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It was demonstrated that rapamycin is metabolized in vitro by pig liver microsomes under the influence of the cytochrome P450‐dependent mixed function oxygenase system to a rapamycin tris‐epoxide metabolite, as demonstrated by electrospray tandem mass spectrometry . The in vitro immunosuppressive activity of this metabolite was found to be lower than that of rapamycin, probably because the rapamycin effector sector was structurally modified. The effector region of rapamycin was recognized to include the conjugated double bonds of this compound and metabolic reactions affecting this region may change the binding affinity of the rapamycin–FKBP binary complex towards another pharmacological receptor bound to the binary complex. Moreover, metabolic modifications in the effector region are probably able to induce a change in the binding affinities of the rapamycin–FKBP binary complex, including the pipecolic acid moiety and the lactone function of the parent drug. Copyright © 1999 John Wiley & Sons, Ltd.

Voacoline, a new minor alkaloid from Voacanga chalotiana Pierre ex Stapf (apocynaceae) is shown to ahve structure I. This structure contains two unusual features : a N,C& indolic group and a hemiketal function. This last feature accounts for the very easy formation of 0-methyl I1 and O-ethylvoacoline 111. A correlation with voachalotine IV, the major alkaloid of the same species, has been achieved by degradation of I to dihydrodeshydroxymethylvoachalotine XIV. UV,IR, NMR and mass spectra of I and some of its derivatives are discussed.La separation des alcaloides totaux de Voacanga chalotiana Pierre ex Stapf (apocynackes) par distribution B contre-courant a 6ttc dCcrite anterieurement (1). La fraction C de cette separation contient au moins trois constituants qui sont mis en evidence par chromatographie sur couche mince. Le plus important d'entre eux peut &tre isole par une nouvelle distribution a contre-courant, par chromatographie sur d i c e ou par cristallisation fractionnee dam l'ether.Cette nouvelle base, la voacoline, se prksente sous forme d'aiguilles incolores, F : 147-147,5" (ether), [LY];~ = -29,8 f 2" (chloroforme, c = 0,5). La teneur en voacoline dans les Ccorces skches de tronc de V. Chalotiana s'elbve a 0,07 % en poids.

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1. Rapamycin is metabolically transformed in rat liver microsomes to 3,4- and 5,6-dihydrodiol metabolites under the influence of the cytochrome P-450 mixed function oxygenase system. These metabolites were produced from dexamethasone-induced as well as from non-induced rat liver microsomes. The comparison of the ion spray mass spectra of the 5,6-dihydrodiol with the 3,4-dihydrodiol of rapamycin shows clearly that dihydrodiols were formed in two distinct positions of rapamycin. 2. FAB mass spectra as well as electrospray mass spectra of two additional peaks isolated from the same chromatographic run confirm the presence of a 3,4-dihydrodiol metabolite of rapamycin as also strongly suggested by UV spectra. Hplc reinjection of each individual peak always resulted in chromatograms showing a combination of the same three peaks and therefore are to be considered as tautomers of the 3,4-dihydrodiol of rapamycin. 3. These tautomeric conformations were found to have no immunosuppressive potency, most probably due to important structural and stereochemical modifications of the rapamycin binding domain to the binding protein (FKBP-12) and/or to important metabolic structural modifications of rapamycin effector domain.