Allozyne AZ01 click chemistry in the drawing

The chemistry of AZ01 in the drawing; triazole click chemistry in purple

Allozyne AZ01 towards the first drug applying click chemistry?

Will AZ01 win the race as the “first” drug applying triazole click chemistry?

10/18/2011 Allozyne announces positive results from multiple ascending dose (MAD) Phase 1B trial of AZ01, the lead product candidate developed by Biociphering platform, for the treatment of relapsing-remitting multiple sclerosis (RRMS). AZ01 is a next-generation long-lasting interferon beta for the treatment of MS, the chronic inflammatory and degenerative brain disease. The MAD study suggested an improved tolerability profile in monthly therapy.


Allozyne Biociphering platforms enable site-specific incorporation of non-natural amino acid in the target protein, allowing further bioconjugation with a host of molecules for enhanced therapeutic properties of target proteins. Click chemistry has been powering this highly efficient conjugation.


Two versions of Biciphering platforms exist: CAESAR (E Coli based) and VIGENERE (mammalian cells based). The former has produced AZ01 (MS) and AZ17 (Crohn’s Disease) in the pipeline, while the latter has AZ05 (Oncology).

See a previous announcement on AZ01 by Allozyne 
7/15/2010 Allozyne licenses Click Chemistry from Scripps
                            
                              

Click chemistry a click away

This is to respond to a reader's excellent request - why not put together a list of vendors of click chemistry reagents, with active links, to make click chemistry a click away? Here it goes:

http://www.sigmaaldrich.com/chemistry/chemical-synthesis/technology-spotlights/click.html


http://www.invitrogen.com/site/us/en/home/Products-and-Services/Applications/Cell-Analysis/Labeling-Chemistry/Click-chemistry-Labeling-and-Detection.html

http://www.lumiprobe.com/c/click-chemistry-reagents


http://www.clickchemistrytools.com/Products.html

http://www.creativepegworks.com/Click_PEG_derivatives.html

http://www.activemotif.com/catalog/681/fluorescent-tools-for-click-chemistry

http://www.jenabioscience.com/cms/en/1/browse/1379_click_chemistry_reagents.html

http://www.idtdna.com/pages/decoded/decoded-articles/find-out-first-2/decoded/2011/09/12/click-chemistry

http://www.iba-go.com/naps/naps_p_edcc.html

http://www.enamine.net/index.php?option=com_content&task=view&id=127

http://www.berryassoc.com/clickmates.asp

http://www.glenresearch.com/GlenReports/GR23-13.html

http://www.anaspec.com/products/promotions.asp?id=55&col=2&row=2

http://www.quantabiodesign.com//

http://www.primetech.by/en/biocon_click.html

http://www.gfschemicals.com/statics/documents/randd/randd2a82dd80b59a4d08a177471f6aadf1a6.html

http://www.baseclick.eu/products.php

http://www.setabiomedicals.com/click-chemistry.php

http://www.interchim.fr/ft/F/FY2780.pdf

http://www.amtechpl.com/docs/AMT%20Click%20Chemistry%20Fact%20Sheet_V1%200_20111129.pdf

http://www.chemgenes.com/products.php

http://www.iris-biotech.de/pegylation/peg-azides-for-click-chemistry.html

http://www.piercenet.com/browse.cfm?fldID=78C8CEF4-5056-8A76-4E62-B899CF83E209

http://www.caymanchem.com/app/template/productQualifiers%2CProductQualifier.vm/productqualifier/click-chemistry

http://www.cambio.co.uk/1160/66/products/azide-tags/

http://www.fluorous.com/groups/174-10.html

http://www.metabion.com/products/click.php

http://www.bachem.com/newsletter/July_2011_New_Products.html

http://pepnet.com/shoppingusers/PdfDocument.aspx?FileName=pepnet242.pdf

http://www.cyanine.com/life-science/applications/click-chemistry

http://www.prochimia.com/compound_description.php?prod_id=8

http://proteinslides.com/click.html

A few notes:
1. No way it is exclusive - please let me know the ones I have missed so I can add them in future updates.
2. Chances are the addresses would change over time - the best way then is to copy the company link to your web browser and click to get to the vendor followed by search that website. 
3. It was stated why "vendors matter" in a separate post.

Diels-Alder Click Chemistry for Tissue Engineering Hydrogel

Biomacromolecules, 2011, 12 (3), pp 824–830

Diels-Alder cycloaddition satisfies click chemistry criteria and features elegant multiple-bond formation in a single step in very high yeild. Here a furan diene was installed onto the natural polymer hyaluronic acid and it was cross-linked by a bifunctional dienophile, dimaleimide poly(ethylene glycol) to form the cytocompatible hydrogels for potential soft tissue engineering. The click reaction runs smoothly in aqueous buffer without initiator, catalyst, or other coupling reagents. 
 

Click chemistry in oleochemicals

2011 marked the fourth annual “Workshop on Fats and Oils as Renewable Feedstocks for the Chemical Industry”, held in Karlsruhe, Germany on March 20 – 22, 2011, by abiosus e.V., Non-Profit Association for the Advancement of Research on Renewable Raw Materials.

