scholarly journals Design and Synthesis of 2- and 3-Substituted-3-phenylpropyl Analogs of 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: Role of Amino, Fluoro, Hydroxyl, Methoxyl, Methyl, Methylene, and Oxo Substituents on Affinity for the Dopamine and Serotonin Transporters

2008 ◽  
Vol 51 (9) ◽  
pp. 2795-2806 ◽  
Author(s):  
Ling-Wei Hsin ◽  
Li-Te Chang ◽  
Richard B. Rothman ◽  
Christina M. Dersch ◽  
Arthur E. Jacobson ◽  
...  
Keyword(s):  
Serotonin Transporters ◽  
Design And Synthesis

The emerging role of COX-2, 15-LOX, and PPARγ in metabolic diseases and cancer: An introduction to novel multi-target directed ligands (MTDLs)

2020 ◽  
Vol 27 ◽  
Author(s):  
Rana A. Alaaeddine ◽  
Perihan A. Elzahhar ◽  
Ibrahim AlZaim ◽  
Wassim Abou-Kheir ◽  
Ahmed S.F. Belal ◽  
...  
Keyword(s):  
Metabolic Diseases ◽  
Biological Effects ◽  
Arachidonic Acid Metabolism ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cellular Targets ◽  
Design And Synthesis ◽  
Early Results ◽  
Cox 2

: Emerging evidence supports an intertwining framework for the involvement of different inflammatory pathways in a common pathological background for a number of disorders. Of importance are pathways involving arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX). Both enzyme activities and their products are implicated in a range of pathophysiological processes encompassing metabolic impairment leading to adipose inflammation and the subsequent vascular and neurological disorders, in addition to various pro-and anti-tumorigenic effects. A further layer of complexity is encountered by the disparate, and often reciprocal, modulatory effect COX-2 and 15-LOX activities and metabolites exert on each other or on other cellular targets, the most prominent of which is peroxisome proliferator-activated receptor gamma (PPARγ). Thus, effective therapeutic intervention with such multifaceted disorders requires the simultaneous modulation of more than one target. Here, we describe the role of COX-2, 15-LOX, and PPARγ in cancer and complications of metabolic disorders, highlight the value of designing multi-target directed ligands (MTDLs) modifying their activity, and summarize the available literature regarding the rationale and feasibility of design and synthesis of these ligands together with their known biological effects. We speculate on the potential impact of MTDLs in these disorders as well as emphasize the need for structured future effort to translate these early results facilitating the adoption of these, and similar, molecules in clinical research.

Design and synthesis of novel porphyrinated polyimide nanofibers as dissolved oxygen sensor: The role of electro-activity and orientation

2019 ◽  
Vol 161 ◽  
pp. 79-88 ◽  
Author(s):  
Huanyu Lei ◽  
Jiaming Lu ◽  
Guoqing Dong ◽  
Guofeng Tian ◽  
Shengli Qi ◽  
...  
Keyword(s):  
Dissolved Oxygen ◽  
Oxygen Sensor ◽  
Design And Synthesis

Electronic Structure and Hydrogen Desorption in NaAlH4

2004 ◽  
Vol 837 ◽  
Author(s):  
S. Li ◽  
P. Jena ◽  
C. M. Araujo ◽  
R. Ahuja
Keyword(s):  
Electronic Structure ◽  
First Principles ◽  
Density Functional ◽  
Metal Hydrides ◽  
Hydrogen Desorption ◽  
Light Metal ◽  
First Principles Calculations ◽  
Functional Theory ◽  
Design And Synthesis

ABSTRACTFirst principles calculations based on gradient corrected density functional theory are carried out to understand the electronic structure and mechanisms responsible for desorption of hydrogen from Ti doped and vacancy containing sodium-alanate (NaAlH4). The energy necessary to remove a hydrogen atom from Ti doped NaAlH4 is significantly smaller than that from pristine NaAlH4 irrespective of whether Ti substitutes the Na or the Al site. However, the presence of Na and Al vacancies is shown to play an even more important role: The removal of hydrogen associated with both Na and Al vacancies is found to be exothermic. It is suggested that this role of vacancies can be exploited in the design and synthesis of complex light metal hydrides suitable for hydrogen storage.

