SELF-IMMOLATIVE CHEMISTRY:
Structural Features and Applications in
Designing Smart Materials
Wei Sheng
1/15/14
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What is “Self-immolative”?
A Changeable Plastic Film
15min, 23˚C
0.3 M TBAF
THF/PBS
EtOAc
Seo, W.; Phillips, S. T. J. Am. Chem. Soc. 2010, 132, 9234-9235.
2
What is “Self-immolative”?
The trick is…….
?
Seo, W.; Phillips, S. T. J. Am. Chem. Soc. 2010, 132, 9234-9235.
3
What is “Self-immolative”?
Self-Immolative: the Nature of PPHA
Ceiling Temperature:
Tpolymerization = Tdepolymerization
-40 ˚C
180 ˚C
SELF-IMMOLATIVE
F- responsive:
Ito, H.; Wilson, C. G. Polym. Eng. Sci. 1983, 23, 1012-1018.
Seo, W.; Phillips, S. T. J. Am. Chem. Soc. 2010, 132, 9234-9235.
Pd(II) responsive:
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Basic Structures
Structures and Degradation Patterns
Type I: Via Quinone-Methide Cascade
1,6-elimination
Modification Tolerance
Senter, P. D.; Pearce, W. E.; Greenfield, R. S.; J. Org. Chem. 1990, 55, 2975-2978.
Li, S.; Szalai, M. L.; Kevwitch, R. M.; McGrath, D. V. J. Am. Chem. Soc. 2003, 125, 10516-10517.
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Basic Structures
Structures and Degradation Patterns
Type I: Via Quinone-Methide Cascade
1,4-elimination
Modification Tolerance

Sella, E.; Shabat, D. J. Am. Chem. Soc. 2009, 131, 9934-9936.
de Groot, F. M. H.; Loos, W. J.; Koekkoek, R.; et al. J. Org. Chem. 2001, 66, 8815-8830.
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Basic Structures
Structures and Degradation Patterns
Modification Tolerance
Amir, R. J.; Pessah, N.; Shamis, M.; ; Shabat, D. Angew. Chem. Int. Ed. 2003, 42, 4494-4499.
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Basic Structures
Structures and Degradation Patterns
Type II: Via Intramolecular Cyclization Cascade
Modification Tolerance
Type III: Via Hemiacetal Cascade
DeWit, M. A.; Gillies, E. R. J. Am. Chem. Soc. 2009, 131, 18327-18334.
Meyer, Y.; Richard, J-A.; Massonneau, M.; Renard, P-Y.; Romieu, A. Org. Lett. 2008, 10, 1517-1520.
Seo, W; Phillips, S. T. J. Am. Chem. Soc. 2010, 132, 9234-9235.
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Basic Structures
Scope of End-Capping Units
Trigger RXN
Cap
Trigger Class
Self-Immolative-Core
Leaving Moiety
Structure and Response to Stimulus
Peterson, G. I.; Larsen, M. B.; Boydston, A. J. Macromolecules. 2012, 45, 7317-7328.
Stimulus
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Basic Structures
Scope of End-Capping Units
Trigger Class
Structure and Response to Stimulus
Peterson, G. I.; Larsen, M. B.; Boydston, A. J. Macromolecules. 2012, 45, 7317-7328.
Stimulus
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Drug Delivery
Common Issues of Small Molecular Therapeutics
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Drug Delivery
Common Issues of Small Molecular Therapeutics
Severe Adverse Effects
Low Target Specificity
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Drug-Delivery
Prodrug: solution to increase specificity
Prodrug: Precursor of active drug
D
Cleavage Site
Sun, Q.; Wang, J.; Radosz, M.; Shen, Y. Polymer-Based Prodrugs for Cancer Therapy. RSC Polymer Chemistry Series
No. 3 Functional Polymers for Nanomedicine. 2013
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Drug-Delivery
Polymer-Based Prodrug
Biodegradable
Linker
Targeting
Moiety
(antibody)
D
Cleavage Polymer
Site
Backbone
Modifier
(PEGylation)
Self-assembly
Passive Targeting
Prolonged Circulation
No Burst Release
Bui, D.T.; Makismenko, A.; Desmaele, D.; et al, J. Biomacromolecules. 2013, 14, 2837-2847.
