Abstract
Pyrrolo[1,4]benzodiazepines are tricyclic compounds that are considered “privileged structures” since they possess a wide range of biological activities. The first encounter with these molecules was the isolation of anthramycin from cultures of Streptomyces, followed by determination of the X-ray crystal structure of the molecule and a study of its interaction with DNA. This opened up an intensive synthetic and biological study of the pyrrolo[2,1-c][1,4]benzodiazepines that has culminated in the development of the dimer SJG-136, at present in Phase II clinical trials. The synthetic efforts have brought to light some new synthetic methodology, while the contemporary work is focused on building trimeric pyrrolo[2,1-c][1,4]benzodiazepines linked together by various heterocyclic and aliphatic chains. It is the broad spectrum of biological activities of pyrrolo[1,2-a][1,4]benzodiazepines that has maintained the interest of researchers to date whereas several derivatives of the even less studied pyrrolo[1,2-d][1,4]benzodiazepines were found to be potent non-nucleoside HIV-1 reverse transcriptase inhibitors. The present review is an update on the synthesis of pyrrolo[2,1-c][1,4]benzodiazepines since the last major review of 2011, while the overview of the synthesis of the other two tricyclic isomers is comprehensive.
Highlights
The pyrrolo[1,4]benzodiazepine (PBD) tricyclic ring system is represented by three possible structural isomers [2,1-c][1,4] 1, [1,2-a][1,4] 2 and [1,2-d][1,4] 3 (Figure 1)
For the purposes of the present review, synthetic chemistry publications from the primary literature were retrieved from the