scholarly journals The efficient synthesis of 1-deoxymannojirimycin and its derivatives

2021 ◽  
Author(s):  
◽  
Benjamin Mark Mandinka Deeble
Keyword(s):  
Total Synthesis ◽  
Lysosomal Storage Diseases ◽  
Heterocyclic Ring ◽  
Lysosomal Storage ◽  
Synthetic Strategy ◽  
Anti Cancer ◽  
Structural Analogues ◽  
Treatment Of Diabetes ◽  
Significant Effort ◽  
Selection Of

<p>Azasugars are structural analogues of carbohydrates whereby the oxygen in the heterocyclic ring is substituted for a nitrogen. These carbohydrates are an important class of compounds with medicinal bioactivities and have shown potential for the treatment of diabetes, viral-infection, cancers, and lysosomal storage diseases. 1-deoxymannojirimycin (DMJ), is a mannosidase inhibiting azasugar which has shown anti-cancer and anti-viral activity. There has been significant effort put towards developing methodology to produce this compound and libraries of its derivatives. This thesis presents the synthesis of DMJ and a selection of its derivatives via an efficient 4 step methodology from a carbohydrate starting material, exploiting chemo and regioselective reactions to allow for a total synthesis with minimal use of protecting groups. The synthesis of DMJ, using the methodology developed herein, surpasses published syntheses in efficiency. This synthetic strategy was then used for the preparation of N-functionalised DMJ derivatives without the requirement of additional synthetic steps. To illustrate the versatility of this methodology, a selection of derivatives incorporating different functionalities have been synthesised.</p>

scholarly journals The efficient synthesis of 1-deoxymannojirimycin and its derivatives

2021 ◽  
Author(s):  
◽  
Benjamin Mark Mandinka Deeble
Keyword(s):  
Total Synthesis ◽  
Lysosomal Storage Diseases ◽  
Heterocyclic Ring ◽  
Lysosomal Storage ◽  
Synthetic Strategy ◽  
Anti Cancer ◽  
Structural Analogues ◽  
Treatment Of Diabetes ◽  
Significant Effort ◽  
Selection Of

<p>Azasugars are structural analogues of carbohydrates whereby the oxygen in the heterocyclic ring is substituted for a nitrogen. These carbohydrates are an important class of compounds with medicinal bioactivities and have shown potential for the treatment of diabetes, viral-infection, cancers, and lysosomal storage diseases. 1-deoxymannojirimycin (DMJ), is a mannosidase inhibiting azasugar which has shown anti-cancer and anti-viral activity. There has been significant effort put towards developing methodology to produce this compound and libraries of its derivatives. This thesis presents the synthesis of DMJ and a selection of its derivatives via an efficient 4 step methodology from a carbohydrate starting material, exploiting chemo and regioselective reactions to allow for a total synthesis with minimal use of protecting groups. The synthesis of DMJ, using the methodology developed herein, surpasses published syntheses in efficiency. This synthetic strategy was then used for the preparation of N-functionalised DMJ derivatives without the requirement of additional synthetic steps. To illustrate the versatility of this methodology, a selection of derivatives incorporating different functionalities have been synthesised.</p>

scholarly journals Loliolide - the most ubiquitous lactone

2015 ◽  
Vol 11 ◽  
pp. 1-8 ◽  
Author(s):  
Małgorzata Grabarczyk ◽  
Katarzyna Wińska ◽  
Wanda Mączka ◽  
Bartłomiej Potaniec ◽  
Mirosław Anioł
Keyword(s):  
Side Effects ◽  
Folk Medicine ◽  
Biological Properties ◽  
Biologically Active ◽  
Complicated Structure ◽  
Tropical Coral ◽  
Anti Cancer ◽  
Structural Analogues ◽  
Treatment Of Diabetes ◽  
Living Organisms

The searching for biologically active compounds produced by living organisms led to the discovery of a number of compounds with more or less complicated structure. One of the simplest molecules are monoterpenoid lactones and loliolide is the most common among them. Loliolide was found in animals (insects) and plants (flowers, shrubs, trees) both terrestrial and marine, such as algae and corals. Many years of research on plants used in traditional folk medicine of different countries have led to the conclusion that this compound has a variety of biological properties such as anti-cancer, antibacterial, antifungal and antioxidant ones. Moreover, plants containing loliolide are used in alternative medicine in treatment of diabetes and depression. It is extremely interesting that this lactone also affects the behavior of ants as well as the development of certain plants (allelopathic activity). However, sometimes there are side effects as in the case of structural analogues of loliolide contributing to extinction of tropical coral.

scholarly journals Impaired selection of invariant natural killer T cells in diverse mouse models of glycosphingolipid lysosomal storage diseases

