ChemInform Abstract: The Interactivity of Complex Synthesis and Tumor Pharmacology in the Discovery Process: Total Synthesis and Comparative in vivo Evaluations of the 15-Aza Epothilones.

ChemInform ◽  
2010 ◽  
Vol 32 (40) ◽  
pp. no-no
Author(s):  
Shawn J. Stachel ◽  
Chul Bom Lee ◽  
Maria Spassova ◽  
Mark D. Chappell ◽  
William G. Bornmann ◽  
...  
Keyword(s):  
Total Synthesis ◽  
Discovery Process

On the Interactivity of Complex Synthesis and Tumor Pharmacology in the Drug Discovery Process:  Total Synthesis and Comparative in Vivo Evaluations of the 15-Aza Epothilones

2001 ◽  
Vol 66 (12) ◽  
pp. 4369-4378 ◽  
Author(s):  
Shawn J. Stachel ◽  
Chul Bom Lee ◽  
Maria Spassova ◽  
Mark D. Chappell ◽  
William G. Bornmann ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Total Synthesis ◽  
Discovery Process ◽  
Drug Discovery Process

scholarly journals Asymmetric and Regiospecific Synthesis of Isotopically Labelled Cyclopropane Fatty Acid (9R,10S)-Dihydrosterculic Acid: Overcoming Spontaneous Protonation During Lithium-Sulfoxide Exchange­

SynOpen ◽  
2018 ◽  
Vol 02 (02) ◽  
pp. 0168-0175
Author(s):  
Samuel Shields ◽  
Peter Buist ◽  
Jeffrey Manthorpe
Keyword(s):  
Fatty Acid ◽  
Total Synthesis ◽  
Cyclopropane Ring ◽  
Rapid Quenching ◽  
Cyclopropane Fatty Acid ◽  
Deuterium Incorporation ◽  
Biologically Relevant ◽  
Dihydrosterculic Acid

The total synthesis of isotopically labelled (9R,10S)-dihydro­sterculic acid, a usual cyclopropane fatty acid with biologically relevant toxicity upon desaturation in vivo, is reported. A diastereoselective Corey­–Chaykovsky reaction was employed to form the cyclopropane ring. Rapid quenching of a lithium-sulfoxide exchange was required to achieve the requisite high levels of deuterium incorporation.

scholarly journals Total synthesis of [ 15 N]-labelled C6-substituted purines from [ 15 N]-formamide—easy preparation of isotopically labelled cytokinins and derivatives

2018 ◽  
Vol 5 (11) ◽  
pp. 181322 ◽  
Author(s):  
Jan Buček ◽  
Marek Zatloukal ◽  
Libor Havlíček ◽  
Lucie Plíhalová ◽  
Tomáš Pospíšil ◽  
...  
Keyword(s):  
Total Synthesis ◽  
Metabolic Profiling ◽  
Growth Regulation ◽  
Plant Tissues ◽  
Chemical Analyses ◽  
Purine Derivatives ◽  
Biological Matrices ◽  
Physico Chemical ◽  
Plant Growth Regulation

Cytokinins (CKs) and their metabolites and derivatives are essential for cell division, plant growth regulation and development. They are typically found at minute concentrations in plant tissues containing very complicated biological matrices. Therefore, defined standards labelled with stable isotopes are required for precise metabolic profiling and quantification of CKs, as well as in vivo elucidation of CK biosynthesis in various plant species. In this work, 11 [ 15 N]-labelled C6-purine derivatives were prepared, among them 5 aromatic ( 4, 5, 6, 7, 8 ) and 3 isoprenoid ( 9, 10, 11 ) CKs. Compared to current methods, optimized syntheses of 6-amino-9H-[ 15 N 5 ]-purine (adenine) and 6-chloro-9H-[ 15 N 4 ]-purine (6-chloropurine) were performed to achieve more effective, selective and generally easier approaches. The chemical identity and purity of prepared compounds were confirmed by physico-chemical analyses (TLC; HRMS; HPLC–MS; 1 H, 13 C, 15 N NMR). The presented approach is applicable for the synthesis of any other desired [ 15 N 4 ]-labelled C6-substituted purine derivatives.

