Cytostatics, alkylating

R. Sohr, G. Schmeck, R. Preiss and M. Matthias, Methodology of the colorimetric determination of alkylating cytostatics with 4-(4 -nitrobenzyl)pyridine (NBP) in plasma. Pharmazie, 1982, 37(11), 777-779. 

See also Individual agents and Alkylating cytostatic agents... 

International Agency for Research on Cancer, Carcinogenicity of Alkylating Cytostatic Drugs Schmahl, D. Kaldor, J.M., Eds. lARC Scientific Publications No. 78, International Agency for Research on Cancer, Lyon, 1986. 

German investigators (Brock et al) worked on the creation of alkylating pro-drugs that have cytostatic activity after specific biotransformation in the tumor tissue. Cyclophosphamide (CTX) has well pronounced antitumor activity with the broadest spectrum. It is metabolized to the cytotoxic phosphoamide mustard. In normal tissues with high enzyme level cyclophosphamide is converted to its inactive metabolites (Fig. 2). These differences in biotransformation can explain the relative selectivity of cyclophosphamide towards... 

Acquired resistance to alkylating agents is a common event. Such resistance against the cytostatic activity can occur through at least three mechanisms. Increased thiol production can inactivate the agents. Also a decreased cell permeability to the drug can play a role. Increased capacity for DNA repair can mitigate cytotoxic activity. 

Kargin and his co-workers (98) have prepared polymeric derivatives of the cytostatic agent sarcolysin by alkylation of poly(vinylpyridine). Simultaneous alkylation with cetyl bromide yields copolymers with the following structure of chain [JO]. 

Brock N, Pohl J, Stekar J. 1981. Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention -1. Experimental studies on the urotoxicity of alkylating compounds. Eur J Cancer 17 595-607. 

Marschalk alkylation (8, 456). The intramolecular Marschalk alkylation is useful in syntheses of the tetracyclic ring system of the cytostatic anthracycline antibiotics. A bimolecular version of the reaction involves condensation of 1 with glyoxylic acid and alcoholic KOH. The product of this reaction is reduced and esterified to afford 2 in 33% overall yield. Less than 5% of the isomeric product 3 is obtained. 9-Deoxy-e-rhodomycinone 4 is available from 2 in two steps (details not provided). ... 

In two additional studies alkylated nucleosides have been investigated, and N-glycosyl(halomethyl)-1,2,3-triazoles (429) and AT-ribosyihalomethyl-1,2,3-triazole (430) have been detected as a new type of alkylating agent showing cytostatic activity (79JMC496). 

It opened an efficient approach to a series of mono n-alkyl esters of o-phos-phonomethylcholine (395) as potential membrane modifying cytostatics. ... 

The nitrosourea cytostatic drugs are alkylating agents that include carmustine, lomustine, nimustine, and streptozocin (all rINNs). 

Fuchs has used this reaction type for the construction of an 11-membered ring in the course of model studies for the [ll]cytochalasin synthesis. These cytostatic compounds, e.g. cytochalasin C (109), are metabolites of microorganisms. Reductive fragmentation of the benzenesulfonates (110 Scheme 37) produces the dienols (111). In contrast, both the sulfonates (112) on treatment with LDA afford the tricyclic ketones (113), the products of internal alkylation. Less than 1% of (111) is formed. In conclusion, the author points out that the enolate conformation (Scheme 37, in parentheses) appears to be all important in determining the reaction products of the four diastereoisomers (110) and (112). Whenever the enolate can easily assume a folded conformation, the tricyclic cyclobutane (113) will result. Models of the enolates of (110), where the intraannular fragmentation successfully occurs, show that the folded conformations are more strained than are the extended conformations. 

Many other polymers with antineoplastic properties have been prepared. For the most part, these polymers contain a known antineoplastic compound attached to the polymer chain as a pendant group. The earliest examples of this type seem to be the aziridine alkylating group containing polymers (XIX) (52), and (XX) (53), and (XXI) (54) which contains the cytostatic agent sarcolysin. 

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