Editing Thalidomide (section)

==Pharmacology==
The precise mechanism of action for thalidomide was not known until the twenty-first century,<ref name="Yamamoto">{{Cite journal |vauthors=Yamamoto J, Ito T, Yamaguchi Y, Handa H |date=August 2022 |title=Discovery of CRBN as a target of thalidomide: a breakthrough for progress in the development of protein degraders |journal=Chemical Society Reviews |volume=51 |issue=15 |pages=6234–6250 |doi=10.1039/D2CS00116K |pmid=35796627 |s2cid=250337170 |doi-access=free}}</ref> although efforts to identify thalidomide's [[Teratology|teratogenic]] action generated more than 2,000 research papers and the proposal of 15 or 16 plausible mechanisms by 2000.<ref name="Stephens2000">{{Cite journal |vauthors=Stephens TD, Bunde CJ, Fillmore BJ |date=June 2000 |title=Mechanism of action in thalidomide teratogenesis |journal=Biochemical Pharmacology |volume=59 |issue=12 |pages=1489–1499 |doi=10.1016/S0006-2952(99)00388-3 |pmid=10799645}}</ref> The primary mechanism of action of thalidomide and its analogs in both their anti-cancer and teratogenic effects is now known to be as [[cereblon]] [[E3 ligase]] modulators.<ref name="Yamamoto" /><ref>{{Cite journal |vauthors=Ito T, Handa H |date=11 June 2020 |title=Molecular mechanisms of thalidomide and its derivatives |journal=Proceedings of the Japan Academy. Series B, Physical and Biological Sciences |volume=96 |issue=6 |pages=189–203 |bibcode=2020PJAB...96..189I |doi=10.2183/pjab.96.016 |pmc=7298168 |pmid=32522938}}</ref><ref>{{Cite journal |vauthors=Asatsuma-Okumura T, Ando H, De Simone M, Yamamoto J, Sato T, Shimizu N, Asakawa K, Yamaguchi Y, Ito T, Guerrini L, Handa H |date=November 2019 |title=p63 is a cereblon substrate involved in thalidomide teratogenicity |journal=Nature Chemical Biology |volume=15 |issue=11 |pages=1077–1084 |doi=10.1038/s41589-019-0366-7 |pmid=31591562 |s2cid=203853198}}</ref><ref>{{Cite journal |vauthors=Gao S, Wang S, Song Y |date=December 2020 |title=Novel immunomodulatory drugs and neo-substrates |journal=Biomarker Research |volume=8 |issue=1 |pages=2 |doi=10.1186/s40364-020-0182-y |pmc=6953231 |pmid=31938543 |doi-access=free}}</ref>

Thalidomide also binds to and acts as an [[receptor antagonist|antagonist]] of the [[androgen receptor]] and hence is a [[nonsteroidal antiandrogen]] of some capacity.<ref name="LiuSu2010">{{Cite journal |vauthors=Liu B, Su L, Geng J, Liu J, Zhao G |date=October 2010 |title=Developments in nonsteroidal antiandrogens targeting the androgen receptor |journal=ChemMedChem |volume=5 |issue=10 |pages=1651–61 |doi=10.1002/cmdc.201000259 |pmid=20853390 |s2cid=23228778}}</ref> In accordance, it can produce [[gynecomastia]] and [[sexual dysfunction]] as side effects in men.<ref name="NuttallWarrier2015">{{Cite journal |vauthors=Nuttall FQ, Warrier RS, Gannon MC |date=May 2015 |title=Gynecomastia and drugs: a critical evaluation of the literature |journal=European Journal of Clinical Pharmacology |volume=71 |issue=5 |pages=569–78 |doi=10.1007/s00228-015-1835-x |pmc=4412434 |pmid=25827472}}</ref>

=== Chirality and biological activity ===
Thalidomide is provided as a [[racemic mixture]] of two [[enantiomer]]s; while there are reports that only one of the enantiomers may cause birth defects, the body converts each enantiomer into the other through mechanisms that are not well understood.<ref name=toxmech2009/> The (R)-enantiomer has the desired sedative effect while the (S)-enantiomer harbors embryo-toxic and teratogenic effects. Attempting to extract solely ''R''-thalidomide does not remove the risk of birth defects, as it was demonstrated that the "safe" ''R''-thalidomide undergoes an ''in vivo'' [[chiral inversion]] to the "teratogenic" ''S''-thalidomide. Under biological conditions, the enantiomers interconvert (''bidirectional chiral inversion'' – (R)- to (S)- and vice versa).<ref>{{Cite book |url=https://www.worldcat.org/oclc/52515592 |title=Stereochemical aspects of drug action and disposition |vauthors=Branch SK, Eichelbaum M, Testa B, Somogyi A |date=2003 |publisher=Springer |isbn=978-3-540-41593-0 |location=Berlin |oclc=52515592}}</ref><ref>{{Cite web |date=20 August 2022 |title=Thalidomide |url=https://chiralpedia.com/blog/thalidomide/ |url-status=live |archive-url=https://web.archive.org/web/20220827093228/https://chiralpedia.com/blog/thalidomide/ |archive-date=27 August 2022 |access-date=27 August 2022 |website=Chiralpedia |language=en-US}}</ref>