title: Structure-activity relationships OF N-methylthiolated beta-lactam antibiotics with C3 substitutions and their selective induction of apoptosis in human cancer cells.
abstract: The development of novel anti-cancer drugs that induce apoptosis has long been a focus of drug discovery. Beta-lactam antibiotics have been used for over 60 years to fight bacterial infectious diseases with little or no side effects observed. Recently a new class of N-methylthiolated beta-lactams has been discovered that have potent activity against methicillin resistant Staphylococcus aureas. Most recently, we determined the potential effects of these N-thiolated beta-lactams on tumorigenic cell growth and found that they are apoptosis-inducers in human cancer cell lines. In the current study, we further determined the effects of the substitution of the O-methyl moiety on C3 and stereochemistry of the beta-lactams on the anti-proliferative and apoptosis-inducing abilities. We have found that lactam 18, in which C3 is substituted with an acrylate ester group, is a very effective proliferation inhibitor against human premalignant and malignant breast, leukemic, and simian virus 40-transformed fibroblast cells. Generally speaking, increasing the size of the moiety on C3 decreases its anti-proliferation potency, possibly indicating steric hindrance with the cellular target or decreased permeability through the cell membrane. We also found that the stereochemistry of the beta-lactams plays an important role in their potency. The 3S,4R isomers are more effective than their enantiomers (3R,4S), suggesting that 3S,4R configuration is more favorable for target interaction.
authors.affiliation: The Prevention, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Kuhn
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Vesna
authors.initials: V
authors.lastname: Minic
authors.forename: Cristina
authors.initials: C
authors.lastname: Coates
authors.forename: G Suresh Kumar
authors.initials: GS
authors.lastname: Reddy
authors.forename: Kenyon G
authors.initials: KG
authors.lastname: Daniel
authors.forename: Jeung-Yeop
authors.initials: JY
authors.lastname: Shim
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Kristin R
authors.initials: KR
authors.lastname: Landis-Piwowar
authors.forename: Fred R
authors.initials: FR
authors.lastname: Miller
authors.forename: Edward
authors.initials: E
authors.lastname: Turos
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D047090:beta-Lactams / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams