[neilmcarthur73]

Hello Guys.

The IC50 values below are for two compounds, one of which may be admistered to a patient suffering of terminal cancer and the other being the parent chemical.

I have a novice history within organic chemistry and have spent weeks trying to solve this myself and I think I have an understanding now but could someone help me establish the potency of the following;

SAR ratios as follows (IC/50);
                       DGC-823                      KB                     A549                       BEL-7402
PARENT            1051 +/-  360        1424 +/- 148          1011 +/- 300               860 +/- 271
Derivitive         31.85 +/- 28.61      1.71 +/- 1.22          2.84 +/- 1.14              12.06 +/- 9.8

We would be so greatful if someone could help us with this as its too important for me to take an estimated guess on.

My understanding is that you divide the Parent value by the Derivitive value to get the rough potencies, so for example DGC-823  -  1051 / 31.85 = 32 fold potency? Am I even close with this calculation and if I am on the right lines, this would make KB around 1000x fold potency???

Thank you
Neil

[mikeja]

Hi Neil,

This falls more under Medicinal chemistry than Organic, but let me give it a shot.  Firstly, the lower the IC50 value, the greater affinity of a substrate to it's target (usually a measure of potency).  This usually means greater activity, but it depends on what the IC50 value is a measurement of, maybe that info was given in the question, but in general it refers to the median inhibitory concentration of drug/substrate to 50% of it's target.  You probably already know this, but it's just a basis.

An SAR study, or structure activity relationship study, aims to change certain functional groups or portions of the original drug/substrate to something similar but slightly different. Maybe the reason is sterics, electronics, solubility, metabolism, a host of other reasons to make a derivative of a previous drug.

I don't believe you should divide any IC50 values by any others to get a measure of potency.  I believe, and hopefully someone can back me up since I'm not a true Medicinal chemist (bioorganometallics), that the lower the IC50 value, the greater potency. Simple as that.

So all the derivatives you've listed have much greater potencies than their parent compounds.  If you'd like to state that the DGC-823 potency is 32x less potent than the derivative, that is fine and acceptable.  Generally the potencies are listed in micromolar or nanomolar. With 20-ish nanomolar being extremely potent.  You haven't listed any concentrations or units, so it's hard to tell.

You can determine some kinetics and other significant substrate binding information if other data is given, like the Bmax, Kd, or EC50.

Hope this helps,
Mike

[neilmcarthur73]

Hi Mike!

Thank you so much for taking the time to help me out!

So my train of thought was not quite right I was thinking along the lines of if PARENT chemical is 1051 on the DGC-823 cancer strain and analogue chemical was 31.85 then you would see how times the parent chemical would go into the analouge chemical so 1051 / 31.85 to gain the sum for the increased potency? It just seems to make sense to me to do it this way, if this isnt correct is there any other way I can gain an idea of how much more potent this is over its parent chemical? Also the potency varies so much across the different cancer strains (accordingly to my novice interpretation of the IC50 values) which is a bit of a worry as were talking 32x for cancer stain 1 and then a whooping 1000x for cancer stain 2, which then makes me think I probably am working out the values completely incorrectly..

I have attached more information, a screenshot from the literature the derivitive im looking at is 3f and the parent is DCA, as I realise I didnt give you enough to go on the first post.

Thanks for your your help
Neil

[mikeja]

Neil,

Sorry if my wording was confusing.  I mean the parent/original drug for the BGC-823 cancer strain is 32x more potent than the new analogue, and your thinking along those lines was correct.

I don't know much about specific cancer strains, but the results shown are consistent across the board of each strain, and that matters more than if one strain's target is not accessible by this certain drug type. btw, Dichloroacetamide on the first row is just a control.

To give you an idea of how one would analyze this table, I would look through the IC50 values until I saw something similar to compound 2n, where the thiomethyl group is substituted at the 4 position which seems to have high potency across the different cell lines, rather than something like 2k, or 4 (unless of course you need the substrate to be more active in some strains than others).

Because of 2n's low potencies, I would consider that a hit. Meaning that's a structure I'd want to look into more because of how well it binds to the target.  It still isn't nanomolar IC50's but it's better than all the rest. For example, you could try to make a methoxy-substituted version at this same position and see how the size/electronics of the sulfur vs oxygen correlate to IC50 values.

There's more info to gather from this table, for example the COOH substituents do not have measurable IC50 values, most likely because they can't diffuse across the cell membrane, they're too polar.  You can see that as the carbon count on this ester substituent increases, it looks as if it becomes more lipophilic and can cross the bilayer membrane.  Lots of other conclusions can be had from this table, but hopefully this gives you something of an idea of how it's used.

[neilmcarthur73]

Hello Mike.

Thank you very much for your detailed response!

However, im a little confused and really need to confirm a few points.

You mentioned that the control drug is 32x less potent than the 3f analogue according to the diagram... was this a typo? Should it have read 32x more potent than the control? As this literature states that potency is increased substantially in the 3f analouge and it was the lead compound for further research? If 3f is 32 less potent than the control DCA, then its miles off our estimated potency and very much takes it to unrealistic doses.


Again, thanks for your help.
Neil