[Diastereomers of nonionic analogs of nucleic acids. V. Alkylation of nucleic acids in the living cells by ethylated derivatives of oligonucleotides containing the residue of nitrous yperite. The effect of the phosphotriester fragment configuration].
The alkylation of the cell biopolymers (RNA, DNA, proteins) by reagents Tp'(Et)Tp'(Et)Tp'(Et)TpU(CHRCl) (1) Tp'(Et)Tp''(Et)Tp'(Et)TpU(CHRCl) (2) Tp''(Et)Tp'(Et)Tp''(Et)TpU(CHRCl) (3) Tp''(Et)Tp''(Et)Tp''(Et)TpU(CHRCl) (4) Tp(Et)Tp(Et)Tp(Et)TpU(CHRCl) (5) Tp(Et)Tp(Et)Tp(Et)Tp(Et)U(CHRCl) (6) TpTpTpTpU(CHRCl) (7) where (CHRCl) is the residue of 2',3'-O-[4-N-(2-chloroethyl)-N-methylamino]-benzylidene has been investigated in the case of the ascite carcinoma Krebs-2. p' and p" designate the enantiomeric configurations at the internucleotide phosphorus atoms of the triester fragment--Tp(Et)T--, and p designates the racemic mixture. Completely and partly ethylated reagents (1)-(6) have been found to bind to the cells 4-15 fold more effectively than the diester derivative. The concentration of reagents (1)-(6) in the cells is 2-7 fold higher than in the external medium. Among the diastereomers (1)-(4) reagent (4) with the p"-configuration is the most efficient in binding with the cells 2-3 fold more efficient than reagents (1)-(3). The main targents of modifications performed in the cells by means of reagents (1)-(7) have been established. These are RNA, DNA and proteins. The share of the reagents which react with nucleic acids increases from 45% [reagent (1)] to 80% [reagent (4)], and that reacting with proteins decreases from 50 to 20% correspondingly. Reagent (4) with the p" configurations at phosphotriester fragments alkylates nucleic acids most effectively among the phosphotriester diastereomers (1)-(4): 11-fold more efficient than reagent (1) with configuration p'. The extent of modification of poly(A)+-tracts of m-RNA by reagent (4) in comparison with reagent (1) is 50-fold higher.
Abramova
T V
TV
Lebedev
A V
AV
Raĭt
A S
AS
D000478:Alkylation; D000818:Animals; D002287:Carcinoma, Krebs 2 / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D009150:Mustard Compounds / Q000633:toxicity*; D009151:Mustard Gas / Q000633:toxicity*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009841:Oligonucleotides / Q000633:toxicity*; D010755:Organophosphates / Q000633:toxicity*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D012334:RNA, Neoplasm / Q000187:drug effects / Q000378:metabolism*; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D004273:DNA, Neoplasm; D009150:Mustard Compounds; D009363:Neoplasm Proteins; D009841:Oligonucleotides; D010755:Organophosphates; D009943:Organophosphorus Compounds; D012334:RNA, Neoplasm; D009151:Mustard Gas
Issledovnie diasteromerov neionnykh analogov oligonukleotidov. V. Alkilirovanie nukleinovykh kislot v zhivykh kletkakh étilirovannymi proizvodnymi oligonukleotidov, soderzhashchikh ostatok azotistogo iprita. Vliianie konfiguratsii fosfotriéfirnogo fragmenta.