Self-disproportionation of enantiomers of thalidomide and its fluorinated analogue via gravity-driven achiral chromatography: mechanistic rationale and implications.
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ABSTRACT:
SUBMITTER: Maeno M
PROVIDER: S-EPMC5811091 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Twenty years after the thalidomide disaster in the late 1950s, Blaschke et al. reported that only the (S)-enantiomer of thalidomide is teratogenic. However, other work has shown that the enantiomers of thalidomide interconvert in vivo, which begs the question: why is teratogen activity not observed in animal experiments that use (R)-thalidomide given the ready in vivo racemization ("thalidomide paradox")? Herein, we disclose a hypothesis to explain this "thalidomide paradox" through the in-vivo self-disproportionation of enantiomers. Upon stirring a 20% ee solution of thalidomide in a given solvent, significant enantiomeric enrichment of up to 98% ee was observed reproducibly in solution. We hypothesize that a fraction of thalidomide enantiomers epimerizes in vivo, followed by precipitation of racemic thalidomide in (R/S)-heterodimeric form. Thus, racemic thalidomide is most likely removed from biological processes upon racemic precipitation in (R/S)-heterodimeric form. On the other hand, enantiomerically pure thalidomide remains in solution, affording the observed biological experimental results: the (S)-enantiomer is teratogenic, while the (R)-enantiomer is not.
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Project description:Therapeutics developed and sold as racemates can exhibit a limited therapeutic index because of side effects resulting from the undesired enantiomer (distomer) and/or its metabolites, which at times, forces researchers to abandon valuable scaffolds. Therefore, most chiral drugs are developed as single enantiomers. Unfortunately, the development of some chirally pure drug molecules is hampered by rapid in vivo racemization. The class of compounds known as immunomodulatory drugs derived from thalidomide is developed and sold as racemates because of racemization at the chiral center of the 3-aminoglutarimide moiety. Herein, we show that replacement of the exchangeable hydrogen at the chiral center with deuterium allows the stabilization and testing of individual enantiomers for two thalidomide analogs, including CC-122, a compound currently in human clinical trials for hematological cancers and solid tumors. Using "deuterium-enabled chiral switching" (DECS), in vitro antiinflammatory differences of up to 20-fold are observed between the deuterium-stabilized enantiomers. In vivo, the exposure is dramatically increased for each enantiomer while they retain similar pharmacokinetics. Furthermore, the single deuterated enantiomers related to CC-122 exhibit profoundly different in vivo responses in an NCI-H929 myeloma xenograft model. The (-)-deuterated enantiomer is antitumorigenic, whereas the (+)-deuterated enantiomer has little to no effect on tumor growth. The ability to stabilize and differentiate enantiomers by DECS opens up a vast window of opportunity to characterize the class effects of thalidomide analogs and improve on the therapeutic promise of other racemic compounds, including the development of safer therapeutics and the discovery of new mechanisms and clinical applications for existing therapeutics.
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Project description:The propagation of flexural gravity waves, routinely used to model wave interaction with sea ice, is studied, including the effect of compression and current. A number of significant and surprising properties are shown to exist. The occurrence of blocking above a critical value of compression is illustrated. This is analogous to propagation of surface gravity waves in the presence of opposing current and light wave propagation in the curved space-time near a black hole, therefore providing a novel system for studying analogue gravity. Between the blocking and buckling limit of the compressive force, the dispersion relation possesses three positive real roots, contrary to an earlier observation of having a single positive real root. Negative energy waves, in which the phase and group velocity point in opposite directions, are also shown to exist. In the presence of an opposing current and certain critical ranges of compressive force, the second blocking point shifts from the positive to the negative branch of the dispersion relation. Such a shift is known as the Hawking effect from the analogous behaviour in the theory of relativity which leads to Hawking radiation. The theory we develop is illustrated with simulations of linear waves in the time domain.
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Project description:An efficient and novel enzymatic method has been developed for the synthesis of β-fluorophenyl-substituted β-amino acid enantiomers through lipase PSIM (Burkholderia cepasia) catalyzed hydrolysis of racemic β-amino carboxylic ester hydrochloride salts 3a-e in iPr2O at 45 °C in the presence of Et3N and H2O. Adequate analytical methods were developed for the enantio-separation of racemic β-amino carboxylic ester hydrochlorides 3a-e and β-amino acids 2a-e. Preparative-scale resolutions furnished unreacted amino esters (R)-4a-e and product amino acids (S)-5a-e with excellent ee values (≥99%) and good chemical yields (>48%).
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Project description: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.
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Project description:Human purine nucleoside phosphorylase (PNP) was crystallized with transition-state analogue inhibitors Immucillin-H and DADMe-Immucillin-H synthesized with ribosyl mimics of l-stereochemistry. The inhibitors demonstrate that major driving forces for tight binding of these analogues are the leaving group interaction and the cationic mimicry of the transition state, even though large geometric changes occur with d-Immucillins and l-Immucillins bound to human PNP.
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Project description:Chromatographic conditions for the separation of fluorinated amino acids and oligopeptides from their non-fluorinated counterparts were explored. The separation of six pairs of analytes, including both aromatic and aliphatic fluorocarbons, was investigated at various temperatures using both hydrocarbon and fluorocarbon columns and eluents. Our results show that when hydrocarbon eluents are used, fluorocarbon column provides better separation of fluorinated amino acids or oligopeptides from their non-fluorinated counterparts; when fluorocarbon eluents are used, hydrocarbon column provides better separation of fluorinated amino acids or oligopeptides from their non-fluorinated counterparts. These chromatographic behaviors reflect the fluorophilicity possessed by fluorinated amino acids and oligopeptides.
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Project description:The sedative and antiemetic drug thalidomide [?-(N-phthalimido)glutarimide] was withdrawn in the early 1960s because of its potent teratogenic effects but was approved for the treatment of lesions associated with leprosy in 1998 and multiple myeloma in 2006. The mechanism of teratogenicity of thalidomide still remains unclear, but it is well-established that metabolism of thalidomide is important for both teratogenicity and cancer treatment outcome. Thalidomide is oxidized by various cytochrome P450 (P450) enzymes, the major one being P450 2C19, to 5-hydroxy-, 5'-hydroxy-, and dihydroxythalidomide. We previously reported that P450 3A4 oxidizes thalidomide to the 5-hydroxy and dihydroxy metabolites, with the second oxidation step involving a reactive intermediate, possibly an arene oxide, that can be trapped by glutathione (GSH) to GSH adducts. We now show that the dihydroxythalidomide metabolite can be further oxidized to a quinone intermediate. Human P450s 2J2, 2C18, and 4A11 were also found to oxidize 5-hydroxythalidomide to dihydroxy products. Unlike P450s 2C19 and 3A4, neither P450 2J2, 2C18, nor 4A11 oxidized thalidomide itself. A recently approved amino analogue of thalidomide, pomalidomide (CC-4047, Actimid), was also oxidized by human liver microsomes and P450s 2C19, 3A4, and 2J2 to the corresponding phthalimide ring-hydroxylated product.
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Project description:DNA oligonucleotides modified with nucleoside monomers which have an electron withdrawing group (EWG) at the 2'-position of the furanose ring form more stable duplexes with complementary RNA as compared to unmodified DNA. Here we show that an anti-periplanar orientation of the nucleobase and the 2'-EWG is important for optimal duplex stabilization even for nucleic acid analogues with conformationally locked furanose rings.
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