Elenoside, a New Cytotoxic Drug, with Cardiac and Extracardiac Activity.

Abstract

A great number of arylnaphthalene lignans have been isolated from different species of Justicia, many of them exhibiting diverse biological activities, of which the most noteworthy are their antitumoral, antiviral, insecticidal, anti-inflammatory and anti-hypertensive properties.1) Also, the lignans on the central nervous system (CNS) are capable of acting both as depressants and antidepressants.2) On the other hand, some lignans are shown to be present in human and certain animal urine or semen and blood plasma.3,4) These mammalian lignans show an inhibitory effect on Ca 2ϩ channels, or digitalis-like action. Thus, 2,3 dibenzilbutane-1,4-diol is noted to inhibit K ϩ depolarization-induced and receptor-mediated contractions, so as to block Ca 2ϩ entry into the smooth muscle of rabbit aorta, and it blocks the insensitive Ca 2ϩ channels to organic Ca 2ϩ blockers, as well as the sensitive channels in rabbit femoral artery. Also, some lignans (enterolactone, prestegane B and 3-O- /Kϩ ATPase activity in red cells and produce inotropic and chronotropic effects, similar to cardiac glycosides. In the present paper, its effects on the isolated cardiac auricle of rabbits and the urinary excretion of rats (an other effect of cardiac glycosides) are studied.In a previous paper 7) we reported the isolation from Justicia hyssopifolia L. of an arylnaphathalene lignan and its aglycone, now called elenoside and elenin, respectively, the first as a b-D-glucoside. This lignan has a central depressant effect in animals [8][9][10] and cytotoxic activity when studied in a human tumor cell line panel of the US National Cancer Institute (NCI).9,10) Cytotoxic compounds produced alterations in the intestinal tract. In this work the effect of elenoside on isolated rat ileum is studied. MATERIAL AND METHODSReagents Elenoside: Phytochemical study of elenoside was realized. Air-dried and ground leaves were extracted in a Soxhlet with EtOH, with heating and under reflux, to afford an extract that was concentrated under reduced pressure. Column chromatography using solvents of increasing polarity (n-hexane, EtOAc, EtOH) gave different groups of fractions. Elenoside was recovered as needles from the most polar fractions of the ethanolic extract and identified by NMR and MS methods and by comparison with reported data. This lignan was determined to have the molecular formula: C 25 H 22 O 11 , with a molecular weight of MWϭ498.7) The elenoside was suspended in a mixture of propylene glycol-ethanol-plant oil-Tween 80 (40 : 10 : 50 : 2).Ouabain: Ouabain octahydrate (Janssen Chimica, Belgium) had the molecular formula C 29 H 44 O 12 · 8H 2 O and a molecular weight of MWϭ728.79.Animals Male albino rabbits (1000-1300 g) and male Sprague-Dawley rats (Letica, Barcelona, Spain; 250-300 g) were used. The animals were housed under normal laboratory conditions at 22°C on a standard light-dark schedule (12 : 12; lights on: 0800 to 2000) and were given free access to standard laboratory diet and water. The animals were assigned to randomized groups of 10 eac...