It has been a timely event reflecting the overall industrial trend to move from petrochemicals towards oleochemicals. The effort is to use renewable fat and oils as raw materials / platform chemicals and to use green and efficient processes in the manufacturing – where click chemistry is to lend a hand.

The champion is thiol-ene addition, initiated either by thermal or photochemical method. In the workshop multiple reports described use of thio-ene click chemistry to prepare monomers such as polyols for polyurethane. Also reported was the introduction of a large variety of functional groups to fatty acids for polyester and polyamides synthesis. Advantages were demonstrated: very high yield, undemanding conditions, insensitivity to oxygen inhibition, and ease of purification.

Application of thiol-ene addition in oleochemicals may present the best opportunity and first breakthrough for click chemistry to get into traditional on-scale chemical industry. Note that currently click chemistry is mostly used for discovery purposes, either in medicinal chemistry or materials science.

BASF press release on Baseclick DNA labeling via click chemistry

BASF press release 8/31/2011

Baseclick GmbH raised an additional 1.2 million Euro from BASF Venture Capital and private investors in the second round of financing. Sequence-specific labeling of DNA with multiple dyes allow "multitasking" in DNA applications.

Two relevant reports are availabe:  
Sunday, May 16, 2010
Notable oligonucleotide modification using click chemistry
Sunday, November 14, 2010
BASF press release on DNA labeling via click chemistry

It has been followed simply because click chemistry is linked to a chemicals industry giant, although loosely.

                        

Ten years of click chemistry summed up

Two recent special issues were dedicated to click chemistry and bioorthogonal chemistry.

1. Chemistry – An Asian Journal, Volume 6, Issue 10, Pages 2565–2847Special Issue: Celebrating the 10th Anniversary of Click Chemistry

October 4, 2011
Guest Editors: Qian Wang, Craig Hawker

2. Accounts of Chemical Research, Volume 44, Issue 9, Pages 651-840Special Issue: A decade of Bioorthogonal Chemistry
September 20, 2011
Guest Editor: Carolyn Bertozzi

Achievements of a decade were summed up and documented in 470-plus pages by active researchers in the field. Editors gave historical perspective as well.

Excellent resources! 

Triazole in polymer under attack by ultrasound 2

A little more work on this topic and two additions:

First, as indicated in the graph, polymer solutions are degraded by ultrasound in a controlled manner. Timothy Mason, Sonochemistry, p 18. 

Second, forward triazole formation, one of the click chemistry examples, was reported to be accelerated by ultrasound, in small molecule context. See the 2011 article and cited ones.
Giancarlo Cravotto et al, "Power ultrasound in metal-assisted synthesis: From classical Barbier-like reactions to click chemistry"
Ultrasonics Sonochemistry Volume 18, Issue 4, July 2011, Pages 836-841

Triazole in polymer under attack by ultrasound

Well, it appears triazole, the iconic click chemistry product,  is under attack by ultrasound, reported by a recent CEN article (and many more coverage to come ?).

It would be more appropriate to put the reported "unclick the click" in the context, as the paper did Bielawski et al, Science 2011, Vol 333, No 6049, 1606 . 

 A few things to point out:

1. a very nice piece of work with ample solid data

2. brings sonochemistry to the front stage (again) using current popular click chemistry

3. similar reactions, reverse Diels-Alder and others are known chemistry

4. With a few scattered exceptions, physical methods such as ultrasound, light, microwave, etc, have yet to prove themselves on large scale in chemicals industry

5. Is forward triazole click chemistry aided by untrasound? Interesting to know

6. Note small molecules or small PMA polymers do not experience this untrasound unclick chemistry

7. Note the triazole linkage needs to be in the center of the PMA chain for this chemistry

8. This chemistry does NOT have much to do with triazole click chemistry or click chemistry in general 

9. Triazole group is known for its stability, hydrogen-bonding capability, amide-analogy, and its resistance to a wide range of chemicals 

Well, so much for now. Will work on triazole groupd chemistry / reactivity. 

Synthesis of very long DNA by click chemistry, functional in E Coli

Very long DNA synthesized by click chemistry was functional in E Coli and in PCR templating.

Click chemistry in RNA - marrying Uridine and Azidocoumarin

Marrying Uridine and Azidocoumarin provided a multifunctional sensing moiety in RNA which allows photoaffinity labeling and click chemistry. The key elements are summarized in the drawing below.

Mark Helm et al, Nucleic Acids Research, doi:10.1093/nar/gkr449 published June 6, 2011

Click chemistry Now and Then

Click chemistry "now and then" by numbers

No intention to be exclusive or "scientific", this is to perform a simple "statistical" count on click chemistry application in different areas . A "historical" view is provided by comparing two periods, 1999-2007 for "then" and 2011 ( Jan 1 - June 12) for "now". The data for the first period was from Sharpless laboratory's compilation of click chemistry (937 articles). The data for the second period was from a Chemical Abstract search (525 articles). 

