Potential Antipsoriatic Agents:  Lapacho Compounds as Potent Inhibitors of HaCaT Cell Growth

Abstract

A number of lapacho compounds, representing the most common constituents of the inner bark of Tabebuia impetiginosa, together with some synthetic analogues, were evaluated in vitro against the growth of the human keratinocyte cell line HaCaT. With an IC(50) value of 0.7 microM, beta-lapachone (4) displayed activity comparable to that of the antipsoriatic drug anthralin. 2-Acetyl-8-hydroxynaphtho[2,3-b]furan-4,9-dione (7), which was prepared in a four-step synthesis from 2,8-dihydroxy-1, 4-naphthoquinone, was the most potent inhibitor among the known lapacho-derived compounds and inhibited cell growth with an IC(50) value of 0.35 microM. Furthermore, other active constituents of lapacho inhibited keratinocyte growth, with IC(50) values in the range of 0.5-3.0 microM. However, as already observed with anthralin, treatment of HaCaT cells with these potent lapacho compounds also caused remarkable damage to the plasma membrane. This was documented by leakage of lactate dehydrogenase into the culture medium, which significantly exceeded that of the vehicle control. Because of their potent activity against the growth of human keratinocytes, some lapacho-derived compounds appear to be promising as effective antipsoriatic agents.

Embryo development alteration in rats treated with lapachol

“…It is known that when a toxic agent causes death, or fetal growth delay without causing malformations, it can be related to the fact that it interferes with vital processes such as glycolysis, mitochondria function or membrane integrity (Manson and Wise, 1991). Lapachol is an antiproliferative agent (Santana et al, 1968;Muller et al, 1999;Dinnen and Ebisuzaki, 1997). The mechanism of its antimitotic effect is due to mitochondrial oxidation and phosphorylation inhibition (Santana et al, 1968), antagonism of K vitamin reactions (Dinnen and Ebisuzaki, 1997), or generation of reactive oxygen species (Muller et al, 1999).…”

“…Lapachol is an antiproliferative agent (Santana et al, 1968;Muller et al, 1999;Dinnen and Ebisuzaki, 1997). The mechanism of its antimitotic effect is due to mitochondrial oxidation and phosphorylation inhibition (Santana et al, 1968), antagonism of K vitamin reactions (Dinnen and Ebisuzaki, 1997), or generation of reactive oxygen species (Muller et al, 1999). During early organogenesis, the embryo is in a state of relative hypoxia, with predominance of anaerobic glycolysis (Brison and Leese, 1994;Shepard et al, 2000) and mitochondria present lamellated cristae, indicating its maturity by the limb bud stage (Shepard et al, 2000).…”

“…A large number of therapeutic activities have been attributed to lapachol and its derivatives such as prevention against Schistosoma mansoni cercarial skin penetration (Austin, 1974;Pinto et al, 1977), was effective against Biomphalaria glabrata (Santos et al, 2000;Lima et al, 2002;Silva et al, 2005), bacteria and fungi (Guiraud et al, 1994;Binutu et al, 1996;Rothery et al, 1998); virus (Lagrota et al, 1987;Sacau et al, 2003), Trypanosoma cruzi (Austin, 1974;Lopes et al, 1978;Pinto et al, 1987;Chiari et al, 1991;Duarte et al, 2000) and showed antimalarial activity (Andrade-Neto et al, 2004) involving the erythrocytic stages of Plasmodium falciparum (Carvalho et al, 1998). It also has antiinflammatory (Duarte et al, 2000, Almeida, 1990, analgesic (Grazziotin et al, 1992), antipsoriatic (Muller et al, 1999), and antineoplasic activities (Santana et al, 1968, Morrison et al, 1970, Rao, 1974Linardi et al, 1975;Saizarbitoria et al, 1997, Duarte et al, 2000, Sieber et al, 1976Hodnett et al, 1983;Houghton et al, 1994;Almeida et al, 1988;Balassiano et al, 2005). On the general toxicology of lapachol, Santana et al (1968) and Morrison et al (1970) have established the LD-50 of this drug in mice and rats.…”

Um panorama atual da química e da farmacologia de naftoquinonas, com ênfase na beta-lapachona e derivados

“…Neste modelo, além do estresse oxidativo também se observam vias biorredutivas alquilantes sobre ácidos nucléicos e/ou proteínas 90,91 . Outras atividades farmacológicas foram atribuídas a esta quinona, podendo-se destacar as atividades antibacteriana e antifúngica 92 , cercaricida e antipsoriática (IC 50 0,7 µM contra queratinocite HaCaT humana) 93 . A β-lapachona (4a) também age como inibidora das topoisomerases I 94 e II 95 .…”

Comparison of three sample preparation methods on the recovery of volatiles from taheebo (Tabebuia impetiginosa Martius ex DC)

“…extracts and their isolated compounds. [9][10][11][12][13][14] To our knowledge, the only volatile constituents of taheebo that have been reported to date are 3,4-dimethoxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde (vanillin) and 4-methoxybenzaldehyde. 6 The volatile chemical composition of the extracts isolated from plants depends on the type of sample preparation technique employed.…”