Rohini; Neeraj, A.; Anupam, J.; Alok, M. J. Antivir. Antiretrovir. 2013, S15. doi: 10.4172/jaa.S15-007.
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Drug-Delivery
Enhanced Permeability and Retention (EPR)
Angiogenesis
Eldon et. al. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. 2007.
Park K. Quant. Imaging Med. Surg. 2012, 2, 106-113.
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Drug Delivery
Problems with Classical Polymer-based Prodrug
HPMA Polymer
Self-immolative ?
Enzyme selectivity
Peptide Linker
Cleavage efficiency
Release Rate
Drug
• Maximum dosage
• Blood Clearance
• Induced resistance
Seymour, L. W.; Ferry, D. R.; Kerr, D. J.; et al. Int. J. Oncol. 2009, 34, 1629-1636.
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Drug Delivery
How to Speed Up Releasing? Self-Immolative Spacer
Enzyme
S
Drug

Enzyme
Drug
S
Enzyme
Enzyme
S
spacer
Drug
S
Drug
Model System
Carl, P. L.; Chakravarty, P. K.; Katzenellenbogen; J. A. J. Med. Chem. 1981, 24, 479-480.
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Drug Delivery
Length Effect of Self-Immolative Linker
Doxorubicin
1.66
Self-immolative
Spacers
0.82
T50 (h): half-life of complete degradation
0.57
de Groot, F. M. H.; Loos, W. J.; Koekkoek, R.; et al. J. Org. Chem. 2001, 66, 8815-8830.
Plasmin
Substrate
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Drug Delivery
Increase Drug Payload?
Polymer Backbone
G3 dendron
Biodegradable
Focal point
Enzyme approachable?
Lebreton, S.; Newcombe, N.; Bradley, M. Tetrahedron Lett. 2002, 43, 2475-2478.
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Drug Delivery
Self-Immolative Dendron
Erez, R.; Segal, E.; Millier, K.; Satchi-Fainaro, R.; Shabat, D. Bioorg. Med. Chem. 2009, 17, 4327-4335.
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Drug Delivery
Self-Immolative Dendron
Erez, R.; Segal, E.; Millier, K.; Satchi-Fainaro, R.; Shabat, D. Bioorg. Med. Chem. 2009, 17, 4327-4335.
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Drug Delivery
Self-Immolative Comb-Copolymer
Erez, R.; Segal, E.; Millier, K.; Satchi-Fainaro, R.; Shabat, D. Bioorg. Med. Chem. 2009, 17, 4327-4335.
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Drug Delivery
Comparison: Self-immolative vs. Classical
Inhibition of proliferation of TRAMP C2 cells
Erez, R.; Segal, E.; Millier, K.; Satchi-Fainaro, R.; Shabat, D. Bioorg. Med. Chem. 2009, 17, 4327-4335.
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Drug Delivery
Comparison: Self-immolative vs. Classical
Inhibition of proliferation of TRAMP C2 cells
Erez, R.; Segal, E.; Millier, K.; Satchi-Fainaro, R.; Shabat, D. Bioorg. Med. Chem. 2009, 17, 4327-4335.
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Primitive Structure-Degradation Study
Understand the Self-Immolation: Monomer Structure
Model Reaction
Schmid, K. M.; Jensen, L.; Phillips, S. T. J. Org. Chem. 2012, 77, 4363-4374.
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Primitive Structure-Degradation Study
Understand the Self-Immolation: Monomer Structure
Schmid, K. M.; Jensen, L.; Phillips, S. T. J. Org. Chem. 2012, 77, 4363-4374.
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Primitive Structure-Degradation Study
Understand the Self-Immolation: Chain Length
Robbins, J. S.; Schmid, K. M.; Phillips, S. T. J. Org. Chem. 2013, 78, 3159-3169.
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Primitive Structure-Degradation Study
Understand the Self-Immolation: Chain Length
McBride, R. A.; Gillies, E. R. Macromolecules. 2013, 46, 5157-5166.
