Click chemistry viability


by gravenewworld
Tags: chemistry, click, viability
gravenewworld
gravenewworld is offline
#1
Mar14-12, 11:16 PM
P: 1,389
With the huge interest in click chemistry for in vivo applications--the staudinger ligation and the Huisgen cycloaddition, I was wondering, just how viable are these reactions in real world settings? Assuming second order kinetics, the fastest ever reported Staudinger ligation click reaction had a rate constant of 7.7x10^-3 M-1s-1 and the fastest ever Huisgen click reaction has kinetic rate constant of 2.3 M-1s-1. In other words, at concentrations of 1uM (which is near physiological concentration ranges of drugs etc), for a rxn time of 1h, and assuming that we get complete conversion and no side products, that those reactions will produce yields of 0.003% and 0.8% respectively.

The kinetic barrier reported seems like a huge obstacle to me. For comparison's sake, enzymes that bioconjugate work with rate constants on the order of 2.7 x 10^6 M-s-1. So really, how viable is the click chemistry approach for in vivo application? Are we primed for failure?
Phys.Org News Partner Chemistry news on Phys.org
Computer program could help solve arson cases
Breakthrough harnesses light for controlled chemical reaction
Large-scale identification and analysis of suppressive drug interactions
amadei
amadei is offline
#2
Mar15-12, 10:23 PM
P: 1
Quote Quote by gravenewworld View Post
With the huge interest in click chemistry for in vivo applications--the staudinger ligation and the Huisgen cycloaddition, I was wondering, just how viable are these reactions in real world settings? Assuming second order kinetics, the fastest ever reported Staudinger ligation click reaction had a rate constant of 7.7x10^-3 M-1s-1 and the fastest ever Huisgen click reaction has kinetic rate constant of 2.3 M-1s-1. In other words, at concentrations of 1uM (which is near physiological concentration ranges of drugs etc), for a rxn time of 1h, and assuming that we get complete conversion and no side products, that those reactions will produce yields of 0.003% and 0.8% respectively.

The kinetic barrier reported seems like a huge obstacle to me. For comparison's sake, enzymes that bioconjugate work with rate constants on the order of 2.7 x 10^6 M-s-1. So really, how viable is the click chemistry approach for in vivo application? Are we primed for failure?
Boy, I love theoreticians who come up with all kinds of explanations and reasons why an experiment should be "primed for failure" and sound very convincing too, using the "right" numbers, yet disregard the obvious: it is already working! Don't rely on the numbers given by pseudo-chemists in pseudo-scientific journals. Just because it is published, it does not have to be true (and often isn't). It is perfectly viable in in vivo applications -- as long as you are willing to actually go and do it. If you continue finding reasons for why it should fail, you'll probably miss the boat.

I wouldn't classify Staudinger as a click reaction, and which one is the "Huisgen click"?
williams99
williams99 is offline
#3
Mar16-12, 01:16 AM
P: 5
If you continue finding reasons for why it should fail, you'll probably miss the boat.

gravenewworld
gravenewworld is offline
#4
Mar16-12, 08:50 AM
P: 1,389

Click chemistry viability


Quote Quote by amadei View Post
Boy, I love theoreticians who come up with all kinds of explanations and reasons why an experiment should be "primed for failure" and sound very convincing too, using the "right" numbers, yet disregard the obvious: it is already working! Don't rely on the numbers given by pseudo-chemists in pseudo-scientific journals. Just because it is published, it does not have to be true (and often isn't). It is perfectly viable in in vivo applications -- as long as you are willing to actually go and do it. If you continue finding reasons for why it should fail, you'll probably miss the boat.

I wouldn't classify Staudinger as a click reaction, and which one is the "Huisgen click"?
Absolutley true on all points. I was really trying to play devil's advocate with the post. So what other uses can click chemistry be used in vivo besides just clicking probes? Fluorescence is highly sensitive and can work on concentrations within the picomolar range, but can click chemistry be used for applications besides just fluorescent tags without needing large concentrations to work in vivo? And will it ever work in a human? Sure you can get away with 100uM concentrations in rats, but what about a human?
Mike H
Mike H is offline
#5
Mar16-12, 04:08 PM
P: 464
I don't follow this well enough to be able to suggest more than Google search terms, but I have this recollection that they're also interested in applying these sorts of in vivo chemical techniques for mass spectrometric studies using isotope tags. Of course, the real advantage to "click chemistry" for non-chemists is that you can buy the materials from your favorite vendor without having to bug the nearest synthetic organic chemist. Heh.

There's also a fair bit of interest in this methodology in the polymer & materials science communities in my observations, especially as it relates to being able to functionalize polymers and modify surfaces. So while "real world," definitely not in vivo. Unless they plan on dosing something with the surface-modified nanoparticle for some reason, naturally.
gravenewworld
gravenewworld is offline
#6
Mar17-12, 09:28 PM
P: 1,389
A lot of click chemistry is applied to cell surface modifications--feed your cells an unnatural sugar that bears and azide or alkyne which then goes through the cell's machinery to express that sugar on the cell surface. Once that happens, "click" your substrate (probes or whatever) to your cell.

Now, what exactly is the turnover of sugars on the cell surface? Cells aren't static, but are constantly shedding and modifying their glycocalyx. So let's say we feed our cells a sugar bearing an azide/alkyne, just how long is it going to be on the cell surface? Couple that with the slow reaction time of the Staudinger ligation and huisgen cycloaddition, just how good of a signal to noise ratio can one obtain from in vivo?


Interestingly, after more digging, Joeseph Fox's group at the University of Delaware has found a set of tetrazine diels alder rxns that occur in water/cell media with no catalysts with rate constants on the order of 10^4.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166440/


Register to reply

Related Discussions
In Atmosphere Ion Drive(Assess Viability For Spacecraft) Engineering Systems & Design 13
How do we quantify the viability of a scientific model? General Discussion 4
Cellular Viability Biology, Chemistry & Other Homework 4
Single-click or double-click? Computing & Technology 3
Viability of Relativity. Special & General Relativity 0