2006 ◽  
Vol 203 (10) ◽  
pp. 2293-2303 ◽  
Author(s):  
Stephan D. Gadola ◽  
Jonathan D. Silk ◽  
Aruna Jeans ◽  
Petr A. Illarionov ◽  
Mariolina Salio ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Models ◽  
Lysosomal Storage Diseases ◽  
Natural Killer T Cells ◽  
Lysosomal Storage ◽  
Inkt Cells ◽  
Storage Diseases ◽  
Killer T Cells ◽  
Invariant Natural Killer ◽  
Selection Of

Glycolipid ligands for invariant natural killer T cells (iNKT cells) are loaded onto CD1d molecules in the late endosome/lysosome. Accumulation of glycosphingolipids (GSLs) in lysosomal storage diseases could potentially influence endogenous and exogenous lipid loading and/or presentation and, thus, affect iNKT cell selection or function. The percentages and frequency of iNKT cells were reduced in multiple mouse models of lysosomal GSL storage disease, irrespective of the specific genetic defect or lipid species stored. Reduced numbers of iNKT cells resulted in the absence of cytokine production in response to α-galactosylceramide (α-GalCer) and reduced iNKT cell–mediated lysis of wild-type targets loaded with α-GalCer. The reduction in iNKT cells did not result from defective expression of CD1d or a lack of antigen-presenting cells. Although H-2 restricted CD4+ T cell responses were generally unaffected, processing of a lysosome-dependent analogue of α-GalCer was impaired in all the strains of mice tested. These data suggest that GSL storage may result in alterations in thymic selection of iNKT cells caused by impaired presentation of selecting ligands.

Electron Microscopy in the diagnosis of lysosomal storage diseases

1989 ◽  
Vol 47 ◽  
pp. 866-867
Author(s):  
Carole Vogler ◽  
Harvey S. Rosenberg
Keyword(s):  
Electron Microscopy ◽  
Lysosomal Enzyme ◽  
Rectal Mucosa ◽  
Lysosomal Storage Diseases ◽  
Cell Types ◽  
Lysosomal Storage ◽  
Storage Material ◽  
Ultrastructural Examination ◽  
Blood Leukocytes ◽  
Storage Diseases

Diagnostic procedures for evaluation of patients with lysosomal storage diseases (LSD) seek to identify a deficiency of a responsible lysosomal enzyme or accumulation of a substance that requires the missing enzyme for degradation. Most patients with LSD have progressive neurological degeneration and may have a variety of musculoskeletal and visceral abnormalities. In the LSD, the abnormally diminished lysosomal enzyme results in accumulation of unmetabolized catabolites in distended lysosomes. Because of the subcellular morphology and size of lysosomes, electron microscopy is an ideal tool to study tissue from patients with suspected LSD. In patients with LSD all cells lack the specific lysosomal enzyme but the distribution of storage material is dependent on the extent of catabolism of the substrate in each cell type under normal circumstances. Lysosmal storages diseases affect many cell types and tissues. Storage material though does not accumulate in all tissues and cell types and may be different biochemically and morphologically in different tissues.Conjunctiva, skin, rectal mucosa and peripheral blood leukocytes may show ultrastructural evidence of lysosomal storage even in the absence of clinical findings and thus any of these tissues can be used for ultrastructural examination in the diagnostic evaluation of patients with suspected LSD. Biopsy of skin and conjunctiva are easily obtained and provide multiple cell types including endothelium, epithelium, fibroblasts and nerves for ultrastructural study. Fibroblasts from skin and conjunctiva can also be utilized for the initiation of tissue cultures for chemical assays. Brain biopsy has been largely replaced by biopsy of more readily obtained tissue and by biochemical assays. Such assays though may give equivical or nondiagnostic results and in some lysosomal storage diseases an enzyme defect has not yet been identified and diagnoses can be made only by ultrastructural examination.

Computationally Augmented Retrosynthesis: Total Synthesis of Paspaline A and Emindole PB

2018 ◽  
Author(s):  
Timothy Newhouse ◽  
Daria E. Kim ◽  
Joshua E. Zweig
Keyword(s):  
Chemical Synthesis ◽  
Total Synthesis ◽  
Small Molecules ◽  
First Principles ◽  
Quantum Chemical ◽  
Computational Analysis ◽  
Empirical Evaluation ◽  
Synthetic Strategy ◽  
Catalyzed Reactions ◽  
Enzyme Catalyzed Reactions

The diverse molecular architectures of terpene natural products are assembled by exquisite enzyme-catalyzed reactions. Successful recapitulation of these transformations using chemical synthesis is hard to predict from first principles and therefore challenging to execute. A means of evaluating the feasibility of such chemical reactions would greatly enable the development of concise syntheses of complex small molecules. Herein, we report the computational analysis of the energetic favorability of a key bio-inspired transformation, which we use to inform our synthetic strategy. This approach was applied to synthesize two constituents of the historically challenging indole diterpenoid class, resulting in a concise route to (–)-paspaline A in 9 steps from commercially available materials and the first pathway to and structural confirmation of emindole PB in 13 steps. This work highlights how traditional retrosynthetic design can be augmented with quantum chemical calculations to reveal energetically feasible synthetic disconnections, minimizing time-consuming and expensive empirical evaluation.

