SELF-IMMOLATIVE CHEMISTRY: Structural Features and Applications in Designing Smart Materials
Wei Sheng
1/15/14
1
A Changeable Plastic Film
Seo, W.; Phillips, S. T. J. Am. Chem. Soc. 2010, 132, 9234-9235. 2
What is “Self-immolative”?
15min, 23˚C
0.3 M TBAF
THF/PBS
EtOAc
Seo, W.; Phillips, S. T. J. Am. Chem. Soc. 2010, 132, 9234-9235. 3
What is “Self-immolative”?
The trick is…….
?
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. 4
What is “Self-immolative”?
Self-Immolative: the Nature of PPHA
Ceiling Temperature:
Tpolymerization = Tdepolymerization
180 ˚C -40 ˚C
SELF-IMMOLATIVE
F- responsive: Pd(II) responsive:
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. 5
Basic Structures
Structures and Degradation Patterns
Type I: Via Quinone-Methide Cascade
1,6-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.
6
Basic Structures
Structures and Degradation Patterns
Type I: Via Quinone-Methide Cascade
1,4-elimination
Modification Tolerance
Amir, R. J.; Pessah, N.; Shamis, M.; ; Shabat, D. Angew. Chem. Int. Ed. 2003, 42, 4494-4499. 7
Basic Structures
Structures and Degradation Patterns
Modification Tolerance
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.
8
Basic Structures
Structures and Degradation Patterns
Type II: Via Intramolecular Cyclization Cascade
Type III: Via Hemiacetal Cascade
Modification Tolerance
Peterson, G. I.; Larsen, M. B.; Boydston, A. J. Macromolecules. 2012, 45, 7317-7328. 9
Basic Structures
Scope of End-Capping Units
Trigger Class Structure and Response to Stimulus Stimulus
Cap Self-Immolative-Core Leaving Moiety
Trigger RXN
10 Peterson, G. I.; Larsen, M. B.; Boydston, A. J. Macromolecules. 2012, 45, 7317-7328.
Basic Structures
Scope of End-Capping Units
Trigger Class Structure and Response to Stimulus Stimulus
11
Common Issues of Small Molecular Therapeutics
Drug Delivery
12
Drug Delivery
Common Issues of Small Molecular Therapeutics
Low Target Specificity
Severe Adverse Effects
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 13
Prodrug: solution to increase specificity
Drug-Delivery
D Cleavage Site
Prodrug: Precursor of active drug
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. 14
Polymer-Based Prodrug
Drug-Delivery
Cleavage
Site
D
Biodegradable
Linker
Polymer
Backbone
Modifier
(PEGylation)
Targeting
Moiety
(antibody)
Self-assembly
No Burst Release
Passive Targeting
Prolonged Circulation
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.
15
Drug-Delivery
Enhanced Permeability and Retention (EPR)
Angiogenesis
Seymour, L. W.; Ferry, D. R.; Kerr, D. J.; et al. Int. J. Oncol. 2009, 34, 1629-1636.
16
Drug Delivery
Problems with Classical Polymer-based Prodrug
Self-immolative ?
HPMA Polymer
Peptide Linker
Drug
Enzyme selectivity Cleavage efficiency
• Maximum dosage • Blood Clearance • Induced resistance
Release Rate
Drug spacer Drug S
S
Carl, P. L.; Chakravarty, P. K.; Katzenellenbogen; J. A. J. Med. Chem. 1981, 24, 479-480.
17
Drug Delivery
How to Speed Up Releasing? Self-Immolative Spacer
Drug Drug
Model System
Enzyme
Enzyme
Enzyme Enzyme
S S
de Groot, F. M. H.; Loos, W. J.; Koekkoek, R.; et al. J. Org. Chem. 2001, 66, 8815-8830. 18
Drug Delivery
Length Effect of Self-Immolative Linker
T50 (h): half-life of complete degradation
1.66
0.82
0.57 Plasmin
Substrate
Self-immolative
Spacers
Doxorubicin
Lebreton, S.; Newcombe, N.; Bradley, M. Tetrahedron Lett. 2002, 43, 2475-2478. 19
Drug Delivery
Increase Drug Payload?
G3 dendron
Focal point
Polymer Backbone
Biodegradable
Enzyme approachable?
20
Drug Delivery
Self-Immolative Dendron
Erez, R.; Segal, E.; Millier, K.; Satchi-Fainaro, R.; Shabat, D. Bioorg. Med. Chem. 2009, 17, 4327-4335.
21
Drug Delivery
Self-Immolative Dendron
Erez, R.; Segal, E.; Millier, K.; Satchi-Fainaro, R.; Shabat, D. Bioorg. Med. Chem. 2009, 17, 4327-4335.
