Answer to Question #150650 in Organic Chemistry for marria

Question

what is the mechanism of action of nitrosoureas and the type of cross-linking.

thank you.

Answer 1

The molecular mechanisms by which CNUs $(2- chloroethyl-N-nitrosoureas)$ exert their antitumour and toxic effects are rather complex. They are

monofunctional as well as bifunctional alkylating agents,

DNA alkylation and cross-linking being considered an

important factor in their activity. Pathways of CNU-decomposition to highly reactive alkylating and carbamoylating species have been proposed by several groups. Chloroethyldiazohydroxide and

hydroxyethyldiazohydroxide or the equivalent bifunctional electrophiles and chloroethylisocyanate are considered the main ultimate reactive agents. The monofunctional alkylating intermediate hydroxyethyldiazohydroxide alkylates RNA and DNA, forming mono-adducts, whereas the bifunctional alkylating intermediate chloroethyldiazohydroxide alkylates RNA and DNA, forming monoadducts and DNA-DNA interstrand or DNA-protein cross-links.

According to Buckley, formation of a gem-diol or diolate tetrahedral intermediate, as first proposed by Snyder & Stock and by Lown & Chauhan, appears the most probable pathway, since the collapse of this intermediateaccounts for all products derived from CNUs.

CNUs are known to produce DNA-DNA cross-links

and good correlations have been observed between killing

of various cell lines and the production of interstrand

cross-links. Interstrand cross-link formation by

CNUs is a two-step process involving rapid alkylation through the ultimate electrophile, 2-chloroethyldiazohydroxide or the like, followed by a much slower second

alkylation through nucleophilic displacement of the chlorine at the beta carbon by an appropriate site of a DNA base.

Hydroxyethylation represents by far the greatest proportion of DNA alkylation in vitro.