29144-95-4

Upstream product

• 21950-36-7 5'-amino-5'-deoxy-2',3'-O-isopropylideneadenosine 

Downstream Products

• 213554-35-9 5'-deoxy-2',3'-O-(1-methylethylidene)-adenosine 5'-N-(N-tertbutoxycarbonyl-L-phenylalanyl)sulfamide 

Relevant academic research and scientific papers

Biosynthesis, Mechanism of Action, and Inhibition of the Enterotoxin Tilimycin Produced by the Opportunistic Pathogen Klebsiella oxytoca

Tilimycin is an enterotoxin produced by the opportunistic pathogen Klebsiella oxytoca that causes antibiotic-associated hemorrhagic colitis (AAHC). This pyrrolobenzodiazepine (PBD) natural product is synthesized by a bimodular nonribosomal peptide synthetase (NRPS) pathway composed of three proteins: NpsA, ThdA, and NpsB. We describe the functional and structural characterization of the fully reconstituted NRPS system and report the steady-state kinetic analysis of all natural substrates and cofactors as well as the structural characterization of both NpsA and ThdA. The mechanism of action of tilimycin was confirmed using DNA adductomics techniques through the detection of putative N-2 guanine alkylation after tilimycin exposure to eukaryotic cells, providing the first structural characterization of a PBD-DNA adduct formed in cells. Finally, we report the rational design of small-molecule inhibitors that block tilimycin biosynthesis in whole cell K. oxytoca (IC50 = 29 ± 4 μM) through the inhibition of NpsA (KD = 29 ± 4 nM).

Synthesis and inhibitory activity of mechanism-based 4-coumaroyl-CoA ligase inhibitors

4-Coumaroyl-CoA ligase (4CL) is ubiquitous in the plant kingdom, and plays a central role in the biosynthesis of phenylpropanoids such as lignins, flavonoids, and coumarins. 4CL catalyzes the formation of the coenzyme A thioester of cinnamates such as 4-coumaric, caffeic, and ferulic acids, and the regulatory position of 4CL in the phenylpropanoid pathway renders the enzyme an attractive target that controls the composition of phenylpropanoids in plants. In this study, we designed and synthesized mechanism-based inhibitors for 4CL in order to develop useful tools for the investigation of physiological functions of 4CL and chemical agents that modulate plant growth with the ultimate goal to produce plant biomass that exhibits features that are beneficial to humans. The acylsulfamide backbone of the inhibitors in this study was adopted as a mimic of the acyladenylate intermediates in the catalytic reaction of 4CL. These acylsulfamide inhibitors and the important synthetic intermediates were fully characterized using two-dimensional NMR spectroscopy. Five 4CL proteins with distinct substrate specificity from four plant species, i.e., Arabidopsis thaliana, Glycine max (soybean), Populus trichocarpa (poplar), and Petunia hybrida (petunia), were used to evaluate the inhibitory activity, and the half-maximum inhibitory concentration (IC50) of each acylsulfamide in the presence of 4-coumaric acid (100 μM) was determined as an index of inhibitory activity. The synthetic acylsulfamides used in this study inhibited the 4CLs with IC50 values ranging from 0.10 to 722 μM, and the IC50 values of the most potent inhibitors for each 4CL were 0.10–2.4 μM. The structure–activity relationship observed in this study revealed that both the presence and the structure of the acyl group of the synthetic inhibitors strongly affect the inhibitory activity, and indicates that 4CL recognizes the acylsulfamide inhibitors as acyladenylate mimics.

SULFANIDE ADENOSINE DERIVATIVES AND USES THEREOF

Described herein are sulfamide adenosine derivatives of Formula (I) or (II), and pharmaceutically acceptable salts, and pharmaceutical compositions thereof. Also provided are methods, uses, and kits involving the inventive compounds or pharmaceutical compositions for treating and/or preventing proliferative diseases (e.g., cancers, inflammatory diseases, and autoimmune diseases) or infectious diseases (e.g., bacterial infections, viral infections, fungal infections, and parasitic diseases) in a subject. The compounds and pharmaceutical compositions as described herein are thought to inhibit aminoacyl tRNA synthetase activity in a biological sample or subject to achieving the treatment of proliferative diseases or infectious diseases.