22
Drug Delivery
Self-Immolative Comb-Copolymer
Erez, R.; Segal, E.; Millier, K.; Satchi-Fainaro, R.; Shabat, D. Bioorg. Med. Chem. 2009, 17, 4327-4335.
Erez, R.; Segal, E.; Millier, K.; Satchi-Fainaro, R.; Shabat, D. Bioorg. Med. Chem. 2009, 17, 4327-4335.
23
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.
24
Drug Delivery
Comparison: Self-immolative vs. Classical
Inhibition of proliferation of TRAMP C2 cells
Schmid, K. M.; Jensen, L.; Phillips, S. T. J. Org. Chem. 2012, 77, 4363-4374. 25
Primitive Structure-Degradation Study
Understand the Self-Immolation: Monomer Structure
Model Reaction
26 Schmid, K. M.; Jensen, L.; Phillips, S. T. J. Org. Chem. 2012, 77, 4363-4374.
Primitive Structure-Degradation Study
Understand the Self-Immolation: Monomer Structure
Robbins, J. S.; Schmid, K. M.; Phillips, S. T. J. Org. Chem. 2013, 78, 3159-3169. 27
Primitive Structure-Degradation Study
Understand the Self-Immolation: Chain Length
McBride, R. A.; Gillies, E. R. Macromolecules. 2013, 46, 5157-5166.
28
Primitive Structure-Degradation Study
Understand the Self-Immolation: Chain Length
29
Chemical Sensing
Chemical Sensing in Our lives
Fluoride US EPA Maximum Contaminant Level = 4ppm
WHO guideline = 1.5 ppm
Website of United States Environmental Protection Agency 30
For example,
Chemical Sensing
Palladium European Medical Agency
PdCl2 LD50= 3 mg/Kg body weight
31
Traditional Chemical Sensing
Chemical Sensing
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.
32
Chemical Sensing
Current Methods: Reaction-based Indication
LoD = 70 μM λem = 596 nm λem = 612 nm
LoD = 0.5 ppm
Highly fluorescent Nonfluorescent
Cho, D-G.; Sessler, J. L. Chem. Soc. Rev. 2009, 38, 1647-1662. 33
Chemical Sensing
Reaction-based indicator system?
Analyte Reporter Trigger • Reporter efficiency • Linear Input/Output
Self-immolative
Trigger cleavage
34
Trigger 1
Trigger 2 Trigger 2
Sella, E.; Shabat, D. J. Am. Chem. Soc. 2009, 131, 9934-9936.
Chemical Sensing
Signal amplification: Dendritic-Chain Reaction (DCR)
Sella, E.; Shabat, D. J. Am. Chem. Soc. 2009, 131, 9934-9936.
35
Chemical Sensing
DCR technique
LoD = 5 μM
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.
36
Chemical Sensing
DCR technique
LoD = 2 μM
Use fluoride to detect fluoride
Inspiration from Nature
Sella, E.; Lubelski, A.; Klafter, J.; Shabat, D. J. Am. Chem. Soc. 2010, 132, 3945-3952.
37
Chemical Sensing
2 Components DCR
Trigger 1
Trigger 2
Trigger 2
Baker, M. S.; Phillips, S. T. J. Am. Chem. Soc. 2011, 133, 5170-5173.
38
Chemical Sensing
A Surprisingly Simple Pd(II) Sensing Array
LoD = 0.36 ppm
Lewis, G. G.; Robbins, J. S.; Phillips, S. T. Anal. Chem. 2013, 85, 10432-10439.
39
Chemical Sensing
NOT just a reaction
A prototype paper-based chip quantifying active enzymes
Alkaline Phosphatase:
320 pM - 14.8 nM
Tmeasurement = Ttotal - Tassay
Lewis, G. G.; Robbins, J. S.; Phillips, S. T. Anal. Chem. 2013, 85, 10432-10439.
40
Chemical Sensing
The Fabrication
Hydrophobic
paper
Hydrophilic
paper
HEPES
buffer
MgCl2
Green
Dye
Enzyme
substrate
Enzyme substrate
& immoblized GOx
Self-immolative
oligomer
Lewis, G. G.; Robbins, J. S.; Phillips, S. T. Anal. Chem. 2013, 85, 10432-10439.
41
Chemical Sensing
General Working Principle
42
Funny
Again, don’t limit chemistry to the reactions!
Zhang, H.; Yeung, K.; Robbins, J. S.; et al. Angew. Chem. Int. Ed. 2012, 51, 2400-2404.
A single-use analyte-responsive microscale pump
• Dr. Babak Borhan,
• Dr. Xuefei Huang,
• Arvind, Kumar, Tanya, Ipek, Nastaran, Hadi,
Bardia, Yi, Liz, Edy, Jun, Xinliang,
• Zeren, Tayeb.
43
Acknowledgement