Bisindole alkaloids antitumor activity

Numerous bisindole alkaloids, formed by dimerization of monomeric monoterpenoid-derived indoles, have been isolated. Probably the best source of these alkaloids is Cathara-nthus roseus bisindole alkaloids from this source have been tabulated (Blasko and Cordell, 1990). Several of these alkaloids antitumor activity (Blasko and Cordell, 1988) most important in this regard are vincristine (55) and vinblastine (56) from Catharanthus roseus (Fig. 34.15). Certain other dimeric indole alkaloids known as curares have paralytic effects in animals (see the subsection Curares from Strychnos species, above). 

The 4-acyl derivatives of 4-deacetylvinblastine (98) are among the earliest semi-synthetic compounds prepared in exploring the medicinal chemistry of the bisindole alkaloids from Catharanthus. By 1965, the clinical utility of vinblastine (1) and vincristine (2) was firmly established, and the naturally occurring congeners leurosine (3) and leurosidine (4) had been well characterized with respect to their experimental antitumor activity. Since these compounds were substantially less active in animal tumor... 

Multiple single-point modification of both halves of the bisindole framework provided vinepidine (144), a bisindole alkaloid that exhibited experimental antitumor activity similar to vincristine without demonstrating the acute neuronal toxicity of this alkaloid. Ultimately, the vinepidine experience was both educational and an exercise in humility, since the compound showed promise in preclinical neurotoxicology models yet demonstrated considerable neurotoxicity in clinical trials. Nevertheless, vinepidine brings a rich example of the combined effects of ring D conformation (with its associated effect on N-6 basicity) and the presence of an N-1 formyl group. 

The tribrominated bisindole alkaloid dragmacidin (30) from the marine sponge Dragmacidon sp. has antitumor activity against P-388 cells (IC5o 15 pg/ml), A-549 (human lung), HCT-8 (human colon), and MDAMB (human mammary) cancer cell lines (IC501-10 pg/ml) [43]. 

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