Beta-lactams and their potential use as novel anticancer chemotherapeutics drugs

Abstract

The discovery of natural and synthetic antibiotics is one of the most important medical breakthroughs in human history. Many diseases, such as bacterial meningitis, pneumonia, and septicemia, are now curable with the use of antibiotics. Antibiotics are efficacious, generally well tolerated in patients, and have a low toxicity level. It is for these reasons antibiotics remain an attractive target for drug discovery. Traditional beta-lactam antibiotics (e.g. penicillins, penems, cephalosporins) have a bicyclic ring structure that is conformationally rigid and functions to inhibit bacterial cell wall synthesis. In addition to the bactericidal action of antibiotics, it has been discovered that many antibiotics are capable of inhibiting tumor cell growth. There are currently many antitumor antibiotics approved for cancer therapy, which work to inhibit tumor cell growth by DNA intercalation. The use of beta-lactams as prodrugs has also met with success by aiding delivery of the chemotherapeutic directly to tumor sites. Recently, a novel class of N-thiolated monobactams, so termed because they possess a monocyclic ring instead of the bicyclic ring, has been found to induce apoptosis potently and specifically in many tumor cell lines but not in normal, non-transformed cell lines. Other beta-lactams, such as the polyaromatics, have been found to slow or inhibit tumor cell growth, and the 4-alkylidene beta-lactams are capable of inhibiting matrix metalloproteinases and leukocyte elactase activity. These data indicate that synthesis and evaluation of beta-lactams are a promising area for further development in anticancer research.

Inhibition of Proliferation of Cervical and Leukemic Cancer Cells by Penicillin G

“…MMP11 expression was significantly higher in invasive carcinomas. Positive immune reaction was detected in the cytoplasm of cervix epithelium tumor cells, differing from other tumor tissues, where MMP11 expression is restricted to stromal cells that surround the neoplastic area (Kuhn et al, 2004). In this study, when HeLa cells were treated with penicillin, expression of MMP11 is down regulated.…”

“…The antibiotic potential of Penicillin was first of all discovered by Alexander Fleming in 1929 (Diggins 1999 (Xing et al, 2008). These beta-lactam based antibiotics inhibit the growth of tumor by DNA intercalation (Kuhn et al, 2004). According to a recent study N-thiolated monobactams induced apoptosis in many tumor cells but not in normal and non-transformed cell lines (Kazi et al, 2004).…”

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

“…The effects of lactam 1 on DNA, RNA, and protein synthesis in S. aureus ATCC 25923 was determined by measuring the respective incorporations of [methyl- 3 To assess the effect on DNA, RNA, and protein synthesis, 50 μL samples were removed from each reaction tube at designated time intervals (5,10,20,30,45, and 60 min) and precipitated in 1 mL of ice cold 10% trichloroacetic acid. After 1 hr, the samples were filtered through glass fiber filters (GF/ A; Whatman), washed with 2 mL of ice-cold 5% trichloroacetic acid and 2 mL of ice-cold 95% ethanol, and dried at room temperature overnight.…”

“…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.…”

Inhibition of Leukocyte Elastase, Polymorphonuclear Chemoinvasion, and Inflammation-Triggered Pulmonary Fibrosis by a 4-Alkyliden-β-lactam with a Galloyl Moiety

“…A core structure of four-membered cyclic amide (␤-lactam or azetidin-2-one) is the common feature of these molecules; the first LE inhibitor ␤-lactams were naturally occurring bicyclic compounds, such as clavams and cephalosporins , but more recently synthetic monocyclic ␤-lactams have been developed. Because the latter perform with extremely good safety profiles and infrequent side effects (Kuhn et al, 2004), they could represent a good model base for designing powerful drugs able to inhibit LE and restore the altered protease/antiprotease ratio at the inflammatory sites.…”