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N-alpha-Aminoacyl Colchicines as Promising Anticancer Agents

Author(s):

Ana Marzo-Mas, Laura Conesa-Milián, Sam Noppen, Sandra Liekens, Eva Falomir*, Juan Murga, Miguel Carda and J. Alberto Marco   Pages 1 - 12 ( 12 )

Abstract:


Background: In the last years, many efforts have been made to find colchicine derivatives with reduced toxicity. Additionally, the deregulation of amino acids 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.

Method: 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 RT-qPCR 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.

Keywords:

Colchicine, L- And D- Amino Acid, Cancer, Non-Toxic, Cell Cycle, Tubulin, In Vivo, Oncogene Downregulation

Affiliation:

Departamento de Química Inorgánica y Orgánica, Univ. Jaume I, E-12071 Castellón, Departamento de Química Inorgánica y Orgánica, Univ. Jaume I, E-12071 Castellón, Laboratorium Virologie en Chemotherapie (Rega Instituut), Rega - Herestraat 49 - bus 1043, 3000 Leuven, Laboratorium Virologie en Chemotherapie (Rega Instituut), Rega - Herestraat 49 - bus 1043, 3000 Leuven, Departamento de Química Inorgánica y Orgánica, Univ. Jaume I, E-12071 Castellón, Departamento de Química Inorgánica y Orgánica, Univ. Jaume I, E-12071 Castellón, Departamento de Química Inorgánica y Orgánica, Univ. Jaume I, E-12071 Castellón, Departamento de Química Orgánica, Univ. Valencia, E-46100 Burjassot, Valencia



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