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16th November 2014 @ 23:13 Edited by
Edit Reason: added back link to AO debate page
16th November 2014 @ 23:07 Edited by
Edit Reason: First Entry
Re: Results of Series 4 Aldehyde Oxidase Assay by Matthew Todd
19th November 2014 @ 11:45
Scott Obach (by email) noted the following 3 points:

1) The AO reaction involves nucleophilic attack on the carbons alpha to a nitrogen (or at electronically equivalent system) on the azaheterocycle. Thus the more electron–deficient the carbon, the faster the rate. The compounds substituted with an electron withdrawing amide would be expected to be better substrates than those with an electron donating group like an ether oxygen.

2) The electron density on the rings is just part of the story. How the enzyme binds substrates and orients them — i.e. the interaction with the protein — will also be important but that is not yet understood.

3) Would you expect the AO product (i.e. the lactams) to retain target activity? Maybe these metabolites would be new leads?

In reply from Mat: With regards this last point, a lactam has been evaluated (MMV669025) at 4 micromolar, whereas the corresponding non-oxo analog (OSM-S-260, MMV675960) is 0.26 micromolar. This strongly implies that the azaheterocyclic N needs to retain its basic character, in turn implying that these metabolites (certainly if oxidised at that position) will not possess activity.

There is also the comparison to be made with the chloro-subst analog MMV668823, which is potent. As Scott subsequently noted, if that site is the site of oxidation, then the Cl will block that site, but such substitution would likely make the ring more susceptible to AO elsewhere, perhaps the other side of the N on that ring. This is on top of any possible inherent chemical reactivity of the chloro analog.

These issues will be discussed at the next online meeting: