Bicyclic and tricyclic analogs of anthramycin

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Abstract
As analogs of pyrrolo[2,1-c] [1,4]benzodiazepine antitumor antibiotics, such as anthramycin and tomaymycin, several benzo[1,4]diazepine imines and carbinolamine ethers were prepared and tested in vivo against P388 leukemia. Two different synthetic approaches, i.e., a reduction of an aromatic nitro group with a concomitant cyclization and a reduction of a lactam, were employed to generate an imine or a carbinolamine moiety. Bicyclic analogs [1,2,3,4-tetrahydro-9-hydroxy-2-methoxy-5H-1,4-benzodiazepin-5-one] and 6g were active, indicating that the pyrroline ring of anthramycin is not an absolute necessity for the antitumor activity. Compound 6g 3,4-dihydro-9-hydroxy-4-propargyl-5H-1,4-benzodiazepin-5-one, was at least as active as neothramycin although it was 5 times less potent. Amont the tricyclic analogs, [8-hydroxy-7-methoxy-2-[(methoxy carbonyl) methylene]-2,3,5,11a-tetrahydro-1H-pyrrolo[2,1-c] [1,4]benzodiazepine-5-one] was active against P388 leukemia, and was more potent than bicyclic analogs.

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