Synthesis and deuterium labelling of the pure selective estrogen receptor modulator (SERM) acolbifene glucuronides

Abstract

Acolbifene (EM-652 Á HCl, SCH 57068 Á HCl), a highly potent and orally active selective estrogen receptor modulator (SERM), is at late stage clinical development for the treatment of estrogen-sensitive breast cancer. Acolbifene-7-glucuronide 1 (major) and acolbifene-4 0 -glucuronide 2 (minor) were identified as metabolites of acolbifene in the human. The two monoglucuronides and a diglucuronide 3 as well as the corresponding 2 H-labelled derivatives 4-6 were synthesised for use as preclinical and clinical standards for LC-MS/MS analysis. All glucuronides were prepared by the Schmidt glycosylation of monoprotected acolbifene with a glucuronyl imidate at À108C to prevent epimerisation at the C-2 position. The two monoglucuronides 1 and 2 of acolbifene were separated by semi-preparative HPLC. Incorporation of three deuteriums was achieved by alkylation of chromanone 15 with C 2 H 3 MgI followed by dehydration with C

Synthesis of a deuterium‐labelled standard of bufotenine (5‐HO‐DMT)

“…General 1 H NMR spectra were obtained at 300 or 400 MHz (indicated in each case), and 13 C NMR spectra were obtained at 100.6 MHz using a Bruker NMR spectrometer. Chemical shifts (d) are reported in ppm relative to CHCl 3 (7.26 and 77.0 ppm).…”

Quantification of Glucuronide Metabolites in Biological Matrices by LC-MS/MS

“…Their isotope labeled analogs (for use as internal standards) can cost even more. To overcome this difficulty, several possibilities exist (Soars, Mattiuz et al 2002;Sanceau, Larouche et al 2007). The first is a chemical synthesis of the glucuronide standards, which can be performed either by a glucopyranoside synthesis or by the use of glucuronide donors or glucuronide precursors and often involves a several step reaction, which is time-consuming and the glucuronide yield is often very low (Yu, Zhu et al 2000;Burkon and Somoza 2008).…”

“…After the analysis of first and second aliquot, the glucuronide response factor is calculated as the ratio between the glucuronide signal from the second aliquot and the rise of the signal of aglycon in the first aliquot (originating from the cleaved glucuronide). Then, in subsequent analyses, the glucuronide response factor is used to quantify the glucuronides without the -glucuronidase treatment and by using the calibration curve of the easily obtainable aglycone (Sanceau, Larouche et al 2007;Farrell, Poquet et al 2011;Trdan, Roskar et al 2011). In such scenarios, a careful study of the possible relative matrix effects on glucuronides is warranted.…”

Engineered Nuclear Hormone Receptor-Biosensors for Environmental Monitoring and Early Drug Discovery

“…These compounds have been developed as fertility drugs, as well as breast cancer, prostate cancer and osteoporosis therapeutics. Among them are Toremifene (Fareston ® by Shire laboratories), lasofoxifene, trioxifene, droloxifene, clomifene (Clomid ® by Hoechst Marion Roussel, Inc.) and ormeloxifene (originally manufactured by Torrent Pharmaceuticals), which was used as a birth control pill, and is now also prescribed to cure uterine bleeding (Blizzard, 2008;Fan et al, 2007;Musa et al, 2007;Sanceau et al, 2007). Pure antagonists were also synthesized such as ICI 182,780 (Faslodex ® by AstraZeneca), which is known as a selective estrogen receptor downregulator; SERD (Abdou et al, 2008).…”