A New Method for Determination of Both Thalidomide Enantiomers Using HPLC Systems

Abstract

Over the last few years, thalidomide has become one of the most important anti-tumour drugs for the treatment of relapsed-refractory multiple myeloma. However, besides its undesirable teratogenic side effect, its configurational instability critically limits any further therapeutic improvements of this drug. In 1999, we developed fluoro-thalidomide which is a bioisostere of thalidomide, but, in sharp contrast to the latter, it is configurationally stable and readily available in both enantiomeric forms. The biological activity of fluoro-thalidomide however, still remains virtually unstudied, with the exception that fluoro-thalidomide is not teratogenic. Herein, we report the first biological evaluation of fluoro-thalidomide in racemic and in both (R)-and (S)-enantiomerically pure forms against (in vitro) H929 cells of multiple myeloma (MM) using an annexin V assay. We demonstrate that all fluoro-thalidomides inhibited the growth of H929 MM cells without any in-vivo activation. Furthermore, we report that the enantiomeric forms of fluoro-thalidomide display different anti-tumour activities, with the (S)-enantiomer being noticeably more potent. The angiogenesis of fluoro-thalidomides is also investigated and compared to thalidomide. The data obtained in this study paves the way towards novel pharmaceutical research on fluoro-thalidomides.

Human Liver Microsomal Cytochrome P450 3A Enzymes Involved in Thalidomide 5-Hydroxylation and Formation of a Glutathione Conjugate

“…The extent of oxidation of thalidomide is very low. It is known that only the ( S )-enantiomer of thalidomide is teratogenic (7, 8). We made a direct comparison of the formation of the GSH conjugate from ( R )- and ( S )-thalidomide (Figure 5) and found that the yields are similar.…”

Drug Interactions of Thalidomide with Midazolam and Cyclosporine A: Heterotropic Cooperativity of Human Cytochrome P450 3A5

“…In Japan, thalidomide was similarly designated for the treatment of refractory multiple myeloma in 2005 as an "orphan" drug (Sembongi et al, 2008), and a decision regarding final approval is expected in 2008. Many clinical trials with thalidomide are ongoing for both anti-inflammatory and antiangiogenic activities (Vogelsang et al, 1992;Macpherson et al, 2003;Kamikawa et al, 2006;Breitkreutz and Anderson, 2008).…”

Tracking the chemical surface properties of racemic thalidomide and its enantiomers using a biomimetic functional surface on a quartz crystal microbalance

“…When it was introduced half a century ago, it was used for inhibiting immune and inflammatory responses mostly in pregnant women. 20 The previous studies reported that thalidomide dramatically decreased the glial activation and the beta amyloid neuropathology in a transgenic mouse model that showed symptoms of Alzheimer's disease. 18 Unfortunately, each mirror image form of the chiral drug had different biological activities, some causing serious toxicity such as those of the (S)-thalidomide.…”