Total Synthesis of DHA and DPAn-3 non-enzymatic oxylipins

Synthesis ◽  
2021 ◽  
Author(s):  
alexandre guy ◽  
Jérémy Merad ◽  
Thomas Degrange ◽  
Guillaume Reversat ◽  
Valérie Bultel-Poncé ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fatty Acids ◽  
Docosahexaenoic Acid ◽  
Polyunsaturated Fatty Acids ◽  
Total Synthesis ◽  
Biological Properties ◽  
Chemical Structures ◽  
Structural Variety ◽  
Synthetic Strategy

Oxylipins are formed in-vivo from polyunsaturated fatty acids (PUFAs). A large structural variety of compounds is grouped under the term oxylipins, which differ from their formation mechanism (involving enzymes or not), as well as their chemical structures (cyclopentanes, tetrahydrofurans, hydroxylated-PUFA etc.). All structures of oxylipins are of great biological interests. Directly correlated to oxidative stress phenomenon, non-enzymatic oxylipins are used as systemic and/or specific biomarkers in various pathologies and more especially, they were found to have their own biological properties. Produced in-vivo as a non-separable mixture of isomers, total synthesis is a keystone to answer biological questions. In this work, we described the total synthesis of three non-enzymatic oxylipins derived from docosahexaenoic acid (DHA) and docosapentanoic acid (DPAn-3) using a unique and convergent synthetic strategy.

scholarly journals Translational Roadmap for the Organs-on-a-Chip Industry toward Broad Adoption

2020 ◽  
Vol 7 (3) ◽  
pp. 112 ◽  
Author(s):  
Vanessa Allwardt ◽  
Alexander J. Ainscough ◽  
Priyalakshmi Viswanathan ◽  
Stacy D. Sherrod ◽  
John A. McLean ◽  
...  
Keyword(s):  
Technology Development ◽  
Technology Readiness ◽  
Disruptive Technology ◽  
Discovery Process ◽  
Drug Discovery Process ◽  
Commercial Viability ◽  
Performance Benchmarks ◽  
Using Data ◽  
Further Development

Organs-on-a-Chip (OOAC) is a disruptive technology with widely recognized potential to change the efficiency, effectiveness, and costs of the drug discovery process; to advance insights into human biology; to enable clinical research where human trials are not feasible. However, further development is needed for the successful adoption and acceptance of this technology. Areas for improvement include technological maturity, more robust validation of translational and predictive in vivo-like biology, and requirements of tighter quality standards for commercial viability. In this review, we reported on the consensus around existing challenges and necessary performance benchmarks that are required toward the broader adoption of OOACs in the next five years, and we defined a potential roadmap for future translational development of OOAC technology. We provided a clear snapshot of the current developmental stage of OOAC commercialization, including existing platforms, ancillary technologies, and tools required for the use of OOAC devices, and analyze their technology readiness levels. Using data gathered from OOAC developers and end-users, we identified prevalent challenges faced by the community, strategic trends and requirements driving OOAC technology development, and existing technological bottlenecks that could be outsourced or leveraged by active collaborations with academia.

Total Synthesis as a Resource in Drug Discovery: The First in vivo Evaluation of Panaxytriol (I) and Its Derivatives.

