33 research outputs found
5-((3-Amidobenzyl)oxy)nicotinamides as SIRT2 Inhibitors: A Study of Constrained Analogs
SIRT2 is a member of NAD+-dependent sirtuins and its inhibition has been proposed as a promising therapeutic approach for treating human diseases, including neurodegenerative diseases, cancer, and infections. Expanding SIRT2 inhibitors based on the 3-aminobenzyloxy nicotinamide core structure, we have synthesized and evaluated constrained analogs and selected stereoisomers. Our structure-activity relationship (SAR) study has revealed that 2,3-constrained (S)-isomers possess enhanced in vitro enzymatic inhibitory activity against SIRT2 and retain excellent selectivity over SIRT1 and SIRT3, provided that a suitable ring A is used. This current study further explores SIRT2 inhibitors based on the 3-aminobenzyloxy nicotinamide scaffold and contributes to the discovery of potent, selective SIRT2 inhibitors that have been actively pursued for their potential therapeutic applications
Theoretical analysis of a high performance protein imprint on a nanosensor
The structural details and flexibilities of protein impose significant challenges to develop protein imprint, especially for the selection of functional monomer. Using NAMD, AutoDock 4 and AutoDock Vina, we investigated the formation of a high performance protein imprint on a nanosensor that detected human papillomavirus (HPV) biomarker protein E7 with high sensitivity. According to molecular dynamics, the phenolic oligomers were shown to assemble with the E7 protein and form a complex at specific targeting areas on the protein. Docking analysis efficiently screened chemical compounds by evaluating the binding affinity. A new parameter, i.e., average binding energy (ΔG/contact), was used together with binding energy (ΔG) to screen compounds. The screening went through 189 compounds and identified a subpopulation of 22 compounds showing unique characteristics of binding, and could potentially be used to develop the specific and robust imprint. Accordingly, the study implicated a novel approach to screen functional compounds for rational design of the protein imprint. Keywords: Molecular imprint, Rational design, Nanosensor, Electropolymerization, Biorecognition, Carbon nanotube, Docking, Molecular dynamic
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A Novel Sirtuin-3 Inhibitor, LC-0296, Inhibits Cell Survival and Proliferation, and Promotes Apoptosis of Head and Neck Cancer Cells.
BackgroundThe survival rate of patients with head and neck squamous cell carcinoma (HNSCC) stands at approximately 50% and this has not improved in decades. This study developed a novel sirtuin-3 (SIRT3) inhibitor (LC-0296) and examined its role in altering HNSCC tumorigenesis.Materials and methodsThe effect of the SIRT3 inhibitor, LC-0296, on cell survival, proliferation, and apoptosis, and reactive oxygen species levels in HNSCC cells were studied.ResultsLC-0296 reduces cell proliferation and promotes apoptosis of HNSCC cells but not of normal human oral keratinocytes. This inhibitory effect is mediated, in part, via modulation of reactive oxygen species levels. Additionally, LC-0296 works synergistically to increase the sensitivity of HNSCC cells to radiation and cisplatin treatment.ConclusionDevelopment of novel SIRT3 inhibitors, such as LC-0296, might enable the development of new targeted therapies to treat and improve the survival rate of patients with head and neck cancer
5‑((3-Amidobenzyl)oxy)nicotinamides as Sirtuin 2 Inhibitors
Derived
from our previously reported human sirtuin 2 (SIRT2) inhibitors
that were based on a 5-aminonaphthalen-1-yloxy nicotinamide core structure,
5-((3-amidobenzyl)Âoxy)Ânicotinamides offered excellent activity against
SIRT2 and high isozyme selectivity over SIRT1 and SIRT3. Selected
compounds also exhibited generally favorable in vitro absorption,
distribution, metabolism, and excretion properties. Kinetic studies
revealed that a representative SIRT2 inhibitor acted competitively
against both NAD<sup>+</sup> and the peptide substrate, an inhibitory
modality that was supported by our computational study. More importantly,
two selected compounds exhibited significant protection against α-synuclein
aggregation-induced cytotoxicity in SH-SY5Y cells. Therefore, 5-((3-amidobenzyl)Âoxy)Ânicotinamides
represent a new class of SIRT2 inhibitors that are attractive candidates
for further lead optimization in our continued effort to explore selective
inhibition of SIRT2 as a potential therapy for Parkinson’s
disease
Hydroxamic Acids Block Replication of Hepatitis C Virus
Intrigued
by the role of protein acetylation in hepatitis C virus
(HCV) replication, we tested known histone deacetylase (HDAC) inhibitors
and a focused library of structurally simple hydroxamic acids for
inhibition of a HCV subgenomic replicon. While known HDAC inhibitors
with varied inhibitory profiles proved to be either relatively toxic
or ineffective, structure–activity relationship (SAR) studies
on cinnamic hydroxamic acid and benzoÂ[<i>b</i>]Âthiophen-2-hydroxamic
acid gave rise to compounds <b>22</b> and <b>53</b>, which
showed potent and selective anti-HCV activity and therefore are promising
starting points for further structural optimization and mechanistic
studies
Multi-Chlorine-Substituted Self-Assembled Molecules As Anode Interlayers: Tuning Surface Properties and Humidity Stability for Organic Photovoltaics
Self-assembled small molecules (SASMs)
are effective materials
to improve the interfacial properties between a metal/metal oxide
and the overlying organic layer. In this work, surface modification
of indium tin oxide (ITO) electrode by a series of Cl-containing SASMs
has been exploited to control the surface properties of ITO and device
performance for organic photovoltaics. Depending on the position and
degrees of chlorination for SASMs, we could precisely manipulate the
work function of the ITO electrode, and chemisorption of SASMs on
ITO as well. Consequently, a power conversion efficiency (PCE) of
9.1% was achieved with tetrachlorobenzoic acid (2,3,4,5-CBA) SASM
by a simple solution-processed method based on PTB7-Th–PC<sub>71</sub>BM heterojunction. More intriguingly, we discover that device
performance is closely associated with the humidity of ambient conditions.
