Novel beta-Lactams as New Anti-Cancer Agents

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The principal goals of this application are 1) to develop selective, potent analogues of lead anticancer beta- lactams that are highly effective in vitro and in vivo and 2) to create an effective learning experience for the minority students who participate in this research. The long-term goal is to identify one or more analogues for clinical evaluation. A need exists for new and novel anticancer agents with high potency, efficacy against malignant cell growth yet with reduced toxicity to non-cancerous cells. Toward this goal, studies of beta-lactams as new chemotherapeutic agents would be very timely and useful. A number of novel beta-lactams that have multicyclic aromatic groups have been synthesized. Some of them have demonstrated promising anticancer activity in vitro. In some instances this activity exceeded that of a well-known and clinically useful drug, cisplatin. In preliminary experiments one of these beta-lactams has shown anticancer activity in vivo against ovarian and colon cancer cell lines to a moderate degree. In an early search for the mechanism of action of these compounds, preliminary studies have demonstrated an extremely active blockade of the G2/M checkpoint in cancer cell lines. To identify the structural and mechanistic relationships and to more carefully identify selectivity of anticancer activity, an extended series of carefully designed beta-lactams analogues, related to lead compounds will be prepared. These include synthesis of racemic and optically active beta-lactams by Staudinger- and metal-mediated, and enolate condensation reactions. As an alternative approach, synthesis of these beta-lactams using domestic and automated microwave oven will also be performed. In vitro cytotoxicity will be utilized to determine the relative activity of these analogues and logical structural-stereochemical based pathway relationships will be explored to enhance their action. The ability of compounds to induce G2 cell cycle blockade for tests of mechanistic targets and efficacy will be investigated. In addition, their activity against DNA replication and induction of apoptosis will be studied. In a later aspect of the testing for the mechanism of action, a selected gene arrays designed to examine key elements of apoptosis will be accomplished. The same array will also be used to examine changes in genes known to be of importance in regulating the cell cycle.