NOVEL PSAMMAPLIN A DERIVATIVES: SYNTHESIS AND USE FOR THE PREVENTION AND/OR TREATMENT OF CANCER
A new method for the synthesis of psammapline A derivatives (UVI5000), of the 2-substituted indole-carboxamide type, a fast, simple method with high yields. This method is more effective than the approaches of Hoshino and Nicolaou; a new synthesis and molecules with increased antitumor action.
Surprisingly, the inventors have discovered that the molecules responding to formula (Figure 1) can be use in the prevention and/or the treatment of cancer exploiting their peculiar properties:
- Induction cell cycle arrest
- Induction of apoptosis
- Inhibition of histone deacetylases (HDACs)
- Induction expression of the TNF-related apoptosis inducing ligand TRAIL.
In particular, the molecules of the invention UVI5008 and UVI5010 induced inhibition of proliferation and/or apoptosis in U937 acute myeloid leukemia cell line (Figure 2). Additionally, UVI5008 is a powerful inhibitor of DNA methyltransferase (DNMT) (Figure 3). Inhibits DNA methylation in the promoter region of the tumour suppressor genes p16INK4a and RARb2 (Figure 4). The inventors speculate about UVI5008 as promising candidate anticancer drugs for its anti-proliferative activity and ability to restore the pharmacosensitivity.
- Greater anti-cancer actions than known molecules;
- Possibility of use in prevention;
- Cell cycle regulation activity of derivatives;
- Inhibiting the activity of DNMT – UVI5008.