Arresting cell growth by novel functionalised indolocarbazoles

Cancer causes about 13% of all human deaths and at least one fifth of all deaths in Europe and North America.¹ Although chemotherapy is increasingly prescribed, it is not without side effects and so new, more selective remedies for cancer sufferers must be found.

Since the discovery of the anticancer properties of the indolocarbazole staurosporine, many analogues have been synthesised in order to obtain compounds that have a higher potency with respect to anticancer mechanisms.^{2, 3} The overall objective of this project is to produce selective and highly potent novel anticancer agents through modification of the indolocarbazole structure and a focus of this work is the replacement of the lactam/maleimide heretocycle to form a series of novel indolocarbazole derivatives including the first reported synthesis of a series of novel substituted indolocarbazole uracils. Biological evaluation via the NCI 60 cell line screen has been completed for a number of these compounds with some showing significant selectivity towards individual leukaemia and melanoma cell lines.

References

1. GLOBOCAN 2008, database (version 1.2) http://globocan.iarc.fr
2. C. Peifer, T. Stoiber, E. Unger, F. Totzke, C. Schächtele, D. Marmé, R. Brenk, G. Klebe, D. Schollmeyer and G. Dannhardt, J. Med. Chem., Design, Synthesis, and Biological Evaluation of 3,4-Diarylmaleimides as Angiogenesis Inhibitors, 2006, 49, 1271.
3. L. T. Pierce, M. C. Cahill, H. J. Winfield and F. O. McCarthy, Eur. J. Med. Chem., Synthesis and Identification of Novel Indolo[2,3-a]pyrimido[5,4-c]carbazoles as a New Class of Anti-cancer Agents 2012, 56, 292.