Methamphetamine-induced hyperthermia and lethal toxicity: Role of the dopamine and serotonin transporters

2007 ◽  
Vol 572 (2-3) ◽  
pp. 120-128 ◽  
Author(s):  
Yohtaro Numachi ◽  
Arihisa Ohara ◽  
Motoyasu Yamashita ◽  
Setsu Fukushima ◽  
Hideaki Kobayashi ◽  
...  
Keyword(s):  
Serotonin Transporters ◽  
Induced Hyperthermia ◽  
Lethal Toxicity

scholarly journals Multiepitope Dendrimeric Antigen-Silica Particle Composites as Nano-Based Platforms for Specific Recognition of IgEs

2021 ◽  
Vol 12 ◽  
Author(s):  
Violeta Gil-Ocaña ◽  
Isabel M. Jimenez ◽  
Cristobalina Mayorga ◽  
Inmaculada Doña ◽  
Jose Antonio Céspedes ◽  
...  
Keyword(s):  
Silica Particle ◽  
Drug Hypersensitivity ◽  
Specific Ige ◽  
Design And Synthesis ◽  
Protein Conjugates ◽  
Drug Hypersensitivity Reactions ◽  
Homogeneous Composition

β-lactam antibiotics (BLs) are the drugs most frequently involved in drug hypersensitivity reactions. However, current in vitro diagnostic tests have limited sensitivity, partly due to a poor understanding of in vivo drug–protein conjugates that both induce the reactions and are immunologically recognized. Dendrimeric Antigen-Silica particle composites (DeAn@SiO2), consisting on nanoparticles decorated with BL-DeAns are promising candidates for improving the in vitro clinical diagnostic practice. In this nano-inspired system biology, the synthetic dendrimer plays the role of the natural carrier protein, emulating its haptenation by drugs and amplifying the multivalence. Herein, we present the design and synthesis of new multivalent mono- and bi-epitope DeAn@SiO2, using amoxicillin and/or benzylpenicillin allergenic determinants as ligands. The homogeneous composition of nanoparticles provides high reproducibility and quality, which is critical for in vitro applications. The suitable functionalization of nanoparticles allows the anchoring of DeAn, minimizing the nonspecific interactions and facilitating the effective exposure to specific IgE; while the larger interaction area increments the likelihood of capturing specific IgE. This achievement is particularly important for improving sensitivity of current immunoassays since IgE levels in BL allergic patients are very low. Our data suggest that these new nano-based platforms provide a suitable tool for testing IgE recognition to more than one BL simultaneously. Immunochemical studies evidence that mono and bi-epitope DeAn@SiO2 composites could potentially allow the diagnosis of patients allergic to any of these drugs with a single test. These organic–inorganic hybrid materials represent the basis for the development of a single screening for BL-allergies.

scholarly journals Design and Synthesis of Simplified Analogues of Pateamine A

2021 ◽  
Author(s):  
◽  
Hemi Cumming
Keyword(s):  
Genetic Diseases ◽  
Optimal Order ◽  
Coupling Reactions ◽  
Protein Targets ◽  
Design And Synthesis ◽  
Synthetic Strategy ◽  
Linear Sequence ◽  
Growth Inhibitory ◽  
Pateamine A

