Biological evaluation of both enantiomers of fluoro-thalidomide using human myeloma cell line H929 and others

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.

Synthesis of fluoro-functionalized diaryl-λ3-iodonium salts and their cytotoxicity against human lymphoma U937 cells

“…Our primary goal has been to develop fluorinating and fluoro-functionalized reagents for fluorination [ 18 – 19 ], trifluoromethylation [ 13 , 18 – 19 ], trifluoromethylthiolation [ 12 , 21 ] and pentafluoroarylation [ 22 – 23 ]. Utilizing these reagents, we have successfully synthesized a wide variety of bioactive organofluorine compounds [ 24 – 30 ] including fluorinated thalidomide (antitumor) [ 24 ], fluorinated donepezil (cholinesterase inhibitor) [ 25 ], and fluorinated camptothecin (anticancer) [ 26 ]. During our research programs focused on the development of novel reagents for fluoro-functionalization [ 12 – 13 16 – 23 ], as well as the design and synthesis of biologically active fluorine-containing compounds [ 24 – 28 ], we noted that a series of fluoro-functionalization reagents could themselves be highly potential drug candidates.…”

“…Utilizing these reagents, we have successfully synthesized a wide variety of bioactive organofluorine compounds [ 24 – 30 ] including fluorinated thalidomide (antitumor) [ 24 ], fluorinated donepezil (cholinesterase inhibitor) [ 25 ], and fluorinated camptothecin (anticancer) [ 26 ]. During our research programs focused on the development of novel reagents for fluoro-functionalization [ 12 – 13 16 – 23 ], as well as the design and synthesis of biologically active fluorine-containing compounds [ 24 – 28 ], we noted that a series of fluoro-functionalization reagents could themselves be highly potential drug candidates. All of the reagents that we developed contain at least one fluorine atom in their structures, which may explain why they have potential biological activity [ 4 – 9 ].…”

Internal chirality descriptors iR and iS and ire and isi. A proposed notation to extend the usefulness of the R/S system by retaining the sense of stereochemistry in cases of ligand ranking changes

“…There is considerable research on F for H substitution, and especially in medicinal chemistry because the non‐fluorinated and fluorinated compounds are considered to be bioisosteres. Thus, structurally, thalidomide ( 10 ) and fluoro‐thalidomide ( 11 ) are too considered bioisosteres (though whether they also constitute chemical isomorphs remains an open question). In the case of fluoro‐thalidomide ( 11 ), the S enantiomer is noticeably more potent than its antipode .…”

“…Thus, structurally, thalidomide ( 10 ) and fluoro‐thalidomide ( 11 ) are too considered bioisosteres (though whether they also constitute chemical isomorphs remains an open question). In the case of fluoro‐thalidomide ( 11 ), the S enantiomer is noticeably more potent than its antipode . However, the S enantiomer of fluoro‐thalidomide ( 11 ) corresponds to the R enantiomer of thalidomide ( 10 ).…”

“…In the case of fluoro-thalidomide (11), the S enantiomer is noticeably more potent than its antipode. 44,47 However, the S enantiomer of fluoro-thalidomide (11) corresponds to the R enantiomer of thalidomide (10). Thus, (R)-10 and (S)-11 are not just bioisosteres but can be considered to be isostereogenic in that they are stereochemically homogeneous (ie, they have analogous absolute configurations).…”