Can someone emurate some of the pharmaceutically important compounds in thiols?

Answer 1

Hey Tyl,

In my following answer I'm interpreting your question as "what are some of the pharmaceutically relevant uses of thiols." If this does not accurately sum up the essence of your question then please let me know and I'd be happy to take another run at it based on any clarification of what exactly you're asking. Also, as a nod to the authors of the scientific review article I found on the subject, here is the citation for the article on which I am basing my answer: Pfaff AR, Beltz J, King E, Ercal N. Medicinal Thiols: Current Status and New Perspectives. Mini Rev Med Chem. 2020;20(6):513-529. doi: 10.2174/1389557519666191119144100. PMID: 31746294; PMCID: PMC7286615.

In order of mention in the article, here are some pharmaceutically relevant thiol compounds, their respective uses and how their chemistry facilitates these uses.

1) N-acetylcysteine: This compound is the only FDA approved treatment for acetaminophen (tylenol a.k.a. APAP) overdose (OD). Excessive APAP doses however, produce enough of an electrophilic downstream metabolite called N-acetyl-p-benzoquinone imine (NAPQI), which alkylates the incredibly important nucleophilic thiol-based antioxidant glutathione (GSH), to exhaust the liver's GSH stores thus allowing NAPQI to react with and damage other biomolecules unchecked. Thankfully N-acetylcysteine is very easily processed into GSH and once administered can therefore support production of enough nucleophilic GSH to react with excess NAPQI forming GSH-S-conjugates which can then be processed into nontoxic metabolites that are easily excreted in urine.

2)meso-2,3-dimercaptosuccinic acid and Dimercaprol (a.k.a. BAL): These compounds are both dithiols which are FDA approved for the treatment of the toxicity of several heavy metals including gold, lead, arsenic and mercury. This is facilitated by these polythiols' ability to chelate, form claw or ring-like structures, around heavy metal ions which prevent these metals from interacting with other molecules which they could damage causing harm on a cellular, local or systemic level depending on the dosage size and modality. Chelation of Lewisite (a WWII era arsenic-containing chemical warfare agent) by BAL for example is caused by the nucleophilic attack of Lewisite's arsenic ion by the lone electron pairs of the thiol's sulfur atoms. The thiols then lose their respective hydrogen atoms completing the bidentate (two-sites of interaction with the metal ion) chelation.

3) D-penicillamine: This compound can form a bidentate chelation of copper ions via a thiol and an amine group similar in chemistry and clinical relevance to the previous compounds' interactions with other heavy metals.

4) Aminofostine: This is a phosphorothioate which, when dephosphorylated into its active form, an aminothiol, dubbed ((aminopropyl)amino)ethanethiol (WR-1065), is one of only three compounds approved by the FDA as a radioprotectant. This property is facilitated by WR-1065's ability to decrease the pO2 of cells thereby reducing the number of reactive oxygen species that incident radiation can create though the mechanism of pO2 decrease is unkown.

5) N-(2-mercaptopropionyl)glycine (a.k.a. tiopronin): Best known for its use in the treatment of cystinuria (cystine kidney stones). tiopronin reacts with the cystine to produce cystine-tiopronin disulfides which are water soluble thereby slowly dissolving the stones. Additionally, this compound is effective in copper(II) chelation and a good antioxidant with fewer side effects than the previously mentioned d-penicillamine.

6) Captopril: An angiotensin-converting enzyme (ACE) inhibitor beneficial in the reduction of strokes and coronary heart disease and heart failure inhibits ACE via its thiol interaction with the zinc ion in ACE's active site.

I hope this was helpful to you! Please let me know if you have any follow up questions or need any clarification on my answer!