| 1. |
- Jian, L. A., et al.
(författare)
-
Discovery of Aminoratjadone Derivatives as Potent Noncovalent CRM1 Inhibitors
- 2023
-
Ingår i: Journal of Medicinal Chemistry. - 0022-2623. ; 66:17, s. 11940-50
-
Tidskriftsartikel (refereegranskat)abstract
- Cancer cells frequently utilize elevated nuclear exportto escapetumor suppression and gain proliferative advantage. Chromosome RegionMaintenance 1 (CRM1/XPO1) mediates macromolecule nuclear export andplays an important role in tumorigenesis and progression. The clinicalapproval of its covalent inhibitor KPT-330 (Selinexor) validates thefeasibility of targeting CRM1 to treat cancers. Here, we synthesizedfour aminoratjadone derivatives and found that two of them, KL1 and KL2, are noncovalent CRM1 inhibitors.The two compounds underwent spontaneous hydrolysis in aqueous buffers,and the resulting products were more active against CRM1. High-resolutioncrystal structures revealed the CRM1-binding mode of these compoundsand explained the observed structure-activity relationships.In cells, KL1 and KL2 localized CRM1 inthe nuclear periphery and led to depletion of nuclear CRM1, therebyinhibiting the nuclear export and growth of colorectal cancer cellsat submicromolar concentrations. This work lays the foundation forfurther development of aminoratjadone-based noncovalent CRM1 inhibitors.
|
|
| 2. |
- Rohrbacher, C., et al.
(författare)
-
Synthesis of an Antimicrobial Enterobactin-Muraymycin Conjugate for Improved Activity Against Gram-Negative Bacteria
- 2023
-
Ingår i: Chemistry-a European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 29:5
-
Tidskriftsartikel (refereegranskat)abstract
- Overcoming increasing antibiotic resistance requires the development of novel antibacterial agents that address new targets in bacterial cells. Naturally occurring nucleoside antibiotics (such as muraymycins) inhibit the bacterial membrane protein MraY, a clinically unexploited essential enzyme in peptidoglycan (cell wall) biosynthesis. Even though a range of synthetic muraymycin analogues has already been reported, they generally suffer from limited cellular uptake and a lack of activity against Gram-negative bacteria. We herein report an approach to overcome these hurdles: a synthetic muraymycin analogue has been conjugated to a siderophore, i. e. the enterobactin derivative Ent(KL), to increase the cellular uptake into Gram-negative bacteria. The resultant conjugate showed significantly improved antibacterial activity against an efflux-deficient E. coli strain, thus providing a proof-of-concept of this novel approach and a starting point for the future optimisation of such conjugates towards potent agents against Gram-negative pathogens.
|
|
| 3. |
|
|
