A short de novo synthesis of nucleoside analogs

Science ◽  
2020 ◽  
Vol 369 (6504) ◽  
pp. 725-730 ◽  
Author(s):  
Michael Meanwell ◽  
Steven M. Silverman ◽  
Johannes Lehmann ◽  
Bharanishashank Adluri ◽  
Yang Wang ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Viral Infections ◽  
De Novo ◽  
Nucleoside Analogs ◽  
Aldol Reactions ◽  
Displacement Reaction ◽  
De Novo Synthesis ◽  
One Pot ◽  
Drug Discovery And Development ◽  
Locked Nucleic Acids

Nucleoside analogs are commonly used in the treatment of cancer and viral infections. Their syntheses benefit from decades of research but are often protracted, unamenable to diversification, and reliant on a limited pool of chiral carbohydrate starting materials. We present a process for rapidly constructing nucleoside analogs from simple achiral materials. Using only proline catalysis, heteroaryl-substituted acetaldehydes are fluorinated and then directly engaged in enantioselective aldol reactions in a one-pot reaction. A subsequent intramolecular fluoride displacement reaction provides a functionalized nucleoside analog. The versatility of this process is highlighted in multigram syntheses of d- or l-nucleoside analogs, locked nucleic acids, iminonucleosides, and C2′- and C4′-modified nucleoside analogs. This de novo synthesis creates opportunities for the preparation of diversity libraries and will support efforts in both drug discovery and development.

scholarly journals General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shay Laps ◽  
Fatima Atamleh ◽  
Guy Kamnesky ◽  
Hao Sun ◽  
Ashraf Brik
Keyword(s):  
Drug Discovery ◽  
Disulfide Bonds ◽  
Unsolved Problem ◽  
De Novo ◽  
Therapeutic Potential ◽  
Selective Activation ◽  
One Pot ◽  
Synthetic Strategy ◽  
The One ◽  
Game Changer

AbstractDespite six decades of efforts to synthesize peptides and proteins bearing multiple disulfide bonds, this synthetic challenge remains an unsolved problem in most targets (e.g., knotted mini proteins). Here we show a de novo general synthetic strategy for the ultrafast, high-yielding formation of two and three disulfide bonds in peptides and proteins. We develop an approach based on the combination of a small molecule, ultraviolet-light, and palladium for chemo- and regio-selective activation of cysteine, which enables the one-pot formation of multiple disulfide bonds in various peptides and proteins. We prepare bioactive targets of high therapeutic potential, including conotoxin, RANTES, EETI-II, and plectasin peptides and the linaclotide drug. We anticipate that this strategy will be a game-changer in preparing millions of inaccessible targets for drug discovery.

De novo synthesis of phenolic dihydroxanthene near-infrared emitting fluorophores

2015 ◽  
Vol 13 (30) ◽  
pp. 8169-8172 ◽  
Author(s):  
Jean-Alexandre Richard
Keyword(s):  
Near Infrared ◽  
De Novo ◽  
De Novo Synthesis ◽  
One Pot

We report a flexiblede novosynthesis of phenolic dihydroxanthenes in 60–70% yield thanks to a one-pot cascade sequence.

scholarly journals Drug Repurposing Is a New Opportunity for Developing Drugs against Neuropsychiatric Disorders

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Hyeong-Min Lee ◽  
Yuna Kim
Keyword(s):  
Drug Discovery ◽  
De Novo ◽  
Drug Repurposing ◽  
Cost Effective ◽  
Neuropsychiatric Disorders ◽  
Mechanisms Of Action ◽  
Drug Discovery And Development ◽  
Cost Effective Method ◽  
Alternative Approach ◽  
Target Effects

Better the drugs you know than the drugs you do not know. Drug repurposing is a promising, fast, and cost effective method that can overcome traditional de novo drug discovery and development challenges of targeting neuropsychiatric and other disorders. Drug discovery and development targeting neuropsychiatric disorders are complicated because of the limitations in understanding pathophysiological phenomena. In addition, traditional de novo drug discovery and development are risky, expensive, and time-consuming processes. One alternative approach, drug repurposing, has emerged taking advantage of off-target effects of the existing drugs. In order to identify new opportunities for the existing drugs, it is essential for us to understand the mechanisms of action of drugs, both biologically and pharmacologically. By doing this, drug repurposing would be a more effective method to develop drugs against neuropsychiatric and other disorders. Here, we review the difficulties in drug discovery and development in neuropsychiatric disorders and the extent and perspectives of drug repurposing.

scholarly journals COMPUTER AIDED DRUG DESIGN: A MINI-REVIEW

2020 ◽  
Vol 9 (5) ◽  
pp. 2584-2591
Author(s):  
Aateka Y Barrawaz
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Development Process ◽  
De Novo ◽  
Computer Aided Drug Design ◽  
Drug Discovery And Development ◽  
Research Activities ◽  
Complex Process ◽  
Computer Aided ◽  
New Chemical Entities