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Chemical Sensing
Chemical Sensing in Our lives
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Chemical Sensing
For example,
Fluoride
US EPA Maximum Contaminant Level = 4ppm
WHO guideline = 1.5 ppm
Palladium
European Medical Agency
PdCl2 LD50= 3 mg/Kg body weight
Website of United States Environmental Protection Agency
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Chemical Sensing
Traditional Chemical Sensing
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Chemical Sensing
Current Methods: Reaction-based Indication
λem = 596 nm
Nonfluorescent
λem = 612 nm
LoD = 70 μM
Highly fluorescent
LoD = 0.5 ppm
Zhu, B.; Kan, H.; Liu, J.; Liu, H.; Wei, Q.; Du, B. Biosensors and Bioelectronics. 2014, 52, 298-303.
Kaur, K.; Saini, R.; Kumar, A.; Luxami, V.; Kaur, N.; Singh, P.; Kumar, S.; Coord. Chem. Rev. 2012, 256, 1992-2008.
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Chemical Sensing
Reaction-based indicator system?
Analyte
Reporter
Trigger
• Reporter efficiency
• Linear Input/Output
Self-immolative
Trigger
cleavage
Cho, D-G.; Sessler, J. L. Chem. Soc. Rev. 2009, 38, 1647-1662.
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Chemical Sensing
Signal amplification: Dendritic-Chain Reaction (DCR)
Trigger 1
Trigger 2
Sella, E.; Shabat, D. J. Am. Chem. Soc. 2009, 131, 9934-9936.
Trigger 2
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Chemical Sensing
DCR technique
LoD = 5 μM
Sella, E.; Shabat, D. J. Am. Chem. Soc. 2009, 131, 9934-9936.
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Chemical Sensing
DCR technique
Use fluoride to detect fluoride
LoD = 2 μM
Inspiration from Nature
Feigenbaum-Perry, R.; Sella, E.; Shabat, D. Chem. Eur. J. 2011, 17, 12123-12128.
Zhu, L.; Anslyn, E. V. Angew. Chem. Int. Ed. 2006, 45, 1190-1196.
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Chemical Sensing
2 Components DCR
Trigger 1
Trigger 2
Trigger 2
Sella, E.; Lubelski, A.; Klafter, J.; Shabat, D. J. Am. Chem. Soc. 2010, 132, 3945-3952.
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Chemical Sensing
A Surprisingly Simple Pd(II) Sensing Array
LoD = 0.36 ppm
Baker, M. S.; Phillips, S. T. J. Am. Chem. Soc. 2011, 133, 5170-5173.
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Chemical Sensing
NOT just a reaction
A prototype paper-based chip quantifying active enzymes
Tmeasurement = Ttotal - Tassay
Alkaline Phosphatase:
320 pM - 14.8 nM
Lewis, G. G.; Robbins, J. S.; Phillips, S. T. Anal. Chem. 2013, 85, 10432-10439.
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Chemical Sensing
The Fabrication
HEPES
buffer
MgCl2
Enzyme substrate
& immoblized GOx
Hydrophilic
paper
Hydrophobic Enzyme
paper
substrate
Lewis, G. G.; Robbins, J. S.; Phillips, S. T. Anal. Chem. 2013, 85, 10432-10439.
Green
Dye
Self-immolative
oligomer
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Chemical Sensing
General Working Principle
Lewis, G. G.; Robbins, J. S.; Phillips, S. T. Anal. Chem. 2013, 85, 10432-10439.
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Funny
Again, don’t limit chemistry to the reactions!
A single-use analyte-responsive microscale pump
Zhang, H.; Yeung, K.; Robbins, J. S.; et al. Angew. Chem. Int. Ed. 2012, 51, 2400-2404.
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Acknowledgement
• Dr. Babak Borhan,
• Dr. Xuefei Huang,
• Arvind, Kumar, Tanya, Ipek, Nastaran, Hadi,
Bardia, Yi, Liz, Edy, Jun, Xinliang,
• Zeren, Tayeb.
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