Fractionation by pH zone-refining countercurrent chromatography of an extract of the stem bark of Erythroxylum pervillei, obtained on a kilogram scale in southern Madagascar, led to the isolation and characterization of four tropane aromatic ester alkaloids as minor constituents, namely, pervilleines G (5) and H (6) and cis-pervilleines B (7) and F (8). Their structures were determined by spectroscopic data interpretation.
An evaluation of 6-[2-(di-n-propylamino)ethyl]indole (4), its rigid analogue N,N-di-n-propyl-5,6,7,8-tetrahydrobenz[f]indol-7-amine (5), and some related congeners, for ability to suppress serum prolactin in reserpinized rats, revealed modest biological activity in this in vivo model of dopaminergic activity. Although the indole N-H in these compounds can be considered to be oriented "meta" with respect to the ethylamine side chain, compounds with the indole N-H located in the other "meta" position (i.e. 4-[2-(di-n-propylamino)ethyl]indole (2) or its rigid benz[e]indole analogue 3) were much more potent dopamine agonists. The results argue for a particular orientation of the indole N-H vector. In addition, relatively potent dopamine agonists also resulted when the pyrrole portion of the indole ring was replaced by a methanesulfonamido function, supporting the idea that the indole N-H serves as a hydrogen-bond donor.
A general synthetic route from elymoclavine (4a) to a variety of C-17 substituted 8-ergolenes has been established. [The C-17 position is the carbon attached to C-8 of the ergoline (1) skeleton as indicated in structure 2.] This route involves displacement reactions on the allylic chloride (4h) prepared from 4a by reaction with thionyl chloride. Conversion of the naturally occurring tricyclic clavines, chanoclavine I (5a) and isochanoclavine I (5b), to the tetracyclic clavine, agroclavine (4i), has been achieved. The new compounds prepared were tested for prolactin-inhibiting ability and were found to possess activity. One of the compounds prepared, 6-methyl-8-ergolenylacetamide (4k), was very potent, comparing favorably in activity to the best prolactin inhibitors reported to date.
Evidence is presented for the assignment of structures for elephantin (3) and elephantopin (4), two tumorinhibitory sesquiterpene dilactones isolated from Elephantopus elutus Bertol. Elemental analysis and highresolution mass spectrometry supported a CZOHI~O~ molecular formula for elephantin (3) and a CIBHZOO~ molecular formula for elephantopin (4). Chemical and spectral evidence indicated the presence of cu,&unsaturated lactone, cr,@-unsaturated ester, and epoxide groupings in 3 and 4. Alkaline hydrolysis of 3 gave elephantol (5) and dimethylacrylic acid, while, under the same conditions, 4 gave elephantol (5) and methacrylic acid. Catalytic hydrogenation of elephantol (5) gave tetrahydroelephantol (9). Treatment of elephantol(5) with p-bromobenzoyl chloride gave elephantol p-bromobenzoate (14). X-Ray crystallographic analysis established the structure and stereochemistry of 14 and 5. Hydrogenation of elephantopin (4) gave tetrahydroelephantopin (6). Alkaline hydrolysis of 6 gave dihydroelephantol (8) and isobutyric acid. Acylation of 5 with methacrylic anhydride gave elephantol methacrylate (ll), while acylation of 8 with isobutyric anhydride gave elephantol isobutyrate (12). Acid hydrolysis of 6 gave dihydroelephantolide (13), which on acylation with isobutyric anhydride gave 6. Low-and high-resolution mass spectra of elephantin (3) and elephantopin (4) and a number of derivatives ( 5 , 6 , 8 , 10, 11, 12, and 13) are discussed.Elephantin and elephantopin are cytotoxic sesquiterpene lactones from Elephantopus elatus Bertol., and their isolation and characterization have recently been reported.*s5 It is the purpose of this paper to present in detail the fractionation of the active extract of E. elatus and the isolation and structural elucidation of the active constituents, elephantin and elephantopin! Fractionation of the concentrated ethanol extract (A in Chart I), guided by assay against KB revealed that the active principles were concentrated (Table I) in the chloroform phase (D) of a chloroformwater partition. Partition of this residue between 10% aqueous methanol and petroleum ether concentrated the activity in the aqueous methanol layer (G). Fraction G was chromatographed on a silicic (1) (a) University of Wisconsin. Part XXXIX: 8. M. Kupchan, W.
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