Lead Molecules Research Articles

Direct inhibition of tumor hypoxia response with synthetic transcriptional repressors.

Many oncogenic transcription factors (TFs) are considered to be undruggable because of their reliance on large protein-protein and protein-DNA interfaces. TFs such as hypoxia-inducible factors (HIFs) and X-box-binding protein 1 (XBP1) are induced by hypoxia and other stressors in solid tumors and bind to unfolded protein response element (UPRE) and hypoxia-induced response element (HRE) motifs to control oncogenic gene programs. Here, we report a strategy to create synthetic transcriptional repressors (STRs) that mimic the basic leucine zipper domain of XBP1 and recognize UPRE and HRE motifs. A lead molecule, STR22, binds UPRE and HRE DNA sequences with high fidelity and competes with both TFs in cells. Under hypoxia, STR22 globally suppresses HIF1α binding to HRE-containing promoters and enhancers, inhibits hypoxia-induced gene expression and blocks protumorigenic phenotypes in triple-negative breast cancer (TNBC) cells. In vivo, intratumoral and systemic STR22 treatment inhibited hypoxia-dependent gene expression, primary tumor growth and metastasis of TNBC tumors. These data validate a novel strategy to target the tumor hypoxia response through coordinated inhibition of TF-DNA binding.

Leveraging long-lived arenium ions in superacid for meta-selective methylation

Electrophilic aromatic substitution is one of the most mechanistically studied reactions in organic chemistry. However, precluded by innate substituent effects, the access to certain substitution patterns remains elusive. While selective C–H alkylation of biorelevant molecules is eagerly awaited, especially for the insertion of a methyl group whose magic effect can boost lead molecules potency, one of the most obvious strategies would rely on electrophilic aromatic substitution. Yet, the historical Friedel-Crafts methylation remains to date poorly selective and limited to activated simple aromatics. Here, we report the development of a selective electrophilic methylation enabling the direct access to highly desirable 1,3-disubstituted arenes. This study demonstrates that this reaction is driven by the generation of long-lived arenium intermediates generated by protonation in superacid and can be applied to a large variety of functionalized (hetero)aromatics going from standard building blocks to active pharmaceutical ingredients.

Disulfide Tethering to Map Small Molecule Binding Sites Transcriptome-wide.

We report the development of Tether-seq, a transcriptome-wide screen to probe RNA-small molecule interactions using disulfide tethering. This technique uses s4U metabolic labeling to provide sites for reversible and covalent attachment of small molecule disulfides to the transcriptome. By screening under reducing conditions, we identify interactions that are stabilized by binding over those driven by the reactivity of the RNA sites. When applied to cellular RNA, Tether-seq with a disulfide analogue of risdiplam, an FDA-approved drug that targets RNA to treat spinal muscular atrophy (SMA), revealed a number of potential binding sites, most prominently at a site within the cytochrome C oxidase 1 (COX1) transcript. Structure probing by SHAPE-MaP revealed a structured motif and confirmed binding to the lead molecule. This work demonstrates that these screens have the power to identify binding sites throughout the transcriptome and provide invaluable insight into the thermodynamic properties that define small molecule binding.

In Silico Molecular Docking and Molecular Dynamics Analysis of Antimicrobial Triazole Derivatives: Insights from Synthesis, Computational and In Vitro Studies.

In the ongoing fight against bacterial resistance to antibiotics, this study focuses on synthesizing and evaluating 1,2,4-triazole derivatives to explore their potential as new antibacterial agents. 1,2,4-Triazole compounds are promising drug candidates with a wide range of therapeutic effects, including pain relief, antiseptic, antimicrobial, antioxidant, antiurease, anti-inflammatory, diuretic, anticancer, anticonvulsant, antidiabetic, and antimigraine properties. The structures of all the synthesized compounds were identified using their physicochemical properties and spectral techniques, such as IR and NMR. These compounds were then evaluated in molecular docking studies against antimicrobial activity in vitro and further supported by molecular dynamics studies. Compound 7, featuring a 6-chloro group on the phenyl ring, emerged as the most effective against Gram-positive S. aureus compared to the standard antibiotic ciprofloxacin. Docking studies revealed high and comparable affinities for all ten ligands, with compounds 4 and 6 showing the best-docked activity against Penicillin Acylase mutants. Further, compounds 6 and 10 displayed significant affinity against D-alanine-D-alanine ligase (DDL) from Yersinia pestis during 100 ns MD simulation. Notably, compound 7 demonstrated the highest binding score to the 5C1P protein, suggesting its potential as a lead molecule for the development of potent and safer antimicrobial agents. This research contributes valuable insights into addressing the escalating challenge of bacterial resistance.

