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CYCLIZATION-BASED SITE-SELECTIVE N-TERMINAL CYSTEINE CONJUGATION, PEPTIDE STAPLING AND HISTONE DEACETYLASE (HDAC) PROBING
Islam, Md Shafiqul
Islam, Md Shafiqul
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Thesis/Dissertation
Date
2023-08
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Chemistry
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http://dx.doi.org/10.34944/dspace/8946
Abstract
Cyclization reactions play an important role in synthesizing a significant number of small molecule scaffolds for various purposes, including drug discovery. However, the
application of cyclization reactions in the modifications of biomolecules in a single step is
still limited. This dissertation reports a stereoselective thiomorpholine ring formation
reaction to site-selectively modify N-terminal cysteines of unprotected peptides or proteins
in a single step. We showed that α-fluoroketone molecules afford the cyclization reaction
with the beta amino thiol group of N-terminal cysteine. Both chemo and stereo-selectivity
of this reaction have been studied using 2D NMR analyses. Cysteine located at the Nterminal of a short protein (VHP protein) has been modified site-selectively with a
fluorescein isothiocyanate (FITC) containing an α-fluoroketone linker to demonstrate the
applicability of this reaction in modifying biomolecules. This chemistry has the potential
to generate homogeneous and stable antibody-drug conjugates (ADCs) for the treatment of
cancer.
This dissertation also demonstrates a fluorine-thiol displacement reaction (FTDR) to
synthesize various macrocyclic and stapled peptides, which renders medicinally privileged
peptides with improved biological properties such as binding affinities and cell membrane
permeability. The cyclization of fluoroacetamide containing peptides with
benzenedimethane thiol linkers enhances peptides' alpha helicity. These FTDR stapled
peptides exhibit better cellular uptake compared to the classic ring-closing metathesis
(RCM) stapled peptides. Compared to the proteoglycan-aided cell penetration by peptides
stapled with RCM, the preliminary mechanistic studies of our FTDR-stapled peptides revealed that our thiolated linkers allowed peptides to enter cells in multiple pathways.
Taken together, our FTDR-based stapling approach may provide a novel class of cell-permeable peptides that might open a new window to probe intracellular targets.
This dissertation reports another cyclization reaction between hydrazine and carbamate,
synthesized from 7-hdyroxy coumarin derivatives. We demonstrate that the secondary
nitrogen of hydrazine is much more reactive than the primary nitrogen for intramolecular
cyclization reactions. Hydrazine affords urea bonds upon the substitution of a coumarin
moiety of carbamates to generate 6 or 7 membered cyclic scaffolds. The exocyclic free
amine might allow facile generation of a library of compounds. In addition, further
optimization of this reaction might allow using these hydrazine containing molecules in
monitoring the real-time activity of histone deacetylases (HDACs).
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