Apparicine

Anti-malarial activity of indole alkaloids isolated from Aspidosperma olivaceum.[Pubmed:24731256]

Malar J. 2014 Apr 14;13:142.

BACKGROUND: Several species of Aspidosperma (Apocynaceae) are used as treatments for human diseases in the tropics. Aspidosperma olivaceum, which is used to treat fevers in some regions of Brazil, contains the monoterpenoid indole alkaloids (MIAs) aspidoscarpine, uleine, Apparicine, and N-methyl-tetrahydrolivacine. Using bio-guided fractionation and cytotoxicity testing in a human hepatoma cell line, several plant fractions and compounds purified from the bark and leaves of the plant were characterized for specific therapeutic activity (and selectivity index, SI) in vitro against the blood forms of Plasmodium falciparum. METHODS: The activity of A. olivaceum extracts, fractions, and isolated compounds was evaluated against chloroquine (CQ)-resistant P. falciparum blood parasites by in vitro testing with radiolabelled [3H]-hypoxanthine and a monoclonal anti-histidine-rich protein (HRPII) antibody. The cytotoxicity of these fractions and compounds was evaluated in a human hepatoma cell line using a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, and the SI was calculated as the ratio between the toxicity and activity. Two leaf fractions were tested in mice with Plasmodium berghei. RESULTS: All six fractions from the bark and leaf extracts were active in vitro at low doses (IC50 < 5.0 mug/mL) using the anti-HRPII test, and only two (the neutral and basic bark fractions) were toxic to a human cell line (HepG2). The most promising fractions were the crude leaf extract and its basic residue, which had SIs above 50. Among the four pure compounds evaluated, aspidoscarpine in the bark and leaf extracts showed the highest SI at 56; this compound, therefore, represents a possible anti-malarial drug that requires further study. The acidic leaf fraction administered by gavage to mice with blood-induced malaria was also active. CONCLUSION: Using a bio-monitoring approach, it was possible to attribute the anti-P. falciparum activity of A. olivaceum to aspidoscarpine and, to a lesser extent, N-methyl-tetrahydrolivacine; other isolated MIA molecules were active but had lower SIs due to their higher toxicities. These results stood in contrast to previous work in which the anti-malarial activity of other Aspidosperma species was attributed to uleine.

The first total synthesis of (+/-)-apparicine.[Pubmed:19503874]

Chem Commun (Camb). 2009 Jun 21;(23):3372-4.

The first total synthesis of the indole alkaloid Apparicine has been developed through a sequence that includes an indole-templated ring-closing metathesis and a vinyl halide Heck cyclization.

Total synthesis of the bridged indole alkaloid apparicine.[Pubmed:19824689]

J Org Chem. 2009 Nov 6;74(21):8359-68.

An indole-templated ring-closing metathesis or a 2-indolylacyl radical cyclization constitute the central steps of two alternative approaches developed to assemble the tricyclic ABC substructure of the indole alkaloid Apparicine. From this key intermediate, an intramolecular vinyl halide Heck reaction accomplished the closure of the strained 1-azabicyclo[4.2.2]decane framework of the alkaloid with concomitant incorporation of the exocyclic alkylidene substituents.

Convergent approach to the tetracyclic core of the apparicine class of indole alkaloids via a key intermolecular nitrosoalkene conjugate addition.[Pubmed:24927230]

J Org Chem. 2014 Jul 3;79(13):6389-93.

Readily available methyl 3-formylindol-2-ylacetate and N-tosyl-4-chloro-3-piperidone oxime have been used to construct the tetracyclic skeleton of the Apparicine class of monoterpene indole alkaloids in only four steps in 80% overall yield. Key transformations in this convergent approach involve use of an intermolecular ester enolate/nitrosoalkene conjugate addition to form the C-15/16 bond, followed by a reductive cyclization to construct the C-ring of the tetracycle.