(<i>R</i>)- and (<i>S</i>)-3-Fluorothalidomides:  Isosteric Analogues of Thalidomide

Takéuchi, Yoshio; Shiragami, Tomoki; Kimura, Kouji; Suzuki, and Emiko; Shibata, Norio

doi:10.1021/ol9902172

Cited by 95 publications

(59 citation statements)

References 28 publications

(14 reference statements)

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“…Attempts to stabilize the (S)-enantiomer of thalidomide analogs have included replacement of the exchangeable hydrogen with methyl (20,37,41,42) or fluorine groups (43,44). If and when the stable enantiomer of these analogs was studied, none were superior to the racemic, protonated thalidomide analog.…”

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confidence: 99%

Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs

Jacques¹,

Czarnik²,

Judge³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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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confidence: 99%

Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs

Jacques¹,

Czarnik²,

Judge³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…First, there have been reported a few potent leads having a chiral fluorine-containing structure, such as fluorothalidomide, fluorodonepezil, etc. [6][7][8][9] These compounds were found to be pharmacologically more effective than the fluorine-free parent compounds. This suggests that the screening of biological activities of chiral fluorine-containing acids 1 could guide the development of new kinds of medicinal agents.…”

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confidence: 99%

Biological Evaluation of 2-Aryl-2-fluoropropionic Acids as Possible Platforms for New Medicinal Agents

Takéuchi

Fujisawa

Fujiwara

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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We have been studying the design, synthesis, and biological evaluation of chiral fluorine-containing organic compounds as effective analogues of pharmaceutically important molecules. Introduction of fluorine into a prototype molecule results in minimal steric alterations, which can facilitate interactions of fluorinated biomolecules or medicinals with enzyme active sites, receptor recognition sites, transport mechanisms, and other biological systems.1) On the other hand, the presence of fluorine can alter the biological consequences of these interactions, often in a useful way. As a part of our research, we recently reported the synthesis of optically active 2-aryl-2-fluoropropionic acids 1, which possess a unique structure with the fluorine atom located at the stereogenic center (Fig. 1).2)The non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX-1 and COX-2 activities. An increasing number of epidemiological, clinical, and laboratory studies have suggested that NSAIDs, including the series of 2-arylpropionic acids 2 (Fig. 2), may also be able to inhibit the initiation and proliferation of some tumors. [3][4][5] For the following reasons we thought that the fluorinated analogues of 2 could be possible platforms for multi-dimensional, clinically effective therapeutic agents. First, there have been reported a few potent leads having a chiral fluorine-containing structure, such as fluorothalidomide, fluorodonepezil, etc.6-9) These compounds were found to be pharmacologically more effective than the fluorine-free parent compounds. This suggests that the screening of biological activities of chiral fluorine-containing acids 1 could guide the development of new kinds of medicinal agents. Secondly, there have been literature reports describing an in vivo inversion of less active (R)-enantiomer into more active (S)-enantiomer in some 2-arylpropionic acids 2 (Fig. 2). [10][11][12][13] Such in vivo epimerization of chiral medicinal agents is quite rare although there are several examples of in vivo racemization. It is apparent that nonepimerizable 2-aryl-2-fluoropropionic acids 1 could serve as useful tools to clarify the roles of stereochemical lability in living organisms.To examine the pharmacological potential of chiral 2-aryl-2-fluoropropionic acids 1 as pharmacological leads, we have evaluated them with respect to both COX inhibitory activities and antiproliferative activities of cancer cell lines. In this paper, we present the results of this biological evaluation and discuss the results in terms of the potential for further drug development. Results and DiscussionWe first investigated the inhibitory activity of the racemic and optically active fluorinated acids 1a-e toward COX-1 and COX-2. The corresponding non-fluorinated racemates 2a-e, indomethacin, and NS-398 were also investigated for reference. Their inhibitory activities are shown in Table 1.The inhibitory activities of (Ϯ)-1c and (Ϯ)-1e toward COX-1 were much lower than those of the corresponding acids (Ϯ)-2c and (Ϯ)-2e, while the activity of (Ϯ)-1c ...

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“…Gyógyszerek hatásának illetve mellékhatásainak kialakulásában is megfigyelték a hatóanyagok egyes enantiomerjeinek a szerepét. Ennek egyik megrázó példája az 1960-as években születési rendellenességgel született gyerekek esete, ahol kimutatták, hogy a nyugtató hatású készítményben, amelyet az édesanyák szedtek a terhesség alatt, a nyugtató hatásért felelős (R)-izomer mellett az (S)-izomer teratogén hatásúnak bizonyult [5,6]. Ezek a megfigyelések és tapasztalatok is igazolják azokat az erőfeszítéseket, amelyek a királis molekulák enantiomertiszta előállítására irányulnak mind ipari, mind akadémiai körökben világszerte.…”

Section: Bevezetésunclassified

“…Másfelől próbálkozások történtek az eddigi rendszerek továbbfejlesztésére, illetve új típusú katalizátorok előállítására. 5 …”

Section: Bevezetésunclassified

“…A hőmérséklet csökkentése szobahőmérsékletről 273 K-re telítetlen karbonsavak hidrogénezésében növeli az enantioszelektivitást [5,126,128] Látható, hogy hőmérséklet csökkentés hatására mindkét aminnal mindkét sav esetében sikerült növelni az ee-t alacsony hőmérsékleten. A két amin azonos optikai tisztaságot eredményezett TIG-nál, MHS-nél viszont az NMBA-nal nagyobb ee-t értem el.…”

Section: Hőmérséklet Hatása Alifás Karbonsavak Hidrogénezéséreunclassified

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Alifás α,β-telítetlen karbonsavak enantioszelektív hidrogénezése módosított Pd katalizátoron

Zsolt

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(R)- and (S)-3-Fluorothalidomides: Isosteric Analogues of Thalidomide

Cited by 95 publications

References 28 publications

Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs

Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs

Biological Evaluation of 2-Aryl-2-fluoropropionic Acids as Possible Platforms for New Medicinal Agents

Alifás α,β-telítetlen karbonsavak enantioszelektív hidrogénezése módosított Pd katalizátoron

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