Fagaronine, a New Tumor Inhibitor Isolated from Fagara zanthoxyloides Lam. (Rutaceae)

Journal of Pharmaceutical Sciences
1972.0

Abstract

During a phytochemical investigation of Fagara zanthoxyloides, we isolated a new alkaloid for which we have assigned the trivial name fagaronine. Fagaronine has been shown to elicit a high order of activity against the P-388 leukemia in mice, giving prolongations of life on the order of 265, 210, and 190% T/C at doses of 100, 50, and 25 mg./kg., respectively. A compound is active if it exhibits a T/C of ≥ 125 % (1). Several leukemic mice treated with fagaronine were considered as 'cures.' Fagaronine crystallized as the chloride (from a mixture of ethyl acetate-methanol) as bright-yellow needles, exhibiting m.p. 202° followed by solidification and melting again at 255°. A UV absorption spectrum of λmax 233 (log ε 4.29), 272 (4.55), 305 (4.44) (sh), and 328 nm. (4.44) indicated that fagaronine belonged to the benzophenanthridine class of alkaloids; in particular, this spectrum resembled that of nitidine (2). The UV spectrum of fagaronine in 0.01 N HCl showed no change; however, in 0.01 N NaOH, a bathochromic shift to λmax 346 nm. (log ε 4.31) was observed, suggesting the presence of a phenolic group in the molecule. The presence of a phenolic hydroxyl group was also indicated by a broad absorption band at 3500-3200 cm.-1 in the IR spectrum. A lack of peaks at 1480 and 940 cm.-1 in the IR spectrum was suggestive of the absence of the methylenedioxy function in the molecule, which was confirmed by a negative Labat's test and by a lack of absorption in the area of 6 p.p.m. in the NMR spectrum. An NMR spectrum of fagaronine (Ia) in dimethyl sulfoxide, with tetramethylsilane as the internal standard, showed peaks for -N+-CH3 (δ in p.p.m., singlet at 5.11), three -OCH3 (singlets at 4.24, 4.11, and 4.04), 6-position proton (singlet at 9.97), protons at positions 11 and 12 (doublets centered at 8.86, J = 9 Hz., and 8.16, J = 9 Hz.), and protons at positions 1, 4, 7, and 10 (singlets at 7.66, 7.94, 8.13, and 8.36). At this point, Structures Ia and Ib were suggested for fagaronine. A molecular ion, M+, was observed at m/e 350 in the mass spectrum of fagaronine, followed by peaks at m/e 349 (M+-1), 348, 335 (base peak, M-15), 334, 320, 306, 292, and a doubly charged species at m/e 167.5. The formation of these ions can be explained by the mode of fragmentation proposed for such compounds by Torto and Mensah (3) and Slavik et al. (4). Structure Ia is favored over Ib for the structure of fagaronine because of the more favorable formulation of the peak at m/e 349 (M+ - 1) (9%). Final proof of the structure of fagaronine by synthesis is in progress.

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