Bicyclic and tricyclic analogs of anthramycin

Abstract

As analogues 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, namely, 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 analogues 6a', 6f, and 6g were found to be 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. Among the tricyclic analogues, compounds 5, 7a, and 8b were active against P388 leukemia, and they generally appear to be more potent than bicyclic analogues.

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

“…Chemical syntheses of naturally occurring PBDs, such as anthramycin, [71][72][73] DC-81, [74][75][76] tomaymycin, 77 and chicaymycin 78 have been reported. More than 60 not naturally occurring monomeric PBDs have been synthesized, 76,[78][79][80][81][82][83][84][85][86][87][88][89][90] as shown in Figures 12 and 13. Chemical synthesis of naturally occurring PBDs and their analogs is hampered by the stability of the N10-C11 imine bond, retention of stereochemistry at C11a, loss of unsaturation in the C-ring under reductive cyclization, and dependency on ring A substituents for the diazepine ring closure.…”

Development of the Applications of Palladium on Charcoal in Organic Synthesis

“…In the past, 1,4‐benzodiazepines were primarily used in central nervous system therapies. They have now been extended to antibiotic, antimalarial, anti‐HIV, anticancer, antidepressant, antitumour, anti‐insectant, analgesic, and fibrinogenic receptor antagonist drugs . Therefore developing efficient methodologies for the synthesis of these diverse scaffolds has attracted much attention.…”

Rhodium(II)‐Catalyzed Intramolecular Annulation of 1‐Sulfonyl‐1,2,3‐Triazoles with Pyrrole and Indole Rings: Facile Synthesis of N‐Bridgehead Azepine Skeletons

“…Among these poly‐heterocycles, the structurally diverse and biologically interesting N‐bridgehead azepine skeletons are of great importance because of their well‐represented and wide distribution in nature. Representative examples, such as Cephalotaxus alkaloids,3 Stemona alkaloids,4 ant venom/frog alkaloids,5a and the antitumor antibiotics anthramycin,5b all have N‐bridgehead azepine skeletons (Figure 1). Construction of N‐bridgehead azepine units usually requires multistep approaches 3–5.…”