therapeutic leads
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Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 463
Luca Pozzetti ◽  
Roberta Ibba ◽  
Sara Rossi ◽  
Orazio Taglialatela-Scafati ◽  
Donatella Taramelli ◽  

The potential of natural and synthetic chalcones as therapeutic leads against different pathological conditions has been investigated for several years, and this class of compounds emerged as a privileged chemotype due to its interesting anti-inflammatory, antimicrobial, antiviral, and anticancer properties. The objective of our study was to contribute to the investigation of this class of natural products as anti-leishmanial agents. We aimed at investigating the structure–activity relationships of the natural chalcone lophirone E, characterized by the presence of benzofuran B-ring, and analogues on anti-leishmania activity. Here we describe an effective synthetic strategy for the preparation of the natural chalcone lophirone E and its application to the synthesis of a small set of chalcones bearing different substitution patterns at both the A and heterocyclic B rings. The resulting compounds were investigated for their activity against Leishmania infantum promastigotes disclosing derivatives 1 and 28a,b as those endowed with the most interesting activities (IC50 = 15.3, 27.2, 15.9 μM, respectively). The synthetic approaches here described and the early SAR investigations highlighted the potential of this class of compounds as antiparasitic hits, making this study worthy of further investigation.

Ashwani K. Dhingra ◽  
Bhawna Chopra ◽  
Akash Jain ◽  
Jasmine Chaudhary

Background: Alzheimer's disease (AD) is a multifactorial disorder coupled with an array of neuropathological mechanisms, including tau phosphorylation, Aβ aggregation, metal ion deregulation, and oxidative stress, along with neuro-inflammation. The clinically available drugs for the management of AD include four acetylcholinesterase inhibitors and one glutamatergic antagonist. These agents provide only temporary relief from the symptoms by altering the neurotransmitter level in the brain. Objective: Keeping in view the focus on research, the numerous pharmacological activities associated with the aromatic diazole heterocyclic nucleus, imidazole, triggered the medicinal chemist to develop a large number of novel anti-AD compounds targeting multiple pathological mechanisms associated with AD. These prepared analogs represent a higher potential against neurological disorders, including AD. This review article aims an ornately pronounce the therapeutic voyage of imidazole and its analogs as anti-AD. Method: It emphasizes the synthesized imidazole derivatives as anti–AD with multiple targets reviewed from the data available on Pubmed. Result: These compounds diminish the pathophysiological aspects of AD; still, further studies are required to prove the safety and efficacy of these compounds in humans. Conclusion: The review aims to provide knowledge and highlight the status of this moiety in the design and development of novel drug candidates against Alzheimer’s disease conditions. Thus, it paves the way for further work.

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7362
Amanda S. Hirata ◽  
Paula Rezende-Teixeira ◽  
João Agostinho Machado-Neto ◽  
Paula C. Jimenez ◽  
James J. La Clair ◽  

Isolated from the marine bacteria Serinicoccus sp., seriniquinone (SQ1) has been characterized by its selective activity in melanoma cell lines marked by its modulation of human dermcidin and induction of autophagy and apoptosis. While an active lead, the lack of solubility of SQ1 in both organic and aqueous media has complicated its preclinical evaluation. In response, our team turned its effort to explore analogues with the goal of returning synthetically accessible materials with comparable selectivity and activity. The analogue SQ2 showed improved solubility and reached a 30–40-fold greater selectivity for melanoma cells. Here, we report a detailed comparison of the activity of SQ1 and SQ2 in SK-MEL-28 and SK-MEL-147 cell lines, carrying the top melanoma-associated mutations, BRAFV600E and NRASQ61R, respectively. These studies provide a definitive report on the activity, viability, clonogenicity, dermcidin expression, autophagy, and apoptosis induction following exposure to SQ1 or SQ2. Overall, these studies showed that SQ1 and SQ2 demonstrated comparable activity and modulation of dermcidin expression. These studies are further supported through the evaluation of a panel of basal expression of key-genes related to autophagy and apoptosis, providing further insight into the role of these mutations. To explore this rather as a survival or death mechanism, autophagy inhibition sensibilized BRAF mutants to SQ1 and SQ2, whereas the opposite happened to NRAS mutants. These data suggest that the seriniquinones remain active, independently of the melanoma mutation, and suggest the future combination of their application with inhibitors of autophagy to treat BRAF-mutated tumors.

2021 ◽  
Peyton J Tebon ◽  
Bowen Wang ◽  
Alexander L Markowitz ◽  
Graeme Murray ◽  
Huyen Thi Lam Nguyen ◽  

There is increasing interest in leveraging tumor organoids for high-throughput drug screenings to investigate tumor biology and identify therapeutic leads. However, functional precision medicine platforms are limited by the difficulties of creating, scaling, and analyzing physiological disease models. Most systems use manually seeded organoids and take advantage of destructive endpoint assays to rapidly characterize response to treatment. These approaches fail to capture transitory changes and intra-sample heterogeneity that underlies much of the clinically observed resistance to therapy. We therefore developed bioprinted tumor organoids linked to real-time growth pattern quantitation via high-speed live cell interferometry (HSLCI). We demonstrate that bioprinting gives rise to 3D organoid structures that preserve histology and gene expression. These are suitable for imaging with HSLCI, enabling accurate parallel mass measurements for thousands of bioprinted organoids. In drug screening experiments, HSLCI rapidly identifies organoids transiently or persistently sensitive or resistant to specific therapies. We show that our approach can provide detailed, actionable information to guide rapid therapy selection.

