1072-09-9Relevant articles and documents
Peptide dimethylation: Fragmentation control via distancing the dimethylamino group
McShane, Adam J.,Shen, Yuanyuan,Castillo, Mary Joan,Yao, Xudong
, p. 1694 - 1704 (2014)
Direct reductive methylation of peptides is a common method for quantitative proteomics. It is an active derivatization technique; with participation of the dimethylamino group, the derivatized peptides preferentially release intense a1 ions. The advantageous generation of a1 ions for quantitative proteomic profiling, however, is not desirable for targeted proteomic quantitation using multiple reaction monitoring mass spectrometry; this mass spectrometric method prefers the derivatizing group to stay with the intact peptide ions and multiple fragments as passive mass tags. This work investigated collisional fragmentation of peptides whose amine groups were derivatized with five linear ω-dimethylamino acids, from 2-(dimethylamino)-acetic acid to 6-(dimethylamino)-hexanoic acid. Tandem mass spectra of the derivatized tryptic peptides revealed different preferential breakdown pathways. Together with energy resolved mass spectrometry, it was found that shutting down the active participation of the terminal dimethylamino group in fragmentation of derivatized peptides is possible. However, it took a separation of five methylene groups between the terminal dimethylamino group and the amide formed upon peptide derivatization. For the first time, the gas-phase fragmentation of peptides derivatized with linear ω-dimethylamino acids of systematically increasing alkyl chain lengths is reported.
Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo
Jayaraman, Muthusamy,Ansell, Steven M.,Mui, Barbara L.,Tam, Ying K.,Chen, Jianxin,Du, Xinyao,Butler, David,Eltepu, Laxman,Matsuda, Shigeo,Narayanannair, Jayaprakash K.,Rajeev, Kallanthottathil G.,Hafez, Ismail M.,Akinc, Akin,Maier, Martin A.,Tracy, Mark A.,Cullis, Pieter R.,Madden, Thomas D.,Manoharan, Muthiah,Hope, Michael J.
supporting information; experimental part, p. 8529 - 8533 (2012/10/18)
Special (lipid) delivery: The role of the ionizable lipid pKa in the in?vivo delivery of siRNA by lipid nanoparticles has been studied with a large number of head group modifications to the lipids. A tight correlation between the lipid pKa?value and silencing of the mouse FVII gene (FVII ED50) was found, with an optimal pKa range of 6.2-6.5 (see graph). The most potent cationic lipid from this study has ED50 levels around 0.005?mg?kg?1 in mice and less than 0.03?mg?kg?1 in non-human primates.
Esters and amides of hexanoic acid substituted with tertiary amino group in terminal position and their activity as transdermal permeation enhancers
Farsa, Oldrich,Dolezal, Pavel,Hrabalek, Alexandr
scheme or table, p. 595 - 603 (2010/08/22)
Series of alkyl esters of 6-(diethylamino)-, 6-(pyrrolidin-1-yl)-, 6-(piperidin-1-yl) and 6-(m orpholin-4-yl)hexanoic acids and alky lamides of 6-(dimethylamino)-, 6-(piperidin-1-y l) and 6-(morpholin-4-yl)hexanoic acids, co n-taining 8-12 c arbon ato ms in the alky l chai n, were prepared by m ethods of classical organi c sy nthesis. The appr opriate secondary a mine wa s alky lated with ethyl 6-bromohexanoate to give ester of ω-substituted hexanoic acid, except of ethy l 6-(di methylamino)hexanoate (1), which wa s pr epared by Esch-weiler-Clarke methylation of 6-a minohexanoic acid followe d by direct est erification with ethanol. The resulted esters of ω-substituted hexanoi c aci ds underwent dire ct transest erification with long chain alka nols to y ield the desired amino esters, or they were treated with long-chain alkylamines to prepare secondary a mides of the appropriate heterocy clic hexa noic a cids. These products were in vitro tested on their activity as transdermal permeation enhancers on the strip s of the excised hu man skin with theophylline as the model permeant. The activity was evaluated u sing para meter enh ancement ratio (ER), defined as the ratio between the overall am ount of the per meant pa ssing through the skin with the t ested enha ncer an d that witho ut tested substance. Decyl 6-(pyrrolidin-1-yl)hexanoate (9) with ER = 30 showed the high est activity. The enhancing effect s of the esters were generally better than those of the amides.