Exploration of green catalytic Hantzsch process for synthesis of polyhydroquinoline derivatives and their in silico & in vitro evaluation as anti-tubercular agents

Polyhydroquinolines (PHQ) were long known for various pharmacological activities and numerous methods were reported for their synthesis by using different reaction conditions and catalysts. An attempt has been made to synthesize PHQs by following the environmental friendly green chemical approaches by using reusable and recyclable catalyst and solvent materials. Twelve compounds (2A-2L) were synthesized with varied substitutions on the aromatic ring by following the Hantzsch one-pot approach with bleaching earth clay and polyethylene glycol. Use of novel reaction conditions has improved the yield and drastically reduced the time required for the completion of the reaction. The DFT analysis revealed the structural features and the stability of the compound, and later the compounds were subjected to molecular docking against two key proteins of the M. tuberculosis H37 Ra InhA and DprE1. It was found that few of the compounds showed excellent binding interactions compared to the co-crystalized ligand. Later, all the synthesized compounds were subjected to the in vitro antimycobacterial activity using the Kirby-Bauer disk diffusion method, MICs were calculated by REMA assay and the hemolytic assay was performed to check cytotoxicity. Compounds 2K and 2E were found to show better inhibitory activity than the standard rifampin. The antimycobacterial activity of the PHQ compounds might be due to the interaction of the InhA and DprE1, which can be correlated positively and supported by the structural features and the in silico interaction data. Parallelly, molecular dynamic simulation studies were carried out with ligand 2K for the time frame of 100 ns against both targets InhA and DprE1 revealing the formation of stable complexes which further validate the ligand 2K as a potential lead molecule for further studies. The compounds can be further subjected to lead optimization for improved activity.

Design of Podophyllotoxin-based Hybrid Compounds as Potential Anticancer Agents

Background: Cancer has been regarded as the leading cause of death worldwide. Identifying new anti-neoplastics with high potency and low toxicity is urgent. Objective: Podophyllotoxin-based hybrid compounds were synthesized by esterification and characterized using NMR and HR-MS. In vitro cytotoxicity and molecular mechanism studies were performed. Methods: Podophyllotoxin was hybridized with three selected known natural compounds via esterification to develop candidates with increased biological activity or decreased toxicity. The CCK-8 assay, cell cycle analysis, AO/EB staining, immunofluorescent analysis, and molecular modeling were used for investigation. Results: Compound B4 displayed potent anticancer effect on HepG2 and HSC-2 cell lines, with IC50 values of 0.809 ± 0.183 and 0.267 ± 0.038 μM, respectively. Furthermore, B4 exhibited less antiproliferative activity in 293T cells with an IC50 value of 2.303 ± 0.216 μM. In addition, B4 demonstrated strong induction of S phase arrest and apoptosis, as well as demolished the microtubules in HSC-2 cells. Molecular docking study revealed that B4 could bind into the colchicine site of β-tubulin, as well as the interface of the α/β-tubulin dimer. Conclusion: Hybrid B4 exhibited potential anticancer activity, and further investigations can help in identifying novel lead molecules.