Justin Melendez ◽  
Ananya Pal ◽  
Sidharth Puram ◽  
Robi Mitra

Targeted gene knockdown has become one of the most powerful tools in molecular biology and holds substantial promise in therapeutic applications. While existing technologies such as siRNAs, CRISPRi, and ASOs effectively and specifically reduce gene expression, few can be used to first discover the genes that influence a particular phenotype and then directly transition to being used as oligonucleotide therapeutics. Thus, a tool that could help bridge the gap between target discovery and the development of therapeutic leads would benefit the scientific community. Here, we present hnRNPA1 recruiting oligonucleotides, or AROs, as single-stranded RNA (ssRNA) molecules that knockdown transcript levels of target genes. AROs target specific pre-mRNA transcripts via sequence homology and leverage the ubiquitous and abundant endogenous RNA-binding protein hnRNPA1 to degrade target transcripts. Using RT-qPCR, we show that AROs effectively knock down target genes when delivered via a plasmid and expressed using a Pol II promoter or when delivered directly as single-strand RNAs. Additionally, as proof of principle, we use a ssRNA ARO to knockdown KRT14 in squamous cell carcinoma and show reduced invasive potential. We believe AROs fill an important niche in the scientific toolbox by taking advantage of endogenous RNA binding machinery for RNA knockdowns.

2021 ◽  
Vol 9 (7) ◽  
pp. 1450
Yoann Maitre ◽  
Rachid Mahalli ◽  
Pierre Micheneau ◽  
Alexis Delpierre ◽  
Marie Guerin ◽  

This systematic review aims to identify probiotics and prebiotics for modulating oral bacterial species associated with mental disorders. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guideline, we search the electronic MEDLINE database published till January 2021 to identify the studies on probiotics and/or prebiotics for preventing and treating major oral dysbiosis that provokes mental disorders. The outcome of the search produces 374 records. After excluding non-relevant studies, 38 papers were included in the present review. While many studies suggest the potential effects of the oral microbiota on the biochemical signalling events between the oral microbiota and central nervous system, our review highlights the limited development concerning the use of prebiotics and/or probiotics in modulating oral dysbiosis potentially involved in the development of mental disorders. However, the collected studies confirm prebiotics and/or probiotics interest for a global or targeted modulation of the oral microbiome in preventing or treating mental disorders. These outcomes also offer exciting prospects for improving the oral health of people with mental disorders in the future.

2021 ◽  
Vol 4 (1) ◽  
Michael Meanwell ◽  
Gaelen Fehr ◽  
Weiwu Ren ◽  
Bharanishashank Adluri ◽  
Victoria Rose ◽  

AbstractGlycomimetics are structural mimics of naturally occurring carbohydrates and represent important therapeutic leads in several disease treatments. However, the structural and stereochemical complexity inherent to glycomimetics often challenges medicinal chemistry efforts and is incompatible with diversity-oriented synthesis approaches. Here, we describe a one-pot proline-catalyzed aldehyde α-functionalization/aldol reaction that produces an array of stereochemically well-defined glycomimetic building blocks containing fluoro, chloro, bromo, trifluoromethylthio and azodicarboxylate functional groups. Using density functional theory calculations, we demonstrate both steric and electrostatic interactions play key diastereodiscriminating roles in the dynamic kinetic resolution. The utility of this simple process for generating large and diverse libraries of glycomimetics is demonstrated in the rapid production of iminosugars, nucleoside analogues, carbasugars and carbohydrates from common intermediates.

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i15-i15
Kelsey Bertrand ◽  
Stephen Mack

Abstract Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas comprise histologically similar tumor entities driven by distinct molecular mechanisms, such as fusion oncoproteins, genome-wide chromosomal instability, or disruption of DNA methylation patterns. Despite these differences, ependymomas resist chemotherapy and lack available targeted agents for clinical trial development. Based on our previous findings, we hypothesized that mapping chromatin landscapes and super enhancers (SE) could uncover transcriptional dependencies as targets for therapy (Mack, Pajtler, Chavez et al., Nature, 2018). To functionally test the requirement of these SE genes for ependymoma cellular growth, we designed a pooled RNA interference screen against 267 SE associated genes. Our screen was performed in one C11ORF95-RELA-fusion model and two PF-EPN-A models as controls in biological triplicates. As an indication that our screen was successful, positive controls scored among lead hits including KIF11, BUB1B, PHF5A and MYC. Importantly, we identified many subtype specific dependencies in both C11ORF95-RELA-fusion and PF-EPN-A models, thus revealing novel pathways that potentially govern subgroup-specific ependymoma cell growth. Further, several candidates detected across all ependymoma lines were also identified as pan-cancer dependencies or glioma/glioblastoma specific essential genes from the DepMap Cancer Dependency Gene Resource. Our findings reveal novel targets and pathways that are essential for ependymoma cell growth, which may provide new insight into therapeutic strategies against these aggressive brain tumors.

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