New drug discovery and development process is considered much complex process which is time consuming and resources accommodating too. So computer aided drug design are being broadly used to enhance the effectiveness of the drug discovery and development process which ultimately saves time and resources. Various approaches to Computer aided drug design are evaluated to shows potential techniques in accordance with their needs. Two approaches are considered to designing of drug first one is structure-based and second one is Ligand based drug designs. In this review, we are discussing about highly effective and powerful techniques for drug discovery and development as well as various methods of Computer aided drug design like molecular docking at virtual screening for lead identification, QSAR, molecular homology, de-novo design, molecular modeling and optimization. It also elaborate about different software used in Computer aided drug design, different application of Computer aided drug design etc. Major objectives of Computer aided drug design are to commence collaborative foundation of research activities and to discover new chemical entities for novel therapeutics drugs

scholarly journals Expression of fatty acyl-CoA ligase drives one-pot de novo synthesis of membrane-bound vesicles in a cell free transcription-translation system

2021 ◽  
Author(s):  
Ahanjit Bhattacharya ◽  
Christy J. Cho ◽  
Roberto J. Brea ◽  
Neal K. Devaraj
Keyword(s):  
High Efficiency ◽  
De Novo ◽  
Fatty Acyl ◽  
Translation System ◽  
De Novo Synthesis ◽  
Dna Encoding ◽  
One Pot ◽  
Coa Ligase ◽  
A Cell ◽  
Membrane Bound

AbstractDespite the central importance of lipid membranes in cellular organization, it is challenging to reconstitute their de novo formation from minimal chemical and biological elements. Here we describe a chemoenzymatic route to membrane-forming non-canonical phospholipids in which cysteine-modified lysolipids undergo spontaneous coupling with fatty acyl-CoA thioesters generated enzymatically by a fatty acyl-CoA ligase. Due to the high efficiency of the reaction, we were able to optimize phospholipid membrane formation in a cell-free transcription-translation (TX-TL) system. Combining DNA encoding for the fatty acyl-CoA ligase with suitable lipid precursors, enabled spontaneous one-pot de novo synthesis of membrane-bound vesicles. Non-canonical sphingolipid synthesis was also possible by using a cysteine-modified lysosphingomyelin as a precursor. When the sphingomyelin-interacting protein lysenin is co-expressed alongside the acyl CoA ligase, the in situ assembled membranes were spontaneously modified with protein. Our strategy of coupling gene expression with membrane lipid synthesis in a one-pot fashion could facilitate the generation of proteoliposomes and brings us closer to the bottom-up generation of synthetic cells using recombinant synthetic biology platforms.

Developing Novel Anticancer Drugs for Targeted Populations: An Update

2020 ◽  
Vol 26 ◽  
Author(s):  
Tadesse Bekele Tafesse ◽  
Mohammed Hussen Bule ◽  
Fazlullah Khan ◽  
Mohammad Abdollahi ◽  
Mohsen Amini
Keyword(s):  
Drug Discovery ◽  
Drug Development ◽  
Anticancer Drugs ◽  
Anticancer Drug ◽  
Development Process ◽  
De Novo ◽  
Drug Repurposing ◽  
Drug Discovery And Development ◽  
Probability Of Success ◽  
Selection Of

Background: Due to higher failure rates, lengthy time and high cost of the traditional de novo drug discovery and development process; the rate of opportunity to get new, safe and efficacious drugs for the targeted population including pediatric patients with cancer becomes sluggish. Objectives: This paper discusses the development of novel anticancer drugs focusing on the identification and selection of target anticancer drug development for the targeted population. Methods: Information presented in this review was obtained from different databases including PUBMED, SCOPUS, Web of Science, and EMBASE. Various keywords were used as search terms. Results: The pharmaceutical companies currently are executing drug repurposing as an alternative means to accelerate the drug development process that reduces the risk of failure, time and cost, which takes 3-12 years with almost 25% overall probability of success as compared to de novo drug discovery and development process (10-17 years) which has less than 10% probability of success. An alternative strategy to the traditional de novo drug discovery and development process, called drug repurposing, is also presented. Conclusion: Therefore, to continue with the progress of developing novel anticancer drugs towards the targeted population, identification and selection of the target to the specific disease type is important considering the aspects of the age of the patient and the disease stages such as each cancer types are different when we consider the disease at a molecular level. Drug repurposing technique becomes an influential alternative strategy to discover and develop novel anticancer drug candidates.

A convenient synthetic route to sulfonimidamides from sulfonamides

RSC Advances ◽  
2015 ◽  
Vol 5 (6) ◽  
pp. 4171-4174 ◽  
Author(s):  
Yantao Chen ◽  
James Gibson
Keyword(s):  
Drug Discovery ◽  
Structural Modification ◽  
Synthetic Route ◽  
One Pot ◽  
Drug Discovery And Development ◽  
One Pot Synthesis ◽  
The Future

This one-pot synthesis of sulfonimidamides provides a new structural modification approach for sulfonamides, and might benefit drug discovery and development in the future.

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