Nitrosoureas structure

GCNU (3-(TETRAACETAR GLUCOPYRANNUA-2-YL)-l-(2-CHLOROETHYL)-l-NITROSOUREA) This is an aminoglycose chloroethyl nitrosourea, structurally related to the non-myelosuppressive but diabetogenic antitumour agent streptozotocin. Preliminary animal studies are reported (75). 

Alkylating Agents. Figure 3 Chemical structure of some nitrosoureas. 

Glutathione reductase (GR) catalyzes the reduction of oxidized glutathione (GSSG) to reduced glutathione (GSH) using NADPH provided from the hexose monophosphate pathway. GR, a ubiquitous flavoenzyme, maintains a high value of two for the GSH/GSSG ratio in the red blood cells. l,3-Bis(2-chloroethyl)-nitrosourea (BCNU) selectively inhibits cellular GR. GR is composed of two identical subunits, each of molecular mass 50 kDa (S8). The three-dimensional structure and mechanism of catalysis have been established for human GR (K17). 

A comparison of structures of V-methyl-V-nitroso-p-nitrobenzamide, N,N -dimethyl-V-nitrosourea, V-methyl-V-nitrosourea, 2-nitroso-2-azabicyclo[2.2.2]octan-3-one to those of V-methyl-V -nitro-V-nitrosoguanidine and V,V -dimethyl-V"-cyano-V-nitrosoguanidine shows that the N—N and C—NNO bond lengths in the nitroguanidines44 are similar to those found in the nitrosoamides, but that the corresponding bonds in... 

Despite knowing the structures of all of the DNA lesions, it remains to be determined if any one lesion is more or less toxic to the cells. As discussed above, it was originally thought that DNA interstrand cross-links were the critical lesion. Once it was realized that these lesions are very rare, opinions shifted to suggest that DNA intrastrand cross-links are more cytotoxic. Unfortunately, there is no specific data that implicates either type of lesion in cytotoxicity. For some drugs like nitrosoureas, DNA repair pathways that remove only selected lesions (i.e., 0(6)-methylguanine DNA methyltransferase) have helped to define the role of a particular lesion [24], No separate pathway has been found for repair of a specific cisplatin adduct, so this approach has not been informative. A number of experiments have been performed in which specific adducts on defined DNA sequence, have been transfected into cells. This approach has shown that an adduct inhibits replication or transcription, but this does not directly address the question of mechanism of cytotoxicity. 

Removal of analogs from the training set was first performed on the highly active A s by Ken Pauli, then with Starks C. P., the acquisitions contractor. He presented Table IV, which classifies analogs among the 846 A s with defined structure. Familiar alkylating agents, which include mustards, methanesulfonates, epoxides, aziridines and nitrosoureas, make up 52% of the 846. Other, more specialized classes reduced the A s further until they were cut by 87%. 

Lomustine is a nitrosourea. Its mechanism of action involves the inhibition of both DNA and RNA synthesis through DNA alkylation. Lomustine has been shown to affect a number of cellular processes including RNA, protein synthesis, and the processing of ribosomal and nucleoplasmic messenger RNA DNA base component structure and the rate of DNA synthesis and DNA polymerase activity. It is cell-cycle nonspecific. It is indicated in the treatment of brain tumors and Hodgkin s disease in adults and children. 

Streptozotocin, a broad spectrum antibiotic with anitumour activity produced by Streptomyces achromogenes [163], has been shown to be the A -methyl-A -nitrosourea derivative of glucosamine (XLa) by chemical degradation and spectroscopic studies [164], Two syntheses have confirmed the structure, one of which is suitable for the commercial preparation of the drug [165]. Treatment of glucosamine with 7V-methylisocyanate has afforded the A -methylurea derivative (XLb), which gave streptozotocin on treatment with nitrogen trioxide. 

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