ChemInform ◽  
2006 ◽  
Vol 37 (19) ◽  
Author(s):  
Heedong Yun ◽  
Ting-Chao Chou ◽  
Huajin Dong ◽  
Yuan Tian ◽  
Yue-ming Li ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Total Synthesis ◽  
In Vivo Evaluation

scholarly journals Ramalin, a Novel Phenyl Hydrazide from the Lichen Ramalina Terebrata; Isolation, Total Synthesis and Biological Activities

2016 ◽  
Vol 30 (2) ◽  
pp. 35-42
Author(s):  
Durga Prasad Pandey ◽  
Hari Datta Bhattarai
Keyword(s):  
Total Synthesis ◽  
Antioxidant Activities ◽  
Biological Activities ◽  
Cost Effective ◽  
Scale Production ◽  
In Vivo Test ◽  
The Antarctic ◽  
Industrial Scale Production

Ramalin, a new L-glutamic acid derivative of phenylhydrazide (Y-glutamyl-N'-(2-hydroxyphenyl) hydrazide, 1) was isolated from the Antarctic lichen, Ramalina terebrata after a series of bioactivity guided fractionation of crude aqueous methanolic extract. Ramalin showed stronger antioxidant activities than commercially available standards, ascorbic acid, trolox, BHA, kojic acid in both, in vitro and in vivo test systems. In addition, ramalin showed no/less toxicity effects against two human cell lines; fibroblast (CCD-986SK) cells and keratinocyte (HaCaT). Thus, realign merits for cosmetic application and industrial scale production were needed. We developed a cost effective total synthesis of ramalin with 71.5% yield and described here.

scholarly journals Radiosynthesis of [18F]-Labelled Pro-Nucleotides (ProTides)

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 704
Author(s):  
Alessandra Cavaliere ◽  
Katrin C. Probst ◽  
Stephen J. Paisey ◽  
Christopher Marshall ◽  
Abdul K. H. Dheere ◽  
...  
Keyword(s):  
Total Synthesis ◽  
Pet Imaging ◽  
Early Stage ◽  
Proof Of Concept ◽  
Synthesis Time ◽  
Positron Emission ◽  
Anti Cancer ◽  
Radiochemical Yields ◽  
Radiochemical Synthesis

Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside therapies and achieving clinical and commercial success. Despite the translation of ProTide technology into the clinic, there remain unresolved in vivo pharmacokinetic and pharmacodynamic questions. Positron Emission Tomography (PET) imaging using [18F]-labelled model ProTides could directly address key mechanistic questions and predict response to ProTide therapy. Here we report the first radiochemical synthesis of [18F]ProTides as novel probes for PET imaging. As a proof of concept, two chemically distinct radiolabelled ProTides have been synthesized as models of 3′- and 2′-fluorinated ProTides following different radiosynthetic approaches. The 3′-[18F]FLT ProTide was obtained via a late stage [18F]fluorination in radiochemical yields (RCY) of 15–30% (n = 5, decay-corrected from end of bombardment (EoB)), with high radiochemical purities (97%) and molar activities of 56 GBq/μmol (total synthesis time of 130 min.). The 2′-[18F]FIAU ProTide was obtained via an early stage [18F]fluorination approach with an RCY of 1–5% (n = 7, decay-corrected from EoB), with high radiochemical purities (98%) and molar activities of 53 GBq/μmol (total synthesis time of 240 min).

scholarly journals An overview of kinase downregulators and recent advances in discovery approaches

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Beilei Wang ◽  
Hong Wu ◽  
Chen Hu ◽  
Haizhen Wang ◽  
Jing Liu ◽  
...  
Keyword(s):  
Drug Evaluation ◽  
Discovery Process ◽  
Design Strategies ◽  
High Failure Rate ◽  
Efficacy Evaluation ◽  
Property Evaluation ◽  
Evaluation Models ◽  
Made In

AbstractSince the clinical approval of imatinib, the discovery of protein kinase downregulators entered a prosperous age. However, challenges still exist in the discovery of kinase downregulator drugs, such as the high failure rate during development, side effects, and drug-resistance problems. With the progress made through multidisciplinary efforts, an increasing number of new approaches have been applied to solve the above problems during the discovery process of kinase downregulators. In terms of in vitro and in vivo drug evaluation, progress was also made in cellular and animal model platforms for better and more clinically relevant drug assessment. Here, we review the advances in drug design strategies, drug property evaluation technologies, and efficacy evaluation models and technologies. Finally, we discuss the challenges and perspectives in the development of kinase downregulator drugs.

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