ABSTRACT
The syntheses of 2-methoxyestradiol analogs with modifications at the 3-position are described. The analogs were assessed for their antiproliferative, antiangiogenic, and estrogenic activities. Several lead substituents were identified with similar or improved antitumor activities and reduced metabolic liability compared to 2-methoxyestradiol.
Subject(s)
Estradiol/analogs & derivatives , Spindle Apparatus/drug effects , 2-Methoxyestradiol , Animals , Cell Proliferation/drug effects , Cells, Cultured , Drug Screening Assays, Antitumor , Estradiol/pharmacology , Estradiol/therapeutic use , Humans , Male , Mice , Mice, Nude , Models, Molecular , Xenograft Model Antitumor Assays/methods , Xenograft Model Antitumor Assays/statistics & numerical dataABSTRACT
The chelation potential of highly lipophilic C-dimethylthiolated monocyclic beta-lactams was examined using electrospray ionization mass spectrometry (ESI-MS). The metal salts NaCl, KCl, CaCl2, ZnCl2, Cu(NO3)2, CdSO4, MnCl2, and Mg(NO3)2 were used for the analysis. The K+ adducts of the compounds studied were more responsive in ESI analysis, compared to their Na+ adducts, regardless of the oxidation state of the sulfur (in the methylthio or the sulfone groups) and the type of the group adjacent to the lactam carbonyl. Opening of the beta-lactam ring, leading to formation of a chargeable N-atom, had little to no effect on the K+ adduct formation. Interactions of the methylthio group with the divalent zinc ion were also observed.
Subject(s)
Mass Spectrometry , Metals/chemistry , Spectrometry, Mass, Electrospray Ionization , Sulfones/metabolism , beta-Lactams/metabolism , Cations/chemistry , Cations/metabolism , Molecular Structure , Solutions/chemistry , Sulfones/chemistry , Water/chemistry , beta-Lactams/chemical synthesis , beta-Lactams/chemistryABSTRACT
4-Aryl-substituted N-thiolated beta-lactams are a new family of antibacterial agents possessing unique structure-activity profiles and a mode of action. Unlike traditional beta-lactam antibiotics, which require highly polar enzyme-binding groups, these lactams bear hydrophobic groups on their side chains. In this study, we examine the effect that increasing hydrophobicity, through fluorine substitution in the C(4) aryl ring, has on the antibacterial properties.