Published articles titles were searched by selected key words and the counts are recorded as a simplified reflection of research intensity or trend. The format is "key word / number from 1st period / number from 2nd period.   

click /415/308
click chemistry /262/178
poly- /389/371
polymer /173/253
dendrimer /37/15
material /17/52
dye /2/6
fluorescence & fluorescent / 12/14
cyclodextrin /4/12
drug /26/21
inhibitor /34/25
enzyme /16/6
screen /9/3
combinatorial /10/1
Sharpless /105/1
Huisgen /22/3
synthesis /315/150
cycloaddition /121/24
nano /51/71
epoxide /9/0
triazole /129/47
Diels-Alder /12/2
water /34/9
ligation /21/5
conjugate /49/46
bioconjugate /16/21
oligo /26/16
DNA /24/18
protein /48/29
peptide /51/32
glyco /64/53
sugar /7/7

The first period was roughly the rising and maturation of click chemistry over a few years (937) while the second is the application of click chemistry in many fields in merely half a year (525). Although to obvious dissatisfaction of statisticians it is safe to conclude that click chemistry is much more widely used now than then.  
                                                       

Large Stokes Shift Dyes for Click Chemistry Applications

Large Stokes Shift Dyes feature a large separation between absorption and emission and allow unique advantages for  multiplexing, FRET and other applications. This is to summarize a few large Stokes shift dyes from recent literature and vendors, including several large Stokes shift dyes carried by Sigma-Aldrich for click chemistry applications. Synthetic or natural polymers and nano particles are not included.

Oligosaccharide Cellulose Membrane by click chemistry for Virus Adsorption

Previously Hatanaka and coworkers demonstrated that production of oligosaccharides (sialyl lactoside derivatives) was achieved by using saccharide primers (azidododecyl beta-lactosides) and B16 cells. 

Chemistry & Biodiversity, 2005, 1063.


Now they have used click chemistry to modify carboxymethylated cellulose (CMC) with terminal alkyne functional groups and introduced oligosaccharide via triazole clcik chemistry. The membrane was shown to have adsorption ability of influenza virus. The click chemistry is shown in the drawing.

The Open Chemical and Biomedical Methods Journal 2009, 13.

            

Click chemistry for regular linking of cellulose nanocrystals

Earth Day - take a look at cellulose, the natural polysaccharide, with beta(1->4) linked D-glucose units.

Here is an interesting article using click chemistry for regular linking of cellulose nanocrystals. The chemistry is shown in the drawing (go green). Modification with azido and terminal alkyne groups is followed by the triazole click chemistry catalyzed by CuSO4-ascrobic acid system. The cellulose nanocrystals were characterized by FTIR, elemental analysis, TGA, gel permeation chromatography, and TEM. The work allows  unique regular packing arrangement at nanochemistry level.

Biomacromolecules, 2010, 1060. Argyropoulos et al.
                     
              

Danishefsky Cyclobutenone in Diels-Alder Reaction

JACS 2010, 11004

Diels-Alder has been a beautiful and powerful cycloadition reaction for many masters such as Woodward. It is an atom-efficient, 4+2, environment-insensitive ring-formation reaction and fits click chemistry concept in many aspects . 

Danishefsky's work expanded its scope by using cyclobutenone as a highly reactive dienophile. The strained cyclobutanone in the Diels-Alder product undergoes regioselective ring-expansion to give cyclopentanone, lactam, lactone. As an example indicated in the graph, the approach provides a variety of structures not accesible via direct Diels-Alder reaction.      
                    

Shapless video of applied click chemistry

NIST Colloquium Series: Applied Click Chemistry: From Dyeing Cotton to Drug Discovery


Click the link above and listen to (and watch) click chemistry described by K Barry Sharpless himself!

He gave the speech at the NIST Colloquium, December 15, 2006. In almost 1.5 hours he described click chemistry as a molecular approach that uses the most practical or reliable chemical transformations in a variety of applications.

                                                                     

Setting standards for polymer click chemistry

Angew Chem. Int. Ed. 2011, 50, 60-62. DOI: 10.1002/anie.201003707
A group of polymer click chemistry leaders have tried to set the standards for the field - and for the terminology "polymer click chemistry" to be meaningful. 

To add a few other points. Polymer chemistry has been using the most efficient reactions for a long time, before the click chemistry philosophy. Core values of click chemistry need to be defended - many published claims are not in the spirit of click chemistry.Click chemistry is not equal to "efficient" or "successful". Click chemistry should meet the set high standards and remain fluid as a philosphy. Exceptions should be allowed in extremely challenging complex systems, such as "spying on" the activities inside a live cell.    
                                                        

Cholesterol & protein studied by Click chemistry

Chemical Communications Received 31st October 2010, Accepted 21st December 2010 DOI: 10.1039/c0cc04710d

Tate and coworkers from Imperial College London reported the bioorthogonal click chemistry of a fluorescent alkyne probe with azido-modified post-translationally cholesterylated proteins - in living cells. The design is shown in the drawing. This enables rapid multiplexed fluorescence detection and affinity labelling of protein cholesterylation. This method, in comparison with the current radiolabeling, offers safety, speed, sensitivity, and flexibility. It may allow the observation of protein cholesterylation over space and time using fluorescence microscopy.

In more complex and challenging environment, click chemistry has found application and success, only due to its extremely high efficiency and orthogonality.