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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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June 19, 2014

Speaking of Polyphenols. . .

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Posted by Derek

4548.jpgYesterday's mention of "nightmare polyphenols" prompted a reader to ask about the one in this paper. That's it over there at the left, and yeah, that sure is a polyphenol. In fact, it's a chaetochromin, a family of mycotoxins originally isolated from moldy rice. The paper doesn't say anything about its stereochemistry, but some can be inferred from their docking models.

Their compound, denoted 4548-G05, does seem to stimulate the insulin receptor, and the list of things that do that is not a long one. A small-molecule IR compound could be quite useful in diabetes patients, of course, but no one's every been able to come up with a plausible drug candidate. Merck made a big splash back in 1999 with another fungal metabolite, L-783,281, but that never became a drug, either. This new paper advances a hypothesis of where the polyphenol binds to the extracellular domain of the insulin receptor and how it might exert its actions.

I would wonder, though, if this compound can't do the same membrane tricks as the other polyphenols mentioned yesterday. The chaetochromins seem to have a number of biological effects, which could be through all sorts of mechanisms. There's nothing to say that some of them aren't due to direct ligand-binding interactions (such as the one proposed in this latest paper), but I wouldn't rule out membrane perturbations, either. And I wouldn't bet on 4058-G05 becoming a drug, although it might lead to one eventually, after a lot of hard work.

Comments (10) + TrackBacks (0) | Category: Diabetes and Obesity | Natural Products


COMMENTS

1. Witold on June 19, 2014 10:51 AM writes...

Compounds like that look like it would stick to everything. Big pi system? Got it, lots of hydroxyls, yep, need some large non-polar VWD contact patches? Sure, We can accommodate by rotating this conjugated bond.

I'm not a fan of symmetry for protein binding usually. (I'm sure I can be proven wrong, but its just a gut call.)

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2. ClutchChemist on June 19, 2014 10:52 AM writes...

I would enjoy seeing an electrochemical profile of that molecule.

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3. Anonymous on June 19, 2014 12:09 PM writes...

I think it's rather easy to measure, e.g.
http://jac.oxfordjournals.org/content/54/6/1127.full.pdf - of course microbs have different membrane but it's give an idea. Also using CACO2 models while adding not 1 compound but two and measuring cell permeability of only one with some quenching effects as end-point. There are ways to measure this, but do we really need to consider this? Future will show, but anyways -in some systems this property can be very important as a co-player.

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4. Barry on June 19, 2014 12:25 PM writes...

Lipinski didn't claim that cmpds outside his "Rule of Five" can't be drugs, but he did argue that they'd have a harder development path and worse odds of getting to market.
This thing is not lead-like. If it can be co-crystallized with the IR, you might have a start to a rational-design project. But that's a long, expensive, uncertain game even by drug-discovery standards.

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5. Lane Simonian on June 19, 2014 3:56 PM writes...

Another possible role of polyphenols in regards to type 2 diabetes is their potential ability to inhibit and reverse tyrosine nitration.

Curr Med Chem. 2011;18(2):280-90.
Peroxynitrite-driven mechanisms in diabetes and insulin resistance - the latest advances.
Stadler K.
Author information
Abstract
Since its discovery, peroxynitrite has been known as a potent oxidant in biological systems, and a rapidly growing body of literature has characterized its biochemistry and role in the pathophysiology of various conditions. Either directly or by inducing free radical pathways, peroxynitrite damages vital biomolecules such as DNA, proteins including enzymes with important functions, and lipids. It also initiates diverse reactions leading eventually to disrupted cell signaling, cell death, and apoptosis. The potential role and contribution of this deleterious species has been the subject of investigation in several important diseases, including but not limited to, cancer, neurodegeneration, stroke, inflammatory conditions, cardiovascular problems, and diabetes mellitus. Diabetes, obesity, insulin resistance, and diabetes-related complications represent a major health problem at epidemic levels. Therefore, tremendous efforts have been put into investigation of the molecular basics of peroxynitrite-related mechanisms in diabetes. Studies constantly seek new therapeutical approaches in order to eliminate or decrease the level of peroxynitrite, or to interfere with its downstream mechanisms. This review is intended to emphasize the latest findings about peroxynitrite and diabetes, and, in addition, to discuss recent and novel advances that are likely to contribute to a better understanding of peroxynitrite-mediated damage in this disease.

