The synthesis and biological evaluation of styelsamine and cystodytin analogues

Abstract

Natural products, especially those of marine origin, have proven to have great potential in the search for anti-cancer agent and drug leads with emerging drugs such as Yondelis and Halaven. A family of compounds, unique to marine organisms, known as the pyridoacridines, have demonstrated cytotoxicity towards bacteria, fungus, viruses and cancerous cells. The biological activity of these compounds is speculated to be largely due to their ability to bind to DNA. In this project, the aim is to synthesize a library of styelsamine pyridoacridine alkaloids and a library of the cystodytin equivalent of each styelsamine analogue. Compounds will contain a variety of ethyl-amido sidechains attached at the C-9 position. After synthesizing the libraries, compounds were subjected to a DNA-binding assay and were submitted to the NCI for evaluation of anti-tumour activity, in-order to investigate the link between the compound cytotoxicity and DNA-binding affinity. The compound libraries of styelsamine and cystodytin were successfully synthesized, along with an O-methyl styelsamine analogues library. DNA binding affinity of each compound was assessed through the ethidium bromide displacement assay, with styelsamine B (1.29), styelsamine D (1.31) and O-methyl styelsamine D (2.22) displaying the highest apparent binding constants [5.33, 3.64 and 4.72 (x 10⁶ M-¹), respectively], while the rest displayed moderate to low DNA-binding affinity (1.80 x 10⁶-0.05 x 10⁶ M-¹). Selected compounds were also evaluated for their cytotoxicity towards the NCI panel of 60 cancer cell lines. At a single dose of 10 μM, compounds 1.37, 2.24 and 1.26 showed no cytotoxicity towards the 60 cancer cell lines. Compounds 1.17, 1.29, 1.31, 1.33, 1.36, 2.19, 2.22, 2.26 and 2.23 displayed inhibition of cancer cell growth greater than 50%, while phenylpropanamides 1.35 and 2.18 exhibited significant cytotoxicity, with a cancer cell kill values of 27 and 15%. A plot was generated between the growth percent of cancer cells and compounds DNA-binding affinity but no consistent correlations were observed between the compound libraries, suggesting other factors also influence the level of cytotoxicity. The most cytotoxic derivatives both had a Clog P values around 5 suggesting permeability and DNA-binding may have joint influence on anti-tumour potency.