View
125
Download
1
Category
Tags:
Preview:
DESCRIPTION
In situ Click chemistry. Mgr. Juraj Dobia š KOCH, PRIF UK . What is Click Chemistry ?. joining molecules by an „ ideal chemical reaction “ fast, irreversible reaction, simple conditions starting materials are readily available, stable (biocompatible ) - PowerPoint PPT Presentation
Citation preview
In situ Click chemistry
Mgr. Juraj DobiašKOCH, PRIF UK
joining molecules by an „ideal chemical reaction“ • fast, irreversible reaction, simple conditions• starting materials are readily available, stable
(biocompatible)• high yielding, high atom economy, wide application• large thermodynamic driving force to give predictable
outcome• easy work-up and product isolation • preferably proceeding in water, insensitive to oxygen• the best by some fusion reaction:
What is Click Chemistry ?
O
N N N
NN
N
O
Synthesis of 1,2,3-triazoles
R1R2 N
NN
14
R1N
NN
R2
4 15
Thermal Huisgen [3+2] cycloaddition• 80-120°C, 12-24h, both regioisomers ca 1/1
E#A= 24-26 kcal/mol
Cu(I) catalyzed (CuSO4 / sodium L-ascorbate)
• only 1,4-regioisomer, high yield, rt, t-BuOH / water environment E#
A= 15 kcal/mol (106 times faster than Huisgen r.)
Ru catalyzed (Cp*RuCl(PPh3)2)
• mainly 1,5-regioisomer
2002, Fokin, Sharpless Melda
1950-70 Huisgen
2005, FokinShrapless
Click Chemistry Exploitation• Material sciences (copolymers, functionalized surfaces, adhesives,
dendrimers, large macrocycles, ....)
• Bioorganic chemistry (biosensors, bioconjugates: tagging of proteins, nucleotides or in situ whole organisms, SPAAC – no metal)
Drug development – Medicinal Chemistry
HO
DIBO
MMps inhibitors
12
8
MMP7 selective, low mcM inhibitors
Org. Lett. 8 2006 3821-24.
Cu(I)
In Situ Click Chemistry (TDS) target driven synthesis
TDS reduces the number of inactive compounds
Compensate the lack of precision in the predictive ability of in Silico chemistry
In situ AA Click chemistry is completely biocompatible, uses irreversible reaction to unite reagents inside the protein´s binding pocket
Target will pick best fitting ligands from diverse sets of chemical building blocks
Significant portion of the activation barrier is entropic (pieces have to approach each other in precisely the right orientation), pre-assembly of building blocks on the target active site can accelerate cycloaddition.
DDT 9 2004 348.
Observation of the controlled assembly of preclickcomponents in the in situ click chemistry
generation of a chitinase inhibitor
• chitinase inhibitors fight against infectious and inflammatory diseases – onchocerciasis.
• screening of over 10,000 extracts from soil microorganisms
2013 PNAS 110 15892-97
In situ clickO
N3
ON
NH
NH
NH O
NH
71 randomly selecteddiverse alkynes
ONN
N
ON
N
580 nM
22 nM
ON
NH
NH
NH O
NH
Triazole komplex
NH
NH
NH O
NH
ON
NH
ONNN
ON
Asp142Glu144
Asp215Arg294
Trp403
Arg338
N
Trp220
Trp973WD1
Captured transition state
NH
NH
NH O
NH
ON
NH
ONN
ON
Asp142Glu144
Asp215Arg294
Trp403
N
Trp220
Trp97
N
• Alkene doesn’t cocrystalyze without azide even at high concentration – induced fit.• Different pose of azide with and without alkene – double induced fit.
NH
NH
NH O
NH
Asp142Glu144
Asp215Trp403
Arg338
NHO
NNN
O
N
Arg294
3WD2 3WD4
Summary
• Identified triazole inhibitor of chinase B by in situ click chemistry approach.
• Solved crystal structure of transition state with alkene analog.• Performed DFT calculations, but did not observe any enthaplic
barrier decrease.• Confirmed in situ click chemistry principle that increase in reaction
rate is caused by entropic factors and greater effective concentration.
• Solved crystal structures that demonstrate protein flexibility and lack of in silico methods accuracy.
Recommended