽

Albino Rats ◽

Reference Drug

Objective. The present study assesses the effect ofPupalia lappacea(L.) Juss. (Amaranthaceae) (PL) leaves ethanolic extract on adipocytes, blood glucose level, and lipid level in streptozotocin (STZ) induced diabetic rats.Materials and Methods. Male Albino rats were rendered diabetic by a single moderately sized dose of STZ (45 mg/kg, intraperitoneally) at once before starting the treatment. Animals were divided into five groups: normoglycemic control, diabetic control, reference group (glibenclamide, 5.0 mg/kg), AS001 (250 mg/kg extract), and AS002 (500 mg/kg extract) each containing six animals forin vivostudy. Antidiabetic and hypolipidemic activity of extract were determined byin vivomethod on STZ induced diabetic rats. Antiadipogenic activity was determined byin vitromethod on 3T3-L1 cell line in comparison to simvastatin as reference drug.Result. The extract showed significant fall in fasting serum glucose (FSG), that is, 234.68 and 211.61 mg/dL, in STZ induced diabetic animals for dose groups AS001 and AS002, respectively. ThePLextract also exhibited noteworthy antiadipogenic activity on 3T3-L1 cell line. The value of inhibitory concentration (IC50) ofPLextract to reduce adipocyte cells was found to be 662.14 μg/mL.Conclusion. ThePLextract exhibited significant antiadipogenic, antidiabetic, and hypolipidemic activities.

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Antiadipogenic Effects ofAster glehniExtract: In Vivo and In Vitro Effects

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/859624 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Heon-Myung Lee ◽

Gabsik Yang ◽

Tae-Gue Ahn ◽

Myung-Dong Kim ◽

Agung Nugroho ◽

...

Keyword(s):

Therapeutic Potential ◽

Control Diet ◽

Epididymal Adipose Tissue ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Master Regulators ◽

In Vitro Effects

Aster glehni(AG) is a Korean traditional herb that grows in Ulleungdo Island, Republic of Korea. None of the several reports on AG include a determination of the effect of AG on adipogenesis. The primary aim of this study was to determine whether AG attenuates adipogenesis in mouse 3T3-L1 cells and epididymal fat tissue. AG blocked the differentiation of 3T3-L1 preadipocytes in a concentration-dependent manner and suppressed the expression of adipogenesis-related genes such asPPARγ,C/EBPα, andSREBP1c, the master regulators of adipogenesis. Male C57BL/6J mice were divided randomly and equally into 4 diet groups: control diet (CON), high-fat diet (HFD), HFD with 1% AG extract added (AG1), and HFD with 5% AG extract added (AG5). The experimental animals were fed HFD and the 2 combinations for 10 weeks. Mice fed HFD with AG gained less body weight and visceral fat-pad weight than did the mice fed HFD alone. Moreover, AG inhibited the expression of important adipogenic genes such asPPARγ,C/EBPα,SREBP1c,LXR, and leptin in the epididymal adipose tissue of the mice treated with AG1 and AG5. These findings indicate antiadipogenic and antiobesity effects of AG and suggest its therapeutic potential in obesity and obesity-related diseases.

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Neuroprotective derivatives of tacrine that target NMDA receptor and acetyl cholinesterase - Design, synthesis and biological evaluation

10.1101/2021.01.18.427058 ◽

2021 ◽

Author(s):

Chandran Remya ◽

K.V. Dileep ◽

Eeda Koti Reddy ◽

Kumar Mantosh ◽

Kesavan Lakshmi ◽

...

Keyword(s):

Cortical Neurons ◽

Therapeutic Potential ◽

Monosodium Glutamate ◽

Biological Evaluation ◽

Potential Candidate ◽

Behavioral Impairment ◽

Neuropsychiatric Diseases ◽

Disease Modifying

AbstractThe complex and multifactorial nature of neuropsychiatric diseases demands multi-target drugs that can intervene with various sub-pathologies underlying disease progression. Targeting the impairments in cholinergic and glutamatergic neurotransmissions with small molecules has been suggested as one of the potential disease-modifying approaches for Alzheimer’s disease (AD). Tacrine, apotent inhibitor of acetylcholinesterase (AChE) is the first FDA approved drug for the treatment of AD. Tacrine is also a low affinity antagonist of N-methyl-D-aspartate receptor (NMDAR). However, tacrine was withdrawn from its clinical use later due to its hepato-toxicity. With an aim to develop novel high affinity multi-target directed ligands (MTDLs) against AChE and NMDAR, with reduced hepatotoxicity, we performed in silico structure-based modifications on tacrine, chemical synthesis of the derivatives and in vitro validation of their activities. Nineteen such derivatives showed inhibition with IC50 values in the range of 18.53±2.09 to 184.09±19.23 nM against AChE and 0.27±0.05 to 38.84±9.64 μM against NMDAR. Some of the selected compounds also protected rat primary cortical neurons from glutamate induced excitotoxicity. Two of the tacrine derived MTDLs, 201 and 208 exhibited in vivo efficacy in rats by protecting against behavioral impairment induced by administration of the excitotoxic agent, monosodium glutamate. Additionally, several of these synthesized compounds also exhibited promising inhibitory activities against butyrylcholinesterase and β-secretase. Given the therapeutic potential of MTDLs in disease-modifying therapy, our studies revealed several promising MTDLs of which 201 appears to be a potential candidate for immediate preclinical and clinical evaluations.

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