Title:N-alpha-Aminoacyl Colchicines as Promising Anticancer Agents
Volume: 17
Issue: 1
Author(s): Ana Marzo-Mas, Laura Conesa-Milián, Sam Noppen, Sandra Liekens, Eva Falomir*, Juan Murga, Miguel Carda and Juan A. Marco
Affiliation:
- Departamento de Química Inorgánica y Orgánica, Universitat Jaume I, E-12071 Castellón,Spain
Keywords:
Colchicine, L- and D- amino acid, cancer, non-toxic, cell cycle, tubulin, in vivo, oncogene downregulation.
Abstract: Background: In the last years, many efforts have been made to find colchicine derivatives
with reduced toxicity. Additionally, the deregulation of amino acid uptake by cancer cells
provides an opportunity to improve anticancer drug effectiveness.
Objective: To design new colchicine derivatives with reduced cytotoxicity and enhanced selectivity
by means of introducing aminoacyl groups.
Methods: 34 colchicine analogues bearing L- and D-amino acid pendants were synthetized and
characterized by NMR, IR and MS techniques. Cytotoxicity and antimitotic properties were assessed
by spectrophotometry and cell cycle assays. Oncogene downregulation was studied by RTqPCR
whereas in vivo studies were performed in SCID mice.
Results: Compounds exhibit high antiproliferative activities at the nanomolar level while being, in
general, less cytotoxic than colchicine. Most compounds inhibit the polymerization of tubulin in a
way similar to colchicine itself, with L-amino acid derivatives being the most active in the inhibition
of tubulin polymerization. All selected compounds caused cell cycle arrest at the G2/M phase
when tested at 1 μM. More specifically, Boc-L-proline derivative 6 arrested half of the population
and showed one of the highest Selectivity Indexes. Derivatives 1 (Boc-glycine), 27 (D-leucine)
and 31 (Boc-glycine-glycine) proved fairly active in downregulating the expression of the c-Myc,
hTERT and VEGF oncogenes, with compound 6 (Boc-L-proline) having the highest activity. This
compound was shown to exert a potent anti-tumor effect when administered intraperitoneally
(LD50 > 100 mg/kg for 6, compared with 2.5 mg/kg for colchicine).
Conclusion: Compound 6 offers an opportunity to be used in cancer therapy with less toxicity
problems than colchicine.
