Effective isomerization of 3', 5'-O-(tetraisopropyldisiloxane-1,3-diyl)nucleosides in the presence of trimethylsilyl trifluoromethanesulfonate

Kulikova, Irina V.; Muradova, Daria A.; Mikhailov, Sergey N.

doi:10.3998/ark.5550190.0010.313

Cited by 1 publication

(1 citation statement)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In order to develop a more convergent approach, we wished to first prepare the TIDPS protected adenosine 26. Direct protection of adenosine (27) with TIDPSCl2 gave the 3',5'-protected adenosine derivative, as expected: unfortunately, attempted isomerisation to the required 2',3'-protected adenosine 26, using previously reported conditions 54,55 was unsuccessful. We therefore elected to carry out initial protection of the 5' position with the dimethoxytrityl (DMTr) protecting group, utilising the conditions developed by Matulic-Adamic et al 56 to afford 28.…”

Section: Thr217supporting

confidence: 69%

Design and synthesis of Coenzyme A analogues as Aurora kinase A inhibitors: An exploration of the roles of the pyrophosphate and pantetheine moieties

Bellany¹,

Tsuchiya

Tran³

et al. 2020

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

The Aurora kinases are a family of highly homologous serine/threonine kinases, 1,2,3 which have welldocumented roles in the control of meiosis, mitosis and cell division. 4 There are three distinct subfamilies, Aurora A, Aurora B and Aurora C, which vary in their function and subcellular location.Since the first observation of the overexpression of Aurora kinases in cancer cell lines by Bischoff et al., 5 they have been regarded as promising drug targets for cancer chemotherapy. Aurora A overexpression is frequently detected in leukemia, breast, prostate and colon cancers, 2,5,6 with a lower overall survival rate seen in colorectal cancer patients with increased Aurora A levels. 7 This has seen a number of Aurora kinase inhibitors progressing through different stages of clinical trials. 3,8,9,10,11 The Aurora kinases are highly homologous, with a highly conserved C-terminal catalytic domain, a short N-terminal domain which varies in size, and an activation loop (Asp274-Glu299) which is conserved between the three family members. 3 The kinase activity of Aurora A is dependent on autophosphorylation of Thr288 (and possibly Thr287), found in the activation loop. In addition, binding of Aurora A to microtubule-associated proteins, in particular TPX2, alters the structure of Aurora A by stabilisation of the activation loop, allowing ATP to bind and driving the kinase into the optimal conformation for catalysis. 1,3,12 Inhibition of Aurora A results in inhibition of this phosphorylation, giving delayed entry into mitosis and the failure of the centrosomes to assemble bipolar spindles, resulting in aneuploidy and mitotic arrest. 13 Different conformational states of Aurora A can be induced or stabilised by different small molecule inhibitors, 14,15,16,17 and in particular the conformation of the activation loop modulates the interaction of Aurora A with its binding partners. 18 Coenzyme A (CoA) is an essential and ubiquitous cofactor made from vitamin B5 (pantothenate), ATP, and cysteine. CoA and its thioester derivatives (Acetyl CoA, Malonyl CoA, HMG CoA among others) are involved in diverse anabolic and catabolic pathways, biosynthesis of neurotransmitters and the regulation of gene expression. 19,20 Dysregulation of CoA biosynthesis or CoA thioester homoeostasis is associated with various human pathologies, including neurodegeneration, cancer and metabolic disorders. [21][22][23][24] Recent studies have uncovered a novel function of CoA in redox regulation, involving covalent modification of cellular proteins by disulphide bond formation, termed CoAlation, in cellular response to oxidative and metabolic stress. 25,26 Protein CoAlation is a widespread and reversible posttranslational modification, which occurs in single-cell and multicellular organisms, and modulates catalytic activity, regulatory interactions, subcellular localization and the stability of modified proteins. [27][28][29][30] Recently, we have reported that CoA is a specific ATP-competitive Aurora A inhibitor in vitro. 31 Using a combination of bioc...

show abstract