“Thiophene”: A Sulphur Containing Heterocycle as a Privileged Scaffold

: In the rapidly expanding chemical realm of heterocyclic compounds with interesting therapeutic properties, the thiophene nucleus has established itself as a prospective entity. The biological activity of comparable substances produced via different pathways is of varying magnitudes. Medicinal chemists use their understanding of multiple synthetic pathways and the various physicochemical properties of such compounds to create a combinatorial library and conduct thorough searches for lead molecules. Due to their vast spectrum of biological actions, heterocyclic compounds play a crucial role in Medicinal chemistry and are extensively researched in the field of drug design and development. Thiophene, a sulfur- containing heterocyclic scaffold, has emerged as a rather well-explored scaffold for the synthesis of a library of molecules with biological functions, including antibacterial, antipsychotic, anticancer, analgesic, anti-inflammatory, anti-arrhythmic, and so on. Depending on the kind and position of substitution, thiophene analogues have been shown to bind to a wide spectrum of cancer-specific protein targets. As a result, thiophene analogues have been found to exert their biological effects by inhibiting various cancerrelated signalling pathways. The study of thiophene in Medicinal chemistry resulted in molecules that combine the thiophene moiety with traditional drug components in a single molecule. This review covers the biological and medical activity of compounds containing a thiophene nucleus, as well as information on thiophene behaviour, synthesis, and agents, with a focus on synthetic techniques, biological profiles, and structure-activity relationship (SAR) research.

EDBD-3,6-Epidioxy-1,10-Bisaboladiene-An Endoperoxide Sesquiterpene Obtained from Drimys brasiliensis (Winteraceae) Exhibited Potent Preclinical Efficacy against Schistosoma mansoni Infection.

Schistosomiasis, a neglected tropical disease impacting over 250 million individuals globally, remains a major public health challenge due to its prevalence and significant impact on affected communities. Praziquantel, the sole available treatment, highlights the urgency of the need for novel anthelmintic agents to achieve the World Health Organization (WHO) goal of schistosomiasis elimination. Previous studies reported the promising antiparasitic activity of different terpenoids against Schistosoma mansoni Sambon (Diplostomida: Schistosomatidae). In the present work, the hexane extract from branches of Drimys brasiliensis afforded a diastereomeric mixture of endoperoxide sesquiterpenes, including 3,6-epidioxy-bisabola-1,10-diene (EDBD). This compound was evaluated in vitro and in vivo against S. mansoni. EDBD exhibited a significant reduction in S. mansoni viability in vitro, with an effective concentration (EC50) value of 4.1 µM. Additionally, EDBD demonstrated no toxicity to mammalian cells. In silico analysis predicted good drug-likeness properties, adhering to pharmaceutical industry standards, including favorable ADME profiles. Furthermore, oral treatment of S. mansoni-infected mice with EDBD (400 mg/kg) resulted in a remarkable egg burden reduction (98% and 99% in tissues and feces, respectively) surpassing praziquantel's efficacy. These findings suggest the promising potential of EDBD as a lead molecule for developing a novel schistosomiasis treatment.

Screening and Identification of Natural Compounds as Potential Inhibitors of Glutamate Racemase and an Emerging Drug Target of Food Pathogen E. coli O157:H7: An In silico Approach to Combat Increasing Drug Resistance.

Shiga Toxin-Producing Escherichia coli (E. coli O157:H7), capable of causing serious food-borne illnesses, is extensively studied and is known to be transmitted through animal reservoirs or person-to-person contact, leading to severe disease outbreaks. The emergence of antibiotic resistance in these strains, coupled with increased adverse effects of existing therapeutics, underscores the urgent need for alternative therapeutic strategies. This study aims to evaluate Glutamate Racemase (MurI protein) of the food-path-ogenic E. coli O157:H7 (EC MurI) as a novel drug target. Furthermore, the study seeks to identify new compounds with potential inhibitory effects against this protein. Using computational tools, the study identified inhibitor binding sites on EC MurI and identified relevant inhibitors capable of binding to these sites. Molecular docking tech-niques were employed to assess potential hits, and selected compounds were further analyzed for their structural activity and binding affinity to the protein. The results of the study revealed that Frigocyclinone and Deslanoside, exhibited the best binding affinity with EC-MurI. Subsequent molecular dynamic (MD) simulations of the selected complexes indicated that both compounds were stable. This suggests that Frigocy-clinone and Deslanoside have the potential to serve as potent inhibitors of EC-MurI. In summary, this study highlights the urgent need for alternative therapies against food-pathogenic E. coli, focusing on E. coli O157:H7. Evaluation of Glutamate Race-mase as a drug target identified Frigocyclinone and Deslanoside as promising inhibitors. MD simulations indicated their stability, suggesting their potential as lead molecules for further research and treatment development.

