Alkylating Potential of Oxetanes

Abstract

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.

Chemoassay Screening of DNA-Reactive Mutagenicity with 4-(4-Nitrobenzyl)pyridine – Application to Epoxides, Oxetanes, and Sulfur Heterocycles

“…Note further that according to a recent investigation, oxetanes do not react with NBP at neutral pH, which is in agreement with our present findings.…”

“…Twelve oxiranes (A1–A4, A6, A7, B3–B7, and C1) and the three oxetanes (C2–C4) of the present compound set had been tested earlier with respect to their mutagenic potential in bacteria ,− and in Chinese hamster V79 cells . Accordingly, to check the applicability of the NBP chemoassay to screen chemicals for their mutagenic potential, the results of common mutagenicity screening assays are compared with our presently determined log k NBP values in Figures and ; the respective mutagenicity data are provided in the Supporting Information (Table S2).…”

Site‐Selective Modification of Proteins with Oxetanes

“…These included oxophilic metallic complexes (Y(OTf) 3 and MgCl 2 ⋅6 H 2 O) and organocatalytic promoters (urea and thiourea) (Supporting Information, Figures S6–S21). The inertness of the oxetane ring towards nucleophiles is in line with previous studies that described their lack of geno/cytotoxicity and mutagenicity, unlike that of epoxides and β‐lactones, because they do not act as alkylating agents at physiological pH . Likewise, other proteins such as AnxV reacted similarly at pH 11 with 10 % DMF and expected product 3 was obtained in >95 % conversion, thus demonstrating the robustness of this alkylation protocol to modify this widely used apoptotic protein marker (Figure b).…”

A Bifunctional Dimethylsulfoxide Substitute Enhances the Aqueous Solubility of Small Organic Molecules

“…28,29 However, a recent report studying the alkylating ability of oxetane, 3,3-dimethyloxetane, and 3-methyl-3-oxetanemethanol (1) demonstrated that these oxetanes are neither mutagenic nor genotoxic. 30 Furthermore, alkylation of 4-( pnitrobenzyl)pyridine was only observed at acidic pH, implicating that oxetanes do not act as alkylating agents at physiological pH. 30 To assess the systemic toxicity of oxetane-substituted sulfoxide 3, we performed a brine shrimp assay ( Table 4).…”

“…30 Furthermore, alkylation of 4-( pnitrobenzyl)pyridine was only observed at acidic pH, implicating that oxetanes do not act as alkylating agents at physiological pH. 30 To assess the systemic toxicity of oxetane-substituted sulfoxide 3, we performed a brine shrimp assay ( Table 4).…”