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.

N-thiolated β-lactams: Studies on the mode of action and identification of a primary cellular target in Staphylococcus aureus

“…Despite their apparent structural similarities to the penicillins and other members of the β-lactam family of antibiotics, these N-thiolated β-lactam compounds behave in many ways differently to all other known antibacterial β-lactams. First, these Nthiolated compounds only target a few genera of bacteria such as Staphylococcus and Bacillus, yet show anticancer properties [8][9][10][11][12] , and are non-lethal to healthy human cells (fibroblasts). 2 Secondly, the bioactivity of these N-thiolated lactams islargely insensitive to changes in structure of the ring substituents at the C3 and C4 centers of the lactam ring, strongly suggesting that the compounds exert their antibacterial effects on a completely different cellular target and through a different mode of action than previously studied β-lactam antibacterials.…”