Metallo-β-lactamases
(MBLs) can efficiently catalyze the
hydrolysis of all classes of β-lactam antibiotics except monobactams.
While serine-β-lactamase (SBL) inhibitors (e.g., clavulanic
acid, avibactam) are established for clinical use, no such MBL inhibitors
are available. We report on the synthesis and mechanism of inhibition
of
N
-sulfamoylpyrrole-2-carboxylates (NSPCs) which
are potent inhibitors of clinically relevant B1 subclass MBLs, including
NDM-1. Crystallography reveals that the
N
-sulfamoyl
NH
2
group displaces the dizinc bridging hydroxide/water
of the B1 MBLs. Comparison of crystal structures of an NSPC and taniborbactam
(VRNX-5133), presently in Phase III clinical trials, shows similar
binding modes for the NSPC and the cyclic boronate ring systems. The
presence of an NSPC restores meropenem efficacy in clinically derived
E. coli
and
K. pneumoniae bla
NDM-1. The
results support the potential of NSPCs and related compounds as efficient
MBL inhibitors, though further optimization is required for their
clinical development.
A number of 24-norbrassinolide biosynthetic precursors containing low polar functional groups (3beta3-OH, 3-keto-, delta2- or 2alpha,3alpha-epoxy-) in A-cycle and (22R,23R)-diol in the side chain has been prepared. Studies of these compounds as proliferation regulators in MCF-7 human breast cancer and LnCaP human prostate adenocarcinoma cells showed that most nonpolar (22R,23R)-derivatives effectively suppressed proliferation. Dependence of proliferation on concentration of studied compounds was found in human prostate carcinoma LnCaP cells (IC50 = 13-28 microM at 72 h of incubation in a medium containing 10% FBS; suppression of DNA biosynthesis). A number of compounds induced apoptosis (23-33%); arrested cell cycle in S- and G2/M-phases; and caused partial cells detachment during prolonged incubations.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.