SELF-IMMOLATIVE CHEMISTRY: Structural Features and Applications in Designing Smart Materials

Wei Sheng

1/15/14

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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.

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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.

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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

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Common Issues of Small Molecular Therapeutics

Drug Delivery

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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.

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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.

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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.

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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?

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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.

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

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.

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Primitive Structure-Degradation Study

Understand the Self-Immolation: Chain Length

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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

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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.

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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

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Chemical Sensing

General Working Principle

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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.

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Acknowledgement