Structure-activity relationships OF N-methylthiolated beta-lactam antibiotics with C3 substitutions and their selective induction of apoptosis in human cancer cells.
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.
Kuhn
Deborah J
DJ
The Prevention, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA.
Wang
Yang
Y
Minic
Vesna
V
Coates
Cristina
C
Reddy
G Suresh Kumar
GS
Daniel
Kenyon G
KG
Shim
Jeung-Yeop
JY
Chen
Di
D
Landis-Piwowar
Kristin R
KR
Miller
Fred R
FR
Turos
Edward
E
Dou
Q Ping
QP
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*
D000900:Anti-Bacterial Agents; D047090:beta-Lactams