3 ms·

trifluoroacetyl is a pretty stable substituent, as far as the fluorines go. trifluoromethyl as a substituent is a classic "medicinal chemist's favorite" and wil

by gpcr1949 5y ago

trifluoroacetyl is a pretty stable substituent, as far as the fluorines go. trifluoromethyl as a substituent is a classic "medicinal chemist's favorite" and will not be labile. for example: efavirenz, fluoxetine, celecoxib all have a TFM. It's true fluorine chemistry is generally tricky, including some organofluorine chemistry, on the other hand in this case trifluoroacetic acid, trifluoroacetyl chloride etc are commercially available, affordable and common so no issue to make the trifluoroacetyl amide at some point. anyway for me this is a really nice "medchem" friendly compound.. i like the little oddball bicyclo[3.1.0]hexane ringsystem in there (the part that looks like a pentagon fused with a triangle).

dekhn 5y ago
I'm fairly certain that all of those compounds derive from some fluorine gas that was incorporated into the source molecules. The molecule I worked with in grad school, 5FU, contains a fluorine, it's a very effective anticancer drug which ultimately came from fluroacetyl which is highly toxic. In fact most of the molecules I worked with in grad school that had fluorine were toxic specifically because of fluorine. Not because they were unstable bonds, but because F is very effective in nucleoside analogs. So you can imagine why I am a bit wary of F and just in general don't think of F as being particularly compatible with life.
- gpcr1949 5y ago
  I think I get what you mean but I don't agree on all fronts. 1. that compounds derive from some difficult to handle gas is only a problem for the process chemists. In this case because the TFA-based precursor is available this is not a problem. Though technically, the production of that commercially available TFA will probably have involved F2. 2. Though indeed there are quite a few toxic compounds that incorporate fluorine, such as 5-fluoro-uracil, fluoroacetate etc this is not quite a general rule, as there are also plenty of non toxic medicines and materials that incorporate fluorine. It seems decently compatible with life compared, certainly compared to some other elements or classes of compounds generally. 3. specifically concerning nucleoside/-tide/-base analogs I wouldn't quite pin their cytotoxicity on fluorine, as a class these will tend to be toxic because they are similar enough to nucleosides to get where they need to be but dissimilar enough to cause problems and make systems that deal with nucleobase derivatives malfunction. Instead of 5-fluoro you can also put 5-iodo, 5-TFM, sulfur, alkynyl, etc there and get antiviral like, cytotoxic compounds In any case, when it comes to this specific pfizer drug, I would say the presence of some fluorines is not a production problem and certainly not a toxicity red flag. For example, Derek Lowe, whose amusing post on some of the more dangerous fluorine chemistry you cite, also has the following to say about fluorine and medicinal chemistry: "We med-chemists just love our fluorines - as long as we don't have to use, like, fluorine itself to make them - because they armor-plate parts of our molecules against being metabolized and can change the binding profiles of the parent structures like nothing else can."[0] [0]https://www.science.org/content/blog-post/new-ways-fluorinate https://www.science.org/content/blog-post/new-ways-fluorinat...
  - dekhn 5y ago
    ok that's a good reply, have an upvote

dekhn 5y ago

I'm fairly certain that all of those compounds derive from some fluorine gas that was incorporated into the source molecules. The molecule I worked with in grad school, 5FU, contains a fluorine, it's a very effective anticancer drug which ultimately came from fluroacetyl which is highly toxic. In fact most of the molecules I worked with in grad school that had fluorine were toxic specifically because of fluorine. Not because they were unstable bonds, but because F is very effective in nucleoside analogs. So you can imagine why I am a bit wary of F and just in general don't think of F as being particularly compatible with life.

gpcr1949 5y ago
I think I get what you mean but I don't agree on all fronts. 1. that compounds derive from some difficult to handle gas is only a problem for the process chemists. In this case because the TFA-based precursor is available this is not a problem. Though technically, the production of that commercially available TFA will probably have involved F2. 2. Though indeed there are quite a few toxic compounds that incorporate fluorine, such as 5-fluoro-uracil, fluoroacetate etc this is not quite a general rule, as there are also plenty of non toxic medicines and materials that incorporate fluorine. It seems decently compatible with life compared, certainly compared to some other elements or classes of compounds generally. 3. specifically concerning nucleoside/-tide/-base analogs I wouldn't quite pin their cytotoxicity on fluorine, as a class these will tend to be toxic because they are similar enough to nucleosides to get where they need to be but dissimilar enough to cause problems and make systems that deal with nucleobase derivatives malfunction. Instead of 5-fluoro you can also put 5-iodo, 5-TFM, sulfur, alkynyl, etc there and get antiviral like, cytotoxic compounds In any case, when it comes to this specific pfizer drug, I would say the presence of some fluorines is not a production problem and certainly not a toxicity red flag. For example, Derek Lowe, whose amusing post on some of the more dangerous fluorine chemistry you cite, also has the following to say about fluorine and medicinal chemistry: "We med-chemists just love our fluorines - as long as we don't have to use, like, fluorine itself to make them - because they armor-plate parts of our molecules against being metabolized and can change the binding profiles of the parent structures like nothing else can."[0] [0]https://www.science.org/content/blog-post/new-ways-fluorinate https://www.science.org/content/blog-post/new-ways-fluorinat...
- dekhn 5y ago
  ok that's a good reply, have an upvote