Alkaloids pancratistatin and narciclasine, isolated from Amaryllidaceae, have been shown to present antitumor activity on preclinical models, including melanoma. Despite extensive investigations, pancratistatin or narciclasine analogues did not succeed to provide sufficient therapeutic benefit, [1] mostly hampered by poor water solubility and systemic toxicity [1]. To overcome those limitations, we developed a chemistry program aimed at improving both their physicochemical and pharmacological properties. A literature survey suggests that any structural modification of this highly oxigenated isocarbostiryl specific scaffold would lead to a loss of activity except on position 1, difficult to achieve but interesting to explore.

A series of 40 novel 1-aminopancratistatin derivatives was synthesised starting from large quantities of narciclasine extracted from Narcissus bulbs. These novel compounds exhibit an improved pharmaceutical profile facing standard solubility, plasmatic and microsomal stability assays. Moreover, a subset of narciclasine derivatives demonstrated a significant enhancement of the antiproliferative effect with IC50 reaching the nM range, consistent with a major induction of pro-apoptotic signals, including mitochondrial depolarisation.

To explore the mode of action of these alkaloids derivatives, we tested their capacity to inhibit protein synthesis, compared their pharmacological profile with 80 anticancer compounds on 16 tumor cell lines (oncoprofile.16) and explored their impact on major cellular functions such as cellular integrity, cell cycle, topoisomerases inhibition, DNA damage and synthesis. We demonstrated thus that inhibition of DNA synthesis is a key component of their mechanism of action.

Based on the pharmacological properties, a structure-activity card can be built to select different categories of pancrastistatin derivatives depending on their ability to inhibit preferentially protein synthesis or/and DNA synthesis. Interestingly, the dimethylaminomethyl benzamide derivative F98604 exhibited a significant antiproliferative activity on the murine B16 and human A375 melanoma xenograft models associated with an increased therapeutic index as compared with the natural compound narciclasine.

In conclusion, modulation of position 1 on the narciclasine pharmacophore overcomes the solubility issue and is a key position to modify their pharmacological profiles, this opening new perspectives as anticancer agents active against melanoma.

1. A. Kornienko, A. Evidente Chem. Rev. 2008, 108, 1982

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3261. doi:10.1158/1538-7445.AM2011-3261