Targeted covalent
inhibitors are an important class of drugs and
chemical probes. However, relatively few electrophiles meet the criteria
for successful covalent inhibitor design. Here we describe α-substituted
methacrylamides as a new class of electrophiles suitable for targeted
covalent inhibitors. While typically α-substitutions inactivate
acrylamides, we show that hetero α-substituted methacrylamides
have higher thiol reactivity and undergo a conjugated addition–elimination
reaction ultimately releasing the substituent. Their reactivity toward
thiols is tunable and correlates with the p
K
a
/p
K
b
of the leaving group. In
the context of the BTK inhibitor ibrutinib, these electrophiles showed
lower intrinsic thiol reactivity than the unsubstituted ibrutinib
acrylamide. This translated to comparable potency in protein labeling,
in vitro kinase assays, and functional cellular assays, with improved
selectivity. The conjugate addition–elimination reaction upon
covalent binding to their target cysteine allows functionalizing α-substituted
methacrylamides as turn-on probes. To demonstrate this, we prepared
covalent ligand directed release (CoLDR) turn-on fluorescent probes
for BTK, EGFR, and K-Ras
G12C
. We further demonstrate a
BTK CoLDR chemiluminescent probe that enabled a high-throughput screen
for BTK inhibitors. Altogether we show that α-substituted methacrylamides
represent a new and versatile addition to the toolbox of targeted
covalent inhibitor design.
Emergence of multidrug-resistant and extreme-drug-resistant strains of Mycobacterium tuberculosis (MTb) can cause serious socioeconomic burdens. Arabinogalactan present on the cellular envelope of MTb is unique and is required for its survival; access to arabinogalactan is essential for understanding the biosynthetic machinery that assembles it. Isolation from Nature is a herculean task and, as a result, chemical synthesis is the most sought after technique. Here we report a convergent synthesis of branched heneicosafuranosyl arabinogalactan (HAG) of MTb. Key furanosylations are performed using [Au]/[Ag] catalysts. The synthesis of HAG is achieved by the repetitive use of three reactions namely 1,2-trans furanoside synthesis by propargyl 1,2-orthoester donors, unmasking of silyl ether, and conversion of n-pentenyl furanosides into 1,2-orthoesters. Synthesis of HAG is achieved in 47 steps (with an overall yield of 0.09%) of which 21 are installation of furanosidic linkages in a stereoselective manner.
Pyrimidine nucleosides are synthesized by using propargyl 1,2-orthoesters and Au(III) salt as a catalyst. Strategically positioned 1,2-orthoesters are found to yield only 1,2-trans nucleosides and enable preparation of 2'-OH containing pyrimidine nucleosides. The glycosyl donor employed in this study is stable and easily accessible. The identified high-yielding protocol is mild, diastereoselective, and catalytic.
Conjugation is an important reaction that enables coupling of molecules. Many protocols exist for the synthesis of binary conjugates from two different molecules or for the polyvalent display of a single molecule. There aren't many methods for the synthesis of ternary conjugates. However, methods for ternary conjugation are important for understanding the interplay of interactions between three biomolecules (or any three molecules per se). A strategy for ternary bioconjugation using inverse electron demand Diels-Alder reaction with tetrazine is studied. Ternary conjugation was demonstrated by the reaction of a model glyco-peptide binary conjugate with a fluorescent tagged olefin.
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