Pyrrole: An Essential Framework in the Development of Therapeutic Agents and Insightful Analysis of Structure‐Active Relationships

AbstractPyrrole is a heterocyclic structure with diverse pharmacophores, enabling the creation of an extensive lead molecule library. Its broad range of pharmacological profiles has concerned significant global research interests. This review highlights recent advancements in pyrrole scaffolds, focusing on their structure active relationship and bioactivities. Pyrrole derivatives recognized for their biological activities, are promising scaffolds for developing antimicrobial, antimalarial, antiviral, antituberculosis, and enzyme‐inhibiting properties. Their unique anti‐inflammatory and antioxidant features have prompted the development of novel cardioprotective and neuroprotective compounds. The review aims to elucidate the SAR of pyrrole mimics, aiding future therapeutic developments.

Inhibition of monoamine oxidases and neuroprotective effects: chalcones vs. chromones.

Eighteen compounds derived from two sub-series, (HC1-HC9) and (HF1-HF9), were synthesized and evaluated for their inhibitory activities against monoamine oxidase (MAO). HC (chalcone) series showed higher inhibitory activity against MAO-B than against MAO-A, whereas the HF (chromone) series showed reversed inhibitory activity. Compound HC4 most potently inhibited MAO-B with an IC50 value of 0.040μM, followed by HC3 (IC50 = 0.049μM), while compound HF4 most potently inhibited MAO-A (IC50 = 0.046μM), followed by HF2 (IC50 = 0.075μM). The selectivity index (SI) values of HC4 and HF4 were 50.40 and 0.59, respectively. Structurally, HC4 (4-OC2H5 in B-ring) showed higher MAO-B inhibition than other derivatives, suggesting that the -OC2H5 substitution of the 4-position in the B-ring contributes to the increase of MAO-B inhibition, especially -OC2H5 (HC4) > -OCH3 (HC3) > -F (HC7) > -CH3 (HC2) > -Br (HC8) > -H (HC1) in order. In MAO-A inhibition, the substituent 4-OC2H5 in the B-ring of HF4 contributed to an increase in inhibitory activity, followed by -CH3 (HF2), -F (HF7), -Br (HF8), -OCH3 (HF3), and-H (HF1). In the enzyme kinetics and reversibility study, the Ki value of HC4 for MAO-B was 0.035 ± 0.005μM, and that of HF4 for MAO-A was 0.035 ± 0.005μM, and both were reversible competitive inhibitors. We confirmed that HC4 and HF4 significantly ameliorated rotenone-induced neurotoxicity, as evidenced by the reactive oxygen species and superoxide dismutase assays. This study also supports the significant effect of HC4 and HF4 on mitochondrial membrane potential in rotenone-induced toxicity. A lead molecule was used for molecular docking and dynamic simulation studies. These results show that HC4 is a potent selective MAO-B inhibitor and HF4 is a potent MAO-A inhibitor, suggesting that both compounds can be used as treatment agents for neurological disorders.

Monoamine oxidase and neurodegeneration: Mechanisms, inhibitors and natural compounds for therapeutic intervention

