Alkylating potential of oxetanes.
Small, highly strained heterocycles are archetypical alkylating agents (oxiranes, beta-lactones, aziridinium, and thiirinium ions). Oxetanes, which are tetragonal ethers, are higher homologues of oxiranes and reduced counterparts of beta-lactones, and would therefore be expected to be active alkylating agents. Oxetanes are widely used in the manufacture of polymers, especially in organic light-emitting diodes (OLEDs), and are present, as a substructure, in compounds such as the widely used antimitotic taxol. Whereas the results of animal tests suggest that trimethylene oxide (TMO), the parent compound, and beta,beta-dimethyloxetane (DMOX) are active carcinogens at the site of injection, no studies have explored the alkylating ability and genotoxicity of oxetanes. This work addresses the issue using a mixed methodology: a kinetic study of the alkylation reaction of 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilicity similar to that of DNA bases, by three oxetanes (TMO, DMOX, and methyloxetanemethanol), and a mutagenicity, genotoxicity, and cell viability study (Salmonella microsome test, BTC E. coli test, alkaline comet assay, and MTT assay). The results suggest either that oxetanes lack genotoxic capacity or that their mode of action is very different from that of epoxides and beta-lactones.
Gómez-Bombarelli
Rafael
R
Departamento de Quimica Fisica, Universidad de Salamanca, Plaza de los Caidos, Salamanca, Spain.
Palma
Bernardo Brito
BB
Martins
Célia
C
Kranendonk
Michel
M
Rodrigues
Antonio S
AS
Calle
Emilio
E
Rueff
José
J
Casado
Julio
J
D000477:Alkylating Agents / Q000737:chemistry* / Q000633:toxicity; D000478:Alkylation; D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity; D020552:Comet Assay; D004988:Ethers, Cyclic / Q000737:chemistry* / Q000633:toxicity; D005027:Ethylene Oxide / Q000737:chemistry; D007700:Kinetics; D007783:Lactones / Q000737:chemistry
D000477:Alkylating Agents; D002273:Carcinogens; D004988:Ethers, Cyclic; D007783:Lactones; C005287:oxetane; D005027:Ethylene Oxide