53064-79-2Relevant articles and documents
Cellular delivery of nucleoside diphosphates: A prodrug approach
Kang, Shin Hong,Sinhababu, Achintya K.,Cory, Joseph G.,Mitchell, Beverly S.,Thakker, Dhiren R.,Cho, Moo J.
, p. 706 - 712 (1997)
Purpose. This study is concerned with cellular delivery/generation of 2'-azido-2'-deoxyuridine and -deoxycytidine diphosphate (N3UDP or N3CDP), potent inhibitors of ribonucleotide reductase. It characterizes the phosphorylation steps involved in the conversion of 2'-azido-2'-deoxyuridine (N3Urd) and 2'-azido-2'-deoxycytidine (N3Cyd) to the corresponding diphosphates and explores a prodrug approach in cellular delivery of the inhibitor which circumvents the requirement of deoxynucleoside kinases. Methods. Cell growth of CHO and 3T6 cells of known deoxycytidine kinase level was determined in the presence of N3Urd and N3Cyd. Activity of ribonucleotide reductase was determined in the presence of the azidonucleosides as well as their mono- or di-phosphates in a Tween 80-containing permeabilizing buffer. A prodrug of 5'-monophosphate of N3Urd was prepared and its biological activity was evaluated with CHO cells as well as with cells transfected with deoxycytidine kinase. Results. N3Urd failed to inhibit the growth of both cell lines, while N3Cyd was active against 3T6 cells and moderately active against CHO cells. These results correlate with the deoxycytidine kinase levels found in the cells. Importance of the kinase was further established with the finding that the nucleoside analogs were inactive as reductase inhibitors in a permeabilized cell assay system while their mono- and di-phosphates were equally active. The prodrug was active in cell growth inhibition regardless of the deoxycytidine kinase level. Conclusions. The azidonucleosides become potent inhibitors of the reductase by two sequential phosphorylation steps. The present study indicates that the first step to monophosphate is rate-limiting, justifying a prodrug approach with the monophosphate.
Esterase-Activatable Synthetic M+/Cl? Channel Induces Apoptosis and Disrupts Autophagy in Cancer Cells
Malla, Javid Ahmad,Sharma, Virender Kumar,Lahiri, Mayurika,Talukdar, Pinaki
supporting information, p. 11946 - 11949 (2020/08/27)
The formation of a supramolecular synthetic M+/Cl? channel in the membrane phospholipid bilayer has been reported upon activation of a methyl pivalate-linked N1,N3-dialkyl-2-hydroxyisophthalamide by esterases. The channel formation induces apoptosis in cancer cells via the intrinsic pathway. Interestingly, the supramolecular channel was also shown to disrupt autophagy in cancer cells by causing alkalization of lysosomes – a feature that has been confirmed at the cellular and protein level.
An improved synthesis of adefovir and related analogues
Jones, David J.,O’Leary, Eileen M.,O’Sullivan, Timothy P.
supporting information, p. 801 - 810 (2019/04/17)
An improved synthesis of the antiviral drug adefovir is presented. Problems associated with current routes to adefovir include capricious yields and a reliance on problematic reagents and solvents, such as magnesium tert-butoxide and DMF, to achieve high conversions to the target. A systematic study within our laboratory led to the identification of an iodide reagent which affords higher yields than previous approaches and allows for reactions to be conducted up to 10 g in scale under milder conditions. The use of a novel tetrabutylammonium salt of adenine facilitates alkylations in solvents other than DMF. Additionally, we have investigated how regioselectivity is affected by the substitution pattern of the nucleobase. Finally, this chemistry was successfully applied to the synthesis of several new adefovir analogues, highlighting the versatility of our approach.
Preparation method of iodomethyl pivalate
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Paragraph 0011; 0012, (2017/02/24)
The invention discloses a preparation method of iodomethyl pivalate as an important medicine intermediate. The preparation method is characterized in that iodomethyl pivalate as a raw material and sodium iodide undergo a replacement reaction in ethyl acetate as a solvent under the condition of reaction backflow time of 6h. Compared with other synthesis methods, the preparation method of iodomethyl pivalate has a high mole yield. The iodomethyl pivalate obtained by the preparation method has product purity (GC) of 98% and thus the product has advantages in cost and purity.