Mammalian flavoenzyme Monoamine oxidase (MAO) resides on the outer mitochondrial membrane (OMM) and it is involved in the metabolism of different monoamine neurotransmitters in brain. During MAO mediated oxidative deamination of relevant substrates, H2O2 is released as a catalytic by-product, thus serving as a major source of reactive oxygen species (ROS). Under normal conditions, MAO mediated ROS is reported to propel the functioning of mitochondrial electron transport chain and phasic dopamine release. However, due to its localization onto mitochondria, sudden elevation in its enzymatic activity could directly impact the form and function of the organelle. For instance, in the case of Parkinson's disease (PD) patients who are on l-dopa therapy, the enzyme could be a concurrent source of extensive ROS production in the presence of uncontrolled substrate (dopamine) availability, thus further impacting the health of surviving neurons. It is worth mentioning that the expression of the enzyme in different brain compartments increases with age. Moreover, the involvement of MAO in the progression of neurological disorders such as PD, Alzheimer's disease and depression has been extensively studied in recent times. Although the usage of available synthetic MAO inhibitors has been instrumental in managing these conditions, the associated complications have raised significant concerns lately. Natural products have served as a major source of lead molecules in modern-day drug discovery; however, there is still no FDA-approved MAO inhibitor which is derived from natural sources. In this review, we have provided a comprehensive overview of MAO and how the enzyme system is involved in the pathogenesis of different age-associated neuropathologic conditions. We further discussed the applications and drawbacks of the long-term usage of presently available synthetic MAO inhibitors. Additionally, we have highlighted the prospect and worth of natural product derived molecules in addressing MAO associated complications.

Discovering new mode-of-action pesticide leads inhibiting protein-protein interactions: example targeting plant O-acetylserine sulfhydrylase.

The widespread evolution of pesticide resistance poses a significant challenge to current agriculture, necessitating the discovery of molecules with new modes of action. Despite extensive efforts, no major molecules with new modes of action have been commercialized for decades. Most pesticides function by binding to specific pockets on target enzymes, enabling a single target site mutation to confer resistance. An alternative approach is the disruption of protein-protein interactions (PPI), which require complementary mutations on both interacting partners for resistance to occur. Thus, our aim is the discovery and design of small-molecule inhibitors that target the interface of the PPI complex of O-acetylserine sulfhydrylase (OASS) and serine acetyltransferase (SAT), key obligatory interacting plant enzymes involved in the biosynthesis of the amino acid cysteine. By employing in silico filtering techniques on a virtual library of 30 million small molecules, we identified initial hits capable of binding OASS and interfering with its interaction with a peptide derived from SAT with a half-maximal inhibitory concentration (IC50) of 34 μm. Subsequently, we conducted molecular chemical optimizations, generating an early lead molecule (PJ4) with an IC50 value of 4 μm. PJ4 successfully inhibited the germination of Arabidopsis thaliana seedlings and inhibited clover growth in a pre-emergence application at an effective concentration of 4.6 kg ha-1. These new compounds described herein can serve as promising leads for further optimization as herbicides with a new mode-of-action. This technology can be used for discovering new modes of action chemicals inhibiting all pest groups. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Design and Efficient Synthesis of New 4-Amino-Substituted 2-(4-Bromobenzyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines of Anticancer Interest and Their In Silico Study

AbstractThienopyrimidines are an emerging class of fused pyrimidines due to their broad spectrum of pharmacological properties, including antimicrobial, anti-inflammatory, antimalarial, anticancer, etc. The anticancer activity of these compounds has been mechanistically proven via the inhibition of validated drug targets, such as EGFR, VEGFR-2, PI3K, and c-kit. In this research article, we designed and synthesized new 4-amino-substituted 2-(4-bromobenzyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines to explore their anticancer potential. These heterocycles were designed based on pharmacophoric features of the core heterocycle, varying its C4 substitution with a variety of amines and considering cancer protein-ligand interactions with the aim to obtain potent lead molecules. The target compound-protein interaction complexes were analyzed, and lead compounds were identified based on their better binding affinity in molecular docking studies.

A Comparative Study on the Antidiabetic Activity, Cytotoxicity and Lipid Profile of Trichilia emetica Oils.

