Quassinoids toxicity

Crude extracts of the root bark from Celastrus paniculatus Willd. (Celastraceae) demonstrated significant activity against cultured P. falciparum (93), and the active principle was shown to be pristimerin, a quinonoid triterpene. The family Simaroubaceae has also yielded a number of compounds with in vivo and in vitro antimalarial activity (94-96) including quassinoids. Bruceantin has been most extensively studied, but is very cytotoxic however, other quassinoids are relatively less toxic to cultured KB cells while retaining potent antimalarial activity (88). Plants from the Meliaceae are commonly used as febrifuges in Africa, and several limonoids from this family, such as nimbolide and gedunin, have also been found to produce moderate inhibition of cultured P. falciparum (97,98). 

Lumonadio et al. isolated five quassinoids from the root bark of Hannoa klaineana. Of these quassinoids, only 15-desacetyl-undulactone (70) was active against P-388 mouse lymphocytic leukemia cells and colon 38 adenocarcinoma in mice. Undulactone (71) and especially 15-0-"-D-glucopyranosyl-21-hydroxy-glaucarubolone (72) were more toxic, while 6a-tigloyloxy-glaucarubol (73) and 21-hydroxy-glaucarubolone (74) were inactive [27]. 

Quassinoids have been widely studied for their anticancer activity in vitro, however, only a few of them have shown interesting activity. Bruceantin was active in animal models against melanoma, colon cancer and leukemia [41,48]. According to Cuendet et al. (2004), male mice seemed to be more sensitive to bruceantin than females, independent of the age of the treated mice. It was claimed that doses of 2.5 and 5.0 mg kg promote the regression of earlier and advanced tumors (multiple myeloma, RPMl 8,226 cells) without apparent toxicity [49]. Phase I and II clinical trials were conducted with this compound. Unfortunately, no objective regression of the proliferative process was observed in humans, whereas a relative toxicity was noticed (hypotension, nausea, and vomiting at low dose, thrombocytopenia at higher dose) [50-53]. 

Compared with the plethoric studies on antiplasmodial activity against P. falciparum in vitro, in vivo antimalarial assays dedicated to quassinoids are scarce and hardly comparable. Nevertheless, the excellent antimalarial activities highlighted in those studies should open the way to complementary studies of their pharmacokinetics and toxicity. Association with other antimalarials should also be investigated in order to define new therapeutic schemes and to lower the administered doses, increasing drugs tolerability. 

Certain quassinoids display in vitro antiviral activity, namely against the oncogenic Rous sarcoma virus 79). This test is performed as follows Chick-embryo fibroblasts are infected by a known amount of the virus which transforms the morphology of the cells into foci. A number of quassinoids inhibit this transformation at concentration ranging from 0.15 to 1 pg/ml, without having toxic effects on normal cells. Some of the results are shown in Table 2. 

Bhatnagar, S., J. Polonsky, T. Prange, and C. Pascard New Toxic Quassinoid Glucosides from Simarouba Glauca (X-Ray Analysis). Tetrahedron Lett. 25, 299 (1984). 

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