Biochem Biophys Res Commun. 2004 Jul 30;320(3):639-47.

Reduction of insulin-stimulated glucose uptake by peroxynitrite is concurrent with tyrosine nitration of insulin receptor substrate-1.
Nomiyama T1, Igarashi Y, Taka H, Mineki R, Uchida T, Ogihara T, Choi JB, Uchino H, Tanaka Y, Maegawa H, Kashiwagi A, Murayama K, Kawamori R, Watada H.
Author information

Abstract
Inducible nitric oxide synthetase plays an essential role in insulin resistance induced by a high-fat diet. The reaction of nitric oxide with superoxide leads to the formation of peroxynitrite (ONOO-), which can modify several proteins. In this study, we investigated whether peroxynitrite impairs insulin-signalling pathway. Our experiments showed that 3-(4-morpholinyl)sydnonimine hydrochloride (SIN-1), a constitutive producer of peroxynitrite, dose-dependently inhibited insulin-stimulated glucose uptake. While SIN-1 did not affect the insulin receptor protein level and tyrosine phosphorylation, it reduced the insulin receptor substrate-1 (IRS-1) protein level, and IRS-1 associated phosphatidylinositol-3 kinase (PI-3 kinase) activity. Although SIN-1 did not induce Ser307 phosphorylation of IRS-1, tyrosine nitration of IRS-1 was detected in SIN-1-treated-Rat1 fibroblasts expressing human insulin receptors. Mass spectrometry showed that peroxynitrite induced at least four nitrated tyrosine residues in rat IRS-1, including Tyr939, which is critical for association of IRS-1 with the p85 subunit of PI-3 kinase. Our results suggest that peroxynitrite reduces the IRS-1 protein level and decreases phosphorylation of IRS-1 concurrent with nitration of its tyrosine residues.


This one is for the nitration of insulin itself but may also apply to the nitration of the insulin receptor substrate.

In addition to nitrating insulin alone, the nitration of insulin can be partially inhibited with a competitor for inhibition such as
acetaminophen, catechin, quercetin or green tea extract. Any mono or polyphenol having aromatic chemistry open to nitration might inhibit
the nitration of insulin. The polyphenols in green tea or the polyphenol quercetin when added at higher concentrations than acetaminophen
or catechin are even effective inhibitors of insulin nitration.

Polyphenols (or at least some polyphenols) have the ability to limit tyrosine phosphorylation and to protect against and potentially reverse tyrosine nitration and one or both functions are applicable to the treatment of a variety of diseases.

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6. anony-mous(e) on June 19, 2014 6:08 PM writes...

I got one (well really two) words for you; Cysteine oxidation

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7. anon on June 19, 2014 9:24 PM writes...

Compounds like that, though smaller, pop up in every HTS hit set as a low uM hit.

They are ignored, as they should be.

If you do SAR on them until the cows come home, you will most likely still have a low uM hit.

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8. Gordonjcp on June 20, 2014 4:22 AM writes...

As a non-chemist I'm not particularly clued up on these things, I guess. Looking at that molecule though, wouldn't it be difficult to use as a drug for no other reason than it would be like trying to inject a tyre iron into your patient?

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9. MoMo on June 20, 2014 8:26 AM writes...

Anon- No one has ever done SAR on this polyketide derived molecular freak of nature. Its prime for the taking! Put on a coupla amines, a sulfone, stitch it to a peptide and Voila! It might make a respectable drug someday!

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10. JAB on June 24, 2014 10:36 AM writes...

Yeah, we've seen these guys as HTS hits but they don't seem to progress. I wouldn't lump them with tannin-like polyphenols, though. I'd go more to the quinone redox angle...

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