The Trichilia emetica plant is traditionally used for medicinal and food purposes. However, there are limited studies on the bioactivity and cytotoxicity of its seed butter and aril oil. This study aimed to assess the antidiabetic activity and cytotoxicity of seed butter and aril oil, obtained via two different extraction methods, and compare their lipid profiles. The plant samples were collected from the Faifa mountains and extracted using a Soxhlet apparatus for hot extraction and a magnetic stirrer for cold maceration. The antidiabetic activity and cytotoxicity were evaluated using the α-amylase and MTT assays, respectively. The fatty acids were quantified utilizing gas chromatography-mass spectrometry. This study proves the impact of the extraction method on the yield, cytotoxicity, antidiabetic activity and lipid profile. The highest cytotoxicity was observed with the seed butter obtained via Soxhlet extraction. The α-amylase inhibition was observed at the highest levels with the seed butter and aril oil obtained via cold maceration. The palmitic acid (PA) and oleic acid (OA) were detected at their maximal concentrations in the seed butter obtained via Soxhlet extraction and aril oil obtained via cold maceration, respectively. This study represents an essential basis for understanding the importance of T. emetica as a valuable tree for food, cosmetic and medicinal purposes. Further experiments can lead to the development of green extraction techniques and isolation of the cytotoxic and antidiabetic molecules that can be developed into new pharmaceutical products or serve as lead molecules for new drugs.

Synthesis of thiazolidinone and methylthiazole derivatives incorporating benzodioxole moiety and evaluation of their antimicrobial activity

One of the most serious future challenges to health care professionals is the emergence of multi-drug resistance pathogenic microbes that rapidly develop resistance to currently used antibiotics. So, as a way to overcome the antimicrobial drug-resistance problems, it is urgent need to synthesize several new lead molecules that are expected to have antibacterial and antifungal activities. So, some new thiazolidinone and methylthiazole derivatives incorporating benzodioxole nucleolus were constructed. Two different series of N-substituted thiosemicarbazones carrying a benzodioxole nucleus were synthesized through mutation reaction of the different aromatic and heterocyclic aldehydes with benzodioxolyl thiosemicarbazide. Cycloalkylation reaction of the latter thiosemicarbazones through with both of the ethyl chloroacetate or chloroacetone gave the thiazolidin-4-ones or 4-methylthiazoles, respectively. The antimicrobial activity of the thiazolidin-4-one and 4-methylthiazole derivatives was investigated. All of compounds showed from weak to moderate effects toward all tested bacteria.

A therapeutic small molecule enhances γ-oscillations and improves cognition/memory in Alzheimer’s disease model mice

Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The γ-oscillations (30 to 120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. These oscillations are reduced in numerous neurological and psychiatric disorders, including early cognitive decline in Alzheimer's disease (AD). Here, we report on a potent brain-permeable small molecule, DDL-920 that increases γ-oscillations and improves cognition/memory in a mouse model of AD, thus showing promise as a class of therapeutics for AD. We employed anatomical, in vitro and in vivo electrophysiological, and behavioral methods to examine the effects of our lead therapeutic candidate small molecule. As a novel in central nervous system pharmacotherapy, our lead molecule acts as a potent, efficacious, and selective negative allosteric modulator of the γ-aminobutyric acid type A receptors most likely assembled from α1β2δ subunits. These receptors, identified through anatomical and pharmacological means, underlie the tonic inhibition of parvalbumin (PV) expressing interneurons (PV+INs) critically involved in the generation of γ-oscillations. When orally administered twice daily for 2 wk, DDL-920 restored the cognitive/memory impairments of 3- to 4-mo-old AD model mice as measured by their performance in the Barnes maze. Our approach is unique as it is meant to enhance cognitive performance and working memory in a state-dependent manner by engaging and amplifying the brain's endogenous γ-oscillations through enhancing the function of PV+INs.

Hippocampal neurogenesis modulated by Quinic acid: A therapeutic strategy for the neurodegenerative disorders.

Neural progenitor cells (NPCs) reside in the brain and participate in the mechanism of neurogenesis that permits the brain to generate the building blocks for enhancement of cognitive abilities and acquisition of new skills. The existence of NPCs in brain has opened a novel dimension of research to explore their potential for treatment of various neurodegenerative disorders. The present study provides novel insights into the intracellular mechanisms in neuronal cells proliferation, maturation and differentiation regulated by Quinic acid (QA). Furthermore, this study might help in discovery and development of lead molecule that can overcome the challenges in the treatment of neurodegenerative diseases. The growth supporting effect of QA was studied using MTT assay. For that purpose, hippocampal cell cultures of neonatal rats were treated with different concentrations of QA and incubated for 24, 48 and 72 h. Gene and protein expressions of the selected molecular markers nestin, neuron-specific class III beta-tubulin (Tuj-1), neuronal nuclear protein (NeuN), neuronal differentiation 1 (NeuroD1), glial fibrillary acidic protein (GFAP), neuroligin (NLGN) and vimentin were analyzed. QA-induced cell proliferation and differentiation of hippocampal progenitor cells was also accompanied by significantly increased expression of progenitor and immature neuronal marker, mature neuronal marker and differentiating factor, that is, nestin, Tuj-1, NeuN and NeuroD1, respectively. On the other hand, vimentin downregulation and constant GFAP expression were observed following QA treatment. Additionally, the effects of QA on the recovery of stressed cells was studied using in vitro model of oxygen glucose deprivation (OGD). It was observed that hippocampal cells were able to recover from OGD following the treatment with QA. These findings suggest that QA treatment promotes hippocampal neurogenesis by proliferating and differentiating of NPCs and recovers neurons from stress caused by OGD. Thus, the neurogenic potential of QA can be explored for the treatment of neurodegenerative disorders.

MI-181 Modulates Cilia Length and Restores Cilia Length in Cells with Defective Shortened Cilia.

Primary cilia are membrane-covered microtubule-based structures that protrude from the cell surface and are critical for cell signaling and homeostasis during human development and adulthood. Dysregulation of cilia formation, length, and function can lead to a spectrum of human diseases and syndromes known as ciliopathies. Although some genetic and chemical screens have been performed to define important factors that modulate cilia biogenesis and length control, there are currently no clinical treatments that restore cilia length in patients. We report that the microtubule-targeting agent MI-181(mitotic inhibitor-181) is a potent modulator of cilia length and biogenesis. Treatment of retinal pigment epithelial-1 cells with MI-181 induced an increase in the average size of cilia and in the percent ciliated cells under nonstarved conditions. Importantly, MI-181 was effective at rescuing cilia length and ciliation defects in cells that had been treated with the intraflagellar transport inhibitor Ciliobrevin D or the O-GlcNAc transferase inhibitor OSMI-1. Most importantly, MI-181 induced an increase in cilia length and restored ciliation in cells with compromised shortened cilia at low nanomolar concentrations and did not show an inhibitory response at high concentrations. Therefore, MI-181 represents a lead molecule for developing drugs targeting ciliopathies characterized by shortened cilia.

Investigation on the Anticancer Activity of [6]-Gingerol of Zingiber officinale and its Structural Analogs against Skin Cancer.

Skin cancer is the most common type of cancer caused by the uncontrolled growth of abnormal cells in the epidermis and the outermost skin layer. This study aimed to study the anti-skin cancer potential of [6]-Gingerol and 21 related structural analogs using in vitro</i> and in silico</i> studies. The ethanolic crude extract of the selected plant was subjected to phytochemical and GC-MS analysis to confirm the presence of the [6]-gingerol. The anticancer activity of the extract was evaluated by MTT (3-[4, 5-dimethylthiazol-2-y]-2, 5-diphenyl tetrazolium bromide) assay using the A431 human skin adenocarcinoma cell line. The GC-MS analysis confirmed the presence of [6]-Gingerol compound, and its promising cytotoxicity IC50 was found at 81.46 ug/ml in the MTT assay. Furthermore, the in silico studies used [6]-Gingerol and 21 structural analogs collected from the PubChem database to investigate the anticancer potential and drug-likeliness properties. Skin cancer protein, DDX3X, was selected as a target that regulates all stages of RNA metabolism. It was docked with 22 compounds, including [6]-Gingerol and 21 structural analogs. The potent lead molecule was selected based on the lowest binding energy value. Thus, the [6]-Gingerol and its structure analogs could be used as lead molecules against skin cancer and future drug development process.