<p>Pateamine A (14) is a natural product that was extracted from a marine sponge off the coast of the South Island of New Zealand. It exhibits potent biological activity, mediated by a number of protein targets. The most sensitive of these towards pateamine are the eIF4A isoforms, which have roles in translation of RNA into proteins and in nonsensemediated decay. The inhibition of these enzymes may be beneficial in the treatment of cancer or certain types of genetic diseases. Unfortunately, the naturally available supply of pateamine is very limited and its total synthesis is complex. This provides an imperative for the design of a synthetic strategy that would allow the preparation of simplified analogues of pateamine to gain further insight into the necessary features for activity and selectivity of the eIF4A isoforms. Based on the principles of pharmacophore modification, chemical synthesis and the structure-activity relationships (SARs) reported by Romo and co-workers, a simplified analogue of pateamine, 107, was targeted that lacked a number of pendant methyl groups and contained a triazole in place of the thiazole. Synthesis of the target analogue 107 was achieved through preparation of four fragments, followed by an investigation of suitable coupling reactions and the optimal order of connectivity. This included the preparation of two macrocycles that lacked the trienecontaining sidechain, and of simplified model substrates that allowed investigation of two olefination reactions (namely, the Wittig and Julia-Kocienski reactions) for the attachment of the sidechain fragment. After substantial optimisation of the fragment preparation and connectivity, the complete synthesis of the target pateamine analogue 107 was achieved. The synthesis features: 1) a Julia Kocienski olefination between a highly functionalised three-carbon sulfone and a conjugated aldehyde to attach the sidechain; 2) copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction to form the triazole; 3) ring opening of a δ-substituted α,β-unsaturated lactone to access the Z,E-dienoate moiety; and 4) Yamaguchi macrolactonisation. This synthesis represents a convergent strategy with 11 steps in the longest linear sequence, which utilises easily accessible starting materials (i.e. furan (or cis-butenediol), epichlorohydrin, ε-caprolactone and 1,3-propanediol) and reagents. The approach is also broadly applicable to the preparation of a range of analogue variants. The simplified analogue (107) was found to have significantly lower activity, in comparison to pateamine A (14), in a growth inhibitory assay. Presuming this loss of bioactivity is at least partially caused by the incorporation of the triazole (in place of the thiazole), this raises an interesting question as to the role of the thiazole moiety in the bioactivity of pateamine A. The adaptation of the synthetic strategy devised in this thesis to the preparation of future analogues will enable study of the mechanism of action of pateamine and related compounds, and probe the requirements for effective binding to the eIF4A isoforms.</p>

scholarly journals A unique peptide deformylase platform to rationally design and challenge novel active compounds

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Sonia Fieulaine ◽  
Rodolphe Alves de Sousa ◽  
Laure Maigre ◽  
Karim Hamiche ◽  
Mickael Alimi ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Peptide Deformylase ◽  
Binding Modes ◽  
Proof Of Concept ◽  
Compound Structure ◽  
3 Dimensional ◽  
Design And Synthesis ◽  
Relationship Analysis

Abstract Peptide deformylase (PDF) is considered an excellent target to develop antibiotics. We have performed an extensive characterization of a new PDF from the pathogen Streptococcus agalactiae, showing properties similar to other known PDFs. S. agalactiae PDF could be used as PDF prototype as it allowed to get complete sets of 3-dimensional, biophysical and kinetic data with virtually any inhibitor compound. Structure-activity relationship analysis with this single reference system allowed us to reveal distinct binding modes for different PDF inhibitors and the key role of a hydrogen bond in potentiating the interaction between ligand and target. We propose this protein as an irreplaceable tool, allowing easy and relevant fine comparisons between series, to design, challenge and validate novel series of inhibitors. As proof-of-concept, we report here the design and synthesis of effective specific bacterial PDF inhibitors of an oxadiazole series with potent antimicrobial activity against a multidrug resistant clinical isolate.

Design and synthesis of novel quinic acid derivatives: in vitro cytotoxicity and anticancer effect on glioblastoma

2020 ◽  
Vol 12 (21) ◽  
pp. 1891-1910
Author(s):  
Akshaya Murugesan ◽  
Suvi Holmstedt ◽  
Kenna C Brown ◽  
Alisa Koivuporras ◽  
Ana S Macedo ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Potential Role ◽  
Chemotherapeutic Agent ◽  
Quinic Acid ◽  
In Vitro Cytotoxicity ◽  
Anticancer Effect ◽  
Design And Synthesis ◽  
Anticancer Properties

Aim: Quinic acid (QA) is a cyclic polyol exhibiting anticancer properties on several cancers. However, potential role of QA derivatives against glioblastoma is not well established. Methodology & results: Sixteen novel QA derivatives and QA-16 encapsulated poly (lactic-co-glycolic acid) nanoparticles (QA-16-NPs) were screened for their anti-glioblastoma effect using standard cell and molecular biology methods. Presence of a tertiary hydroxy and silylether groups in the lead compound were identified for the antitumor activity. QA-16 have 90% inhibition with the IC50 of 10.66 μM and 28.22 μM for LN229 and SNB19, respectively. The induction of apoptosis is faster with the increased fold change of caspase 3/7 and reactive oxygen species. Conclusion: QA-16 and QA-16-NPs shows similar cytotoxicity effect, providing the opportunity to use QA-16 as a potential chemotherapeutic agent.

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