Diverse thiophenes as scaffolds in anti-cancer drug development: A concise review

2020 ◽  
Vol 20 ◽  
Author(s):  
Neha V. Bhilare ◽  
Pratibha B. Auti ◽  
Vinayak S. Marulkar ◽  
Vilas J. Pise
Keyword(s):  
Drug Development ◽  
Anticancer Agents ◽  
Heterocyclic Ring ◽  
Biologically Active Compounds ◽  
Biologically Active ◽  
Cancer Drug ◽  
Active Compounds ◽  
Natural Origin ◽  
Concise Review ◽  
Anti Cancer

: Thiophenes are one among the abundantly found heterocyclic ring systems in many biologically active compounds. Moreover various substituted thiophenes exert numerous pharmacological actions on account of their isosteric resemblance with compounds of natural origin thus rendering them with diverse actions like antibacterial, antifungal, antiviral, anti-inflammatory, analgesic, antiallergic, hypotensives etc.. In this review we specifically explore the chemotherapeutic potential of variety of structures consisting of thiophene scaffolds as prospective anticancer agents.

The Chemistry of Triazine Isomers: Structures, Reactions, Synthesis and Applications

2020 ◽  
Vol 20 ◽  
Author(s):  
Neelottama Kushwaha ◽  
C S Sharma
Keyword(s):  
Basic Property ◽  
Electrophilic Substitution ◽  
Antimicrobial Agents ◽  
Resonance Energy ◽  
Heterocyclic Ring ◽  
Ring System ◽  
Agricultural Fields ◽  
Substitution Reactions ◽  
Anti Cancer ◽  
Benzene Structure

: Triazine is the six-membered heterocyclic ring containing three nitrogen which replaces carbon-hydrogen unit in the benzene ring. Based on nitrogen position present in the ring system, it is categorized in three isomeric forms i.e.1, 2, 3-triazine (vicinal triazine), 1, 2, 4-triazine (asymmetrical triazine or isotriazine) and 1, 3, 5-triazine (symmetrical or s-triazine or cyanidine). Triazines have weakly basic property. Its isomers have much weaker resonance energy than benzene structure, so nucleophilic substitution reactions are more preferred than electrophilic substitution reactions. Triazine isomers and their derivatives are known to play important roles possessing various activities in medicinal and agricultural fields such as anti-cancer, antiviral, fungicidal, insecticidal, bactericidal, herbicidal, antimalarial and antimicrobial agents.

1,4-Dihydropyridine: A Dependable Heterocyclic Ring with the Promising and the Most Anticipable Therapeutic Effects

2019 ◽  
Vol 19 (15) ◽  
pp. 1219-1254 ◽  
Author(s):  
Abhinav Prasoon Mishra ◽  
Ankit Bajpai ◽  
Awani Kumar Rai
Keyword(s):  
Calcium Ion ◽  
Heterocyclic Compounds ◽  
Channel Blocker ◽  
Heterocyclic Ring ◽  
Therapeutic Effects ◽  
Voltage Gated ◽  
Therapeutic Benefits ◽  
Anti Cancer ◽  
Anti Oxidant ◽  
Synthetic Medicinal

: Nowadays, heterocyclic compounds act as a scaffold and are the backbone of medicinal chemistry. Among all of the heterocyclic scaffolds, 1,4-Dihydropyridine (1,4-DHP) is one of the most important heterocyclic rings that possess prominent therapeutic effects in a very versatile manner and plays an important role in synthetic, medicinal, and bioorganic chemistry. The main aim of the study is to review and encompass relevant studies related to 1,4-DHP and excellent therapeutic benefits of its derivatives. An extensive review of Pubmed-Medline, Embase and Lancet’s published articles was done to find all relevant studies on the activity of 1,4-DHP and its derivatives. 1,4-DHP is a potent Voltage-Gated Calcium Channel (VGCC) antagonist derivative which acts as an anti-hypertensive, anti- anginal, anti-tumor, anti-inflammatory, anti-tubercular, anti-cancer, anti-hyperplasia, anti-mutagenic, anti-dyslipidemic, and anti-ulcer agent. From the inferences of the study, it can be concluded that the basic nucleus, 1,4-DHP which is a voltage-gated calcium ion channel blocker, acts as a base for its derivatives that possess different important therapeutic effects. There is a need of further research of this basic nucleus as it is a multifunctional moiety, on which addition of different groups can yield a better drug for its other activities such as anti-convulsant, anti-oxidant, anti-mutagenic, and anti-microbial. This review would be significant for further researches in the development of several kinds of drugs by representing successful matrix for the medicinal agents.

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