Synthesis and Antitumor Activity of a New Class of Pyrazolo[4,3-e]pyrrolo[1,2-a][1,4]diazepinone Analogs of Pyrrolo[1,4][2,1-c]benzodiazepines

Abstract

A new class of pyrrolo[1,4]benzodiazepine (PBD) analogues featuring a pyrazolo[4,3-e]pyrrolo[1,2-a][1,4]diazepinone ring system has been designed and synthesized. These compounds, 2a-o, are characterized by the substitution of the aromatic A ring, characteristic of the PBDs, with a disubstituted pyrazole ring bearing alkyl and benzyl substituents at N6 or N7 and alkyl or carbomethoxy substituents at C8. Biological evaluation revealed an appreciable in vitro cytotoxic activity for compounds 2a,b,f-i.

Effect of A-Ring Modifications on the DNA-Binding Behavior and Cytotoxicity of Pyrrolo[2,1-c][1,4]benzodiazepines

“…Cytotoxicity. As with previous studies on pyrrolobenzodiazepines, a broad correlation between cytotoxicity and DNA-binding affinity was observed. ,,,,, The C-ring-unsaturated compounds 1 − 3 had the highest DNA-binding affinity as judged by thermal denaturation studies and were also the most cytotoxic across the three cell lines examined (i.e., range of IC 50 values = 0.000017−0.32 μM). Sibiromycin ( 3 ) was the most cytotoxic compound examined in the L1210 and ADJ/PC6 cell lines and also gave the largest Δ T m value of 16.3 °C after incubation for 18 h (see Table ).…”

“…Doyle and co-workers have published the results of a study of bicyclic analogues of PBDs comprising only the A- and B-rings, demonstrating the importance of the presence of the C-ring for significant cytotoxicity . More recently, Baraldi and co-workers have reported conversion of the aromatic A-ring of the PBD system into a pyrazole . We report here the results of an investigation into the effect of modifying the A-ring complexion and substitution pattern on both DNA-binding reactivity and cytotoxic potency.…”

Pyrrolobenzodiazepines as Sequence Selective DNA Binding Agents

“…Baraldi and co-workers [41] [42] have synthesized some other A-ring heterocyclic PBDs and evaluated their DNA binding affinity. In this study pyrazine and pyrimidine A-ring analo g u e s o f P B D s h a v e b e e n p r e p a r e d a n d evaluated for their cytotoxic potential.…”

Combinatorial Library Synthesis and Biological Evaluation of Pyrazolo[4,3‐e][1,4]diazepine as a Potential Privileged Structure

“…Although two isomers (6 and 7) are commonly synthesized under these conditions, the N-2 regioisomers 7 were predominantly produced in the presence of NaH. [21] The ester group was cleaved using NaOH in MeOH (1 m) to give the free acid, which was then coupled with l-Ser esters and d-Phe esters (compound 8). The aryl nitro group was reduced by catalytic hydrogenation to give compound 9.…”