1. N-terminal globin adducts as biomarkers for formation of butadiene derived epoxides
Gunnar Boysen, Nadia I Georgieva, Patricia B Upton, Vernon E Walker, James A Swenberg Chem Biol Interact. 2007 Mar 20;166(1-3):84-92. doi: 10.1016/j.cbi.2006.10.005. Epub 2006 Nov 7.
The aim of this review is to summarize our recent data on butadiene (BD) derived hemoglobin adducts as biomarkers for the internal formation of the individual epoxides formed by butadiene (BD). It is well known that BD is oxidized by cytochrome P450s to several epoxides that form DNA and protein adducts. 1,2-Epoxy-3-butene (EB), 1,2;3,4-diepoxybutane (DEB) and 1,2-epoxy-3,4-butanediol (EB-diol) form N-(2-hydroxy-3-butenyl)-valine (HB-Val), N,N-(2,3-dihydroxy-1,4-butadiyl)-valine (pyr-Val) and N-(2,3,4-trihydroxybutyl)-valine (THB-Val) adducts, respectively. The analysis of HB-Val and THB-Val by the modified Edman degradation and GC-MS/MS has generated valuable insights into BD metabolism across species. In addition, a recently established method for the analysis of pyr-Val has been proven to be suitable for detection of pyr-Val in rodents exposed to BD as low as 1 ppm. These technologies have been applied to study a wide range of exposures to BD, EB, DEB, and 3-butene-1,2-diol as a precursor of EB-diol in male and female mice and rats. Altogether the data have shown that BD metabolism is species and concentration dependent, consistent with metabolism and carcinogenesis data. Mice form much more HB-Val and pyr-Val than rats, especially at low exposures. After 10 days of inhalation exposure to 3 ppm BD, mice formed 12.5-fold more pyr-Val than rats. In contrast, the amounts of THB-Val were similar in mice and rats exposed to 3 or 62.5 ppm BD. Furthermore, it appears that the formation of THB-Val is supralinear in mice and rats due to saturation of metabolic activation pathways. Gender differences in metabolism are less well established. One study with male and female rats exposed to 1000 ppm BD for 90 days demonstrated a 1.6-, 3.5- and 2.0-fold gender difference in formation of HB-Val, pyr-Val and THB-Val, respectively, with females being more efficient in epoxide formation. The analyses of BD derived protein adducts correlate well with the observed species and gender differences in BD-carcinogenesis and suggest that DEB may indeed be the most important metabolite.
2. Epoxides: Developability as active pharmaceutical ingredients and biochemical probes
Baljit Kaur, Palwinder Singh Bioorg Chem. 2022 Aug;125:105862. doi: 10.1016/j.bioorg.2022.105862. Epub 2022 May 11.
Epoxide functional group is a part of several natural as well as synthetic compounds. Irrespective of the role of epoxide group in drug efficacy and the use of epoxide compounds as tool molecules, uncertainty prevails over concerns associated with the reactivity of this functional group. Herein, we compile information about epoxide-based medicinal compounds and biochemical probes and look into the related advantages and challenges of the epoxide functional group. As a whole, this study is focussed on analyzing the strategies which have been adopted for the successful development of epoxide-based compounds within drug discovery programs.
3. Ceramide-epoxides
A Möllenberg, G Spiteller Chem Phys Lipids. 2001 Feb;109(2):225-8. doi: 10.1016/s0009-3084(00)00208-5.
Previously unknown 4,5-epoxy-N-acetyl-sphingosine (1) was synthesized by epoxidation of N-acetyl-sphingosine with 1,1-dimethyldioxirane. A by-product generated by HPLC purification is the tetrahydrofuryl derivative of acetamide (2). Mainly allylic oxidation was observed when natural ceramides were reacted with dimethyldioxirane.
