Mitosenes of both the pyrrolo- and pyrido[1,2-a]indole type have been prepared via modification of these heterotricyclic compounds. Several mitosenes have been studied for their reactions with nucleophiles under reductive conditions. The results of these experiments show that the biological activity of mitosenes is based on the mechanism of bioreductive activation. When both leaving groups at C-1 and C-10 in the mitosene are the same, the nucleophile preferably adds to C-10 under reductive conditions. All mitosenes were studied for their biological activities in vitro against L1210, WiDr, and A204. On the basis of these results a selection of three mitosenes was made for a more detailed biological evaluation. Several tumor model systems were used, viz. P388, human tumor xenografts, MAC 13, and MAC 16. The results of these studies show that mitosenes have a more limited range of activities than mitomycin C. Surprisingly, the in vivo activities of mitosene diol 8b and mitosene diacetate 10b against the gastric human tumor xenograft GXF 97 were very high and comparable with that of mitomycin C.
097ChemInform Abstract The substrates of the title reaction, i.e. the lactams (III), (V) and (VII), are prepared from the acyl chlorides (I) and the appropriate alkylanilines (II) (cf. the synthesis of (III)). The procedures A) or B) can be employed to effect cyclization to the target compounds (IV) and (VI), and to transform (VII) to (VIII). Application of method A) to (IIIa) results in the formation of polymeric material, while transesterification occurs in the case of (IIIg) and procedure B) (giving (IVf) in 58% yield). Quinones of type (X) and (XV), incorporating the basic skeleton of mitomycin antibiotics and mitosenes, are accessible either by functionalization of the above-mentioned products (cf. (IVb) → (X)) or by subjecting a protected quinone such as (XIV) (prepared from (XI)) to the cyclizationprocedure.
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