When the humidity increases from 35–55% to 80–95%, device
performance with 2,3,4,5-CBA has negligible reduction, in contrast
with other SASMs that show a sharp reduction in PCEs. The increased
device performance is primarily attributed to a matched work function,
stable chemisorption, and beneficial wettability with overlying active
layer. These findings suggest an available approach for manufacturing
inexpensive, stable, efficient, and environmentally friendly organic
photovoltaics by appropriate self-assembled small molecules
Up-regulated SPP1 increases the risk from IPF to lung cancer via activating the pro-tumor macrophages
The incidence of lung cancer (LC) in Idiopathic Pulmonary Fibrosis (IPF) patients is more than twice that in non-IPF. This study aims to investigate IPF-to-LC pathogenesis and to develop a predictor for detecting IPF predisposing patients to LC. We conducted unsupervised clustering to detect high-risk subtypes from IPF to LC. Subsequently, we performed single-cell RNA-seq analysis to characterize high-risk IPF by examining the immune microenvironment. We identified 42 common immune function-related pathogenic genes between IPF and LC. We developed an LC risk classifier for IPF patients, comprising five genes: SPP1, MMP9, MMP12, FABP4, and IL1B. The five-gene classifier can successfully distinguish the high-risk population from IPF patients. High-risk IPF patients exhibited an immunosuppressive microenvironment with higher oncogene expression than low-risk patients. Single-cell analysis revealed that SPP1+ macrophages at the terminal of macrophages' developmental trajectory may promote the progression from IPF to LC. The strong crosstalk between SPP1+ macrophages and inflammation-related cancer-associated fibroblasts promoted the tumorigenic process in IPF. In vitro, assays showed that co-culturing macrophages overexpressing SPP1 with MRC-5 cells induced the transition of fibroblasts into cancer-associated fibroblasts. SPP1 produced by macrophages promoted epithelial-mesenchymal transition in alveolar epithelial cells via stimulating the upregulation of N-cadherin and Vimentin in MLE-12 cells. This study provided a novel method to identify the LC risk population from IPF, revealing the cellular interactions involved in the transition from IPF to LC. Our findings highlighted SPP1 as a critical driver in IPF progression, offering a potential target for therapy in fibrosis
Discovery of Potent and Selective Sirtuin 2 (SIRT2) Inhibitors Using a Fragment-Based Approach
Sirtuin
2 (SIRT2) is one of the sirtuins, a family of NAD<sup>+</sup>-dependent
deacetylases that act on a variety of histone and non-histone
substrates. Accumulating biological functions and potential therapeutic
applications have drawn interest in the discovery and development
of SIRT2 inhibitors. Herein we report our discovery of novel SIRT2
inhibitors using a fragment-based approach. Inspired by the purported
close binding proximity of suramin and nicotinamide, we prepared two
sets of fragments, namely, the naphthylamide sulfonic acids and the
naphthalene–benzamides and −nicotinamides. Biochemical
evaluation of these two series provided structure–activity
relationship (SAR) information, which led to the design of (5-benzamidonaphthalen-1/2-yloxy)Ânicotinamide
derivatives. Among these inhibitors, one compound exhibited high anti-SIRT2
activity (48 nM) and excellent selectivity for SIRT2 over SIRT1 and
SIRT3. In vitro, it also increased the acetylation level of α-tubulin,
a well-established SIRT2 substrate, in both concentration- and time-dependent
manners. Further kinetic studies revealed that this compound behaves
as a competitive inhibitor against the peptide substrate and most
likely as a noncompetitive inhibitor against NAD<sup>+</sup>. Taken
together, these results indicate that we have discovered a potent
and selective SIRT2 inhibitor whose novel structure merits further
exploration