Research Summary
Near-IR Uncaging Chemistry: Discovery and Applications
Many
key fundamental and applied questions in biology require unraveling
issues relating to the spatial and temporal organization of
multi-cellular systems. The combination of photocaged small molecule
probes and the spatially controlled application of light could in
principle provide key insights. However, existing photoremovable caging
groups are often not suitable, particularly for organismal applications.
This is due to the general requirement of UV or blue light, which
suffers from associated toxicity and poor tissue penetration. By
contrast, light between 650 and 900 nm, often referred to as the near-IR
window, is cytocompatible and has significant tissue penetration
(~centimeters). My group develops new single photon near-IR uncaging
methods. This is a challenging chemistry problem because these
wavelengths have only modest photonic energy. Our approach is been to
define and then take advantage of photochemical reactions of
long-wavelength fluorophores. In our most advanced project, we have
shown that the photooxidative reactivity of heptamethine cyanines can be
used for small molecule drug delivery. We have also shown that the
photoredox ligand exchange of silicon phthalocyanines can be used for
hypoxia-selective drug delivery. We use our methods towards two key
unmet challenges in biology: (1) the development of a general
theranostic approach for site-specific optical imaging and drug delivery
and (2) the spatial and temporal regulation of gene expression to track
and control cell fate.
Modern Synthetic Approaches for Small Molecule Imaging
There
is a significant need for improved near-IR fluorophores for emerging
applications in basic and applied biomedical science. Existing molecules
are often prepared through inefficient classical synthetic methods that
suffer from poor substrate scope and harsh reaction conditions. The
limitations of existing methodologies dictate that researchers must
choose from a small collection of probes whose chemical and physical
properties are not ideal. We create reactions that enable the efficient
preparation of novel near-IR fluorophores. We then use this chemistry to
develop molecules with excellent chemical and photochemical stability
and improved optical properties. These molecules are then applied
towards several key cancer-related imaging applications. In related
efforts, we are mining the structural diversity of natural products for
light emitting scaffolds to develop broadly useful optical probes. Key
to this work is the development of concise total syntheses to access
compounds of interest.
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1) Nani RR, Shaum JB, Gorka AP, Schnermann MJ.
Electrophile-integrating smiles
rearrangement provides previously inaccessible c4"-o-alkyl heptamethine
cyanine fluorophores.
Org. Lett. 17: 302-5, 2015.
[Journal]
2) Chan
Susanna T S, Patel Paresma R, Ransom Tanya R, Henrich Curtis J, McKee
Tawnya C, Goey Andrew K L, Cook Kristina M, Figg William D, McMahon
James B, Schnermann Martin J, Gustafson Kirk R.
Structural Elucidation and Synthesis of
Eudistidine A: An Unusual Polycyclic Marine Alkaloid that Blocks
Interaction of the Protein Binding Domains of p300 and HIF-1α.
J.+Am.+Chem.+Soc. 137: 5569-75, 2015.
[Journal]
3) Gorka AP, Nani RR, Zhu J, Mackem S, Schnermann MJ.
A Near-IR Uncaging Strategy Based on Cyanine Photochemistry.
J. Am. Chem. Soc. 136: 14153-14159, 2014.
Full Text Article.
[Journal]
4) Schnermann MJ, Shenvi RA.
Syntheses and biological studies of marine terpenoids derived from inorganic cyanide.
Nat Prod Rep. 2014.
[Journal]
5) Schnermann MJ, Overman LE.
A Concise Synthesis of (-)-Aplyviolene
Facilitated by a Strategic Tertiary Radical Conjugate Addition.
Angew. Chem. Int. Ed. Engl. 2012.
[Journal]
1) Schnermann MJ, Gorka
AJ, Kobayashi HJ, Nani RJ (submitted in 2015) Near-ir Light-cleavable
Conjugates And Conjugate Precursors.
Patent pending:
62/204,381 (US application).
Patent pending:
62/204,381 (US application).
2) Gustafson KR, Chan
SR, Figg WR, McMahon JR, Patel PR, Schnermann MR (submitted in 2015)
Hypoxia-inducible Factor 1 Hif-1 Inhibitors.
Patent pending:
62/144,182 (US application).
Patent pending:
62/144,182 (US application).
