Determining the Toxicity of CpM(CO)nR on B16 Cell Lines: A Proposed Reaction Scheme for the Addition of a Malonamide Derivative to Increase Cell Invasiveness
Jennifer Sallman, Jack Arbiser, MD/PhD, Debra Mohler, PhD
Department of Chemistry, Emory University

Abstract

Complexes of the general formula, CpM(CO)nR has been found to produce carbon- centered radicals that cleave DNA. These organometallic DNA cleaving agents are photodynamic, non- toxic in the dark, and can potentially lead to more efficient chemotherapeutics. They have exhibited activity against a human melanoma cell line, showing growth inhibition with irradiation, while showing no major background toxicity. I propose to further test the toxicity of the organometallic DNA cleaving agent CpW(CO)3CH3 on mouse melanoma (B16) cell lines upon UV irradiation. Preliminary cell line studies has suggested that the complex can be made more cell invasive; Therefore, the addition of a malonamide derivative to the cyclopentadienyl- ring will be synthesized.

Introduction

Chemotherapy is often referred to as chemo. Anticancer drugs are administered to cancer patients; however, these drugs are highly toxic and have severe side effects (I.e. nausea, hair loss). Many of these drugs are only effective during certain cell division processes; therefore, they are often used in combination. CpW(CO)3CH3 Complex- Targets only cancer cells by entering the body inactive (minor toxicity). Only once the complex has been taken in by the cancer cells are they activated (increased toxicity) by a light source, whose frequency does not damage DNA. If successful, this process will eliminate many unwanted side effects! See Reaction Scheme and Addition of Malonamide Deriative.

Methods and Materials

Mulitiple reactions were examined. One reaction was done using 1,3- dibromopropane and NaOMe as the base. Another was done with acrylonitrile and either KOH, K2CO3, or NaOMe as the base.

Results

Each reaction had different types of difficulties. 1,3- dibromopropane lost both bromines instead of simply one causing many undesired side reactions. KOH proved to be too strong of a base, abstracting both hyrodgens from the alpha carbon of the dimethylmalonate. Further studies on K2CO3 and NaOMe are needed for conclusive results.

Conclusions and Future Studies

Further studies need to be pursued in order to successfully obtain the desired product. The use of a weaker base and possibly lowering the temperature (rxn preformed at room temperature) of the reaction will be tested to reduce the abstraction of both hydrogens from the malonate.

Future Studies:
To complete the addition of the malonamide derivative to the Cp ring of the CpW(CO)3CH3 complex. Determine the toxicity of the novel complex on mouse melanoma (B16) cell lines.

Acknowledgements and Funding Attributions

Thanks to SURE, HHMI, Jennifer Downs, Tom Shell, The Mohler Team.

In Plain English

Chemotherapy has many unwanted side effects because it is non-selective and kills cancer and normal cells. Using a drug that would selectively kill only cancer cells would reduce many unwanted side effects and the life of the patients. Our complex has potential to selectively kill cancer cells by cleaving DNA upon irradiation. Priliminary studies on melanoma (skin cancer) cell lines demonstrate that the complex has minor toxicity in the dark and is only effective once activated by a light source.

Techniques

Synthesis, NMR, TLC, and Column Chromatography.