Medicinal Chemistry of Copper and Vanadium Bioactive Compounds

SUSANA B. ETCHEVERRY; PATRICIA AM WILLIAMS

Medicinal Chemistry Research Progress

Nova Science Publishers, Inc.

Lugar: Hauppauge, NY ; Año: 2008; p. 1 - 53

Transition metals play a fundamental role in different living systems. In particular in aerobic organisms, the presence of Copper is essential for the function of many enzymes related to cellular respiration, iron homeostasis, neurotransmitter production, peptide biogenesis, connective tissue biosynthesis, and antioxidant defense. Copper compounds are reported to act as antioxidant, anti-inflammatory, antimicrobial, antiparasitic, anticonvulsant and antitumoral agents.  Besides, in vertebrates, copper deficiency causes skeletal alterations. Vanadium, another transition metal is present in trace amounts in higher animals. Even though its essentiality has not been clearly established yet, experimental results both in vivo and in vitro suggest that vanadium compounds may participate in important biological functions acting as insulinmimetic, osteogenic and antitumoral compounds. Once absorbed vanadium and copper are distributed among tissues and stored mainly in bone. In this chapter the behavior of these metal derivatives on bone related cells in cultures is discussed in detail. Two cellular lines, MC3T3E1 derived from mouse calvaria, and UMR106 from rat osteosarcoma have been used as a model for normal and tumoral bone processes. To expand the studies on antineoplastic metal drug activity, experiments with copper and vanadium compounds have been undertaken on two tumoral cell lines of human colon adenocarcinoma (Caco-2 and TC7). Different copper complexes with pharmacologically active ligands such as the antihypertensive drug Losartan and a derivative of the antiparasitic Santonin, Santonic acid, were synthesized and tested in vitro in the mentioned cell lines. Both complexes improve the antitumoral effect of free copper ions. This behavior agreed with the morphological cellular alterations. On the other hand, the biological effects of vanadyl(IV) complexes with the  flavonoids quercetin and hesperidin were discussed and compared with a vanadium(IV) derivative of the structural related ligand, the disaccharide trehalose. In the tumoral cell lines these compounds were deleterious. The effects on cellular differentiation (specific alkaline phosphatase activity and collagen type I production) were also described for the osteosarcoma cells. Besides, for the complexes with quercetin and trehalose the effect on the activation of ERK (extracellular regulated kinase) cascade was investigated using specific antibodies in order to identify one of the possible mechanisms of action. Altogether these promissory results of a first stage in medicinal chemistry on metal based drugs merit to be further investigated in animal models.