Leurosine from Catharanthus roseus

Leurosine (75) (Scheme 20) is the most abundant of the dimeric antitumor alkaloids isolated from Catharanthus roseus G. Don. Several species of Strep-tomyces produced a common metabolite of the alkaloid, and S. griseus (UI1158) was incubated with 400 mg of leurosine sulfate to obtain 28 mg of pure metabolite (180). The metabolite was identified as 76 primarily on the basis of its H-NMR spectrum. The mass spectrum indicated that the metabolite contained one oxygen atom more than 75. The H-NMR spectrum contained all of the aromatic proton signals of the vindoline portion of the molecule, and aromatic proton signals for the Iboga portion of the compound occurred as a doublet of doublets... 

The chemical reactivity of N-6 (or N ), directed entirely by the basicity of this atom, is controlled by the nature and stereochemistry of the substituents at C-4 (vide supra). Oxidation of N-6 occurs under mild conditions in several naturally occurring bisindole alkaloids. Thus, treatment of a dichloromethane solution of leurosine (4) with m-chloroperben-zoic acid at -20°C for 4 hr gives the N -oxide (15) in greater than 90% yield after preparative reversed-phase chromatography (46). Leurosine A/ -oxide has also been isolated from Catharanthus roseus and should therefore be considered a naturally occurring bisindole (50). The analogous conversion of vinblastine (1) to its A/ -oxide (16) proceeds under similar conditions but requires longer exposure to the peraeid (24 hr) (5/) 3, 4 -anhydrovinblastine is converted to its N -oxide (17) in 10 min at 0°C... 

Vindolicine (vindoline 10,10 -dimer) and fourteen bisindole alkaloids of the vinblastine group have been isolated from the aerial parts of Catharanthus ovalis.ny These include leurosine, 21 -hydroxyleurosine, vinblastine, 20 -deoxy-leurosidine, 20 -deoxyvinblastine, pleurosine, Catharine, catharinine, vincristine, and vincathicine. A new alkaloid is 21 -oxoleurosine (198), which has also been found recently in Catharanthus roseus.U8 The three remaining alkaloids are vincovaline (199) and vincovalinine (16 -desmethoxycarbonyl-leurosine), whose structures119 have now been confirmed, and vincovalicine, which has... 

A number of alkaloids with the aspidospermine skeleton occur in the genus Vinca and are dealt with in detail in Chapter 12. They include the very important base vindoline (CIII) which not only occurs as the free base in Vinca rosea (= Lochnera rosea = Catharanthus roseus) but also as part of the dimeric alkaloids vinblastine (vincaleucoblastine) and leurosine, whereas the Aa-formyl analog, CIV, forms part of the dimeric alkaloid leurocristine (5, 72a). These dimeric alkaloids have been used successfully for the treatment of certain forms of cancer in man (5). Vindolinine (CVI) has also been isolated from V. rosea and its dihydro-decarbomethoxy derivative, tuboxenin (CVI-A), which is the parent member of the series, occurs in a Pleiocarpa species (53). ( + )-Vincadif-formine (XCIII, 6, 74) has already been mentioned as the racemic form of (— )-6,7-dihydrotabersonine (Section II, O). It has been found in V. difformis and in Rhazya stricta (51b) where the (+) form also occurs. 

In 1959 a series of bisindole alkaloids were isolated from Vinca rosea L. Catharanthus roseus G. Don). Of signal importance have been vinblastine (169) (= vincaleukoblastine) and vincristine (170) (= leurocristine), both of which show anti-tumour activity (see Section 18, p. 333). Structurally clarified also are leurosidine (= vinrosidine), leurosine, pleurosine, and isoleurosine , while only one half of Catharine is known. 

The Eli Lilly team isolated from a Madagascan Catharanthus roseus VLB-sulphate, as well as the new alkaloid leurosine (vinleurosine, VLR), which is chemically closely related to VLB. Leurosine has also been isolated from Catharanthus lanceus Pich. ... 

Piperine (54) and antiepilepsirine (55), piperidine alkaloids that occur in Piper species (Piperaceae), are MAOIs with greater selectivity for MAO-B [173], yet they have not been studied extensively for therapeutic potential in PD. Some Vinca alkaloids, including vincristine, vinblastine, leurosine, and vindoline from Catharanthus roseus (L.) G.Don (Apocynaceae), are reported as selective MAO-B inhibitors, but cytotoxicity limits their development as potential drug candidates for PD [174, 175] (see Sect. 6) (Scheme 42.14). 

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