Abstract A176: On the search for new tools to fight tumors and cancer pain with the aid of organic synthesis: Quicker access to pancratistatins and tetrodotoxins

• Published in: Molecular cancer therapeutics 2009-12, Vol.8 (12_Supplement), p.A176-A176
• Main Authors: Nieto-García, Olaia, Cagide-Fagín, Fernando, Alonso, Ricardo
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-09-A176

One of the biggest hurdles in the fight against cancer is the non-selective nature of most current treatments. On the other hand, opioids-refractive cancer pain is a most important unsolved problem. Consequently, the search and development of new drugs that are tumor-killing (while non-cytotoxic to normal cells) and/or potent analgesics are major goals in cancer research. In this context, pancratistatin and tetrodotoxin, the most prominent representatives of two different families of natural products, have been identified as highly promising leads for cancer treatment and cancer pain, respectively; in fact, they are currently at the focus of some initiatives for pharmaceutical development. Interest in pancratistatin stems from its high level of in vitro and in vivo cell growth inhibitory activity on a wide variety of human cancer cell lines, but particularly from its mode of action that, while yet unknown, is very selective: pancratistatin does not affect normal cells in clear contrast with other agents clinically used at the moment such as paclitaxel (taxol®) or VP-16. On the other hand, the exceptional potency and selectivity of tetrodotoxin in blocking voltage-gated sodium channels is responsible for its strong analgesic activity (3000 times more potent than morphine without the secondary side effects of opioids). Unfortunately, the limited supply of pancratistatin, tetrodotoxin and their analogues from their natural sources is seriously precluding further progress in the area; thus stretching the need for practical chemical synthesis. We have now developed novel synthetic schemes to both families of compounds based on the expeditive gram-scale assemblage of an advanced common intermediate (a polyfunctionalized cyclohexanic core) in just three steps from commercially available compounds. In this way, we have just completed the shortest synthetic access to tetrodotoxin reported to date and two different routes to pancratistatins. We are currently preparing a number of derivatives pretended to be useful as biological probes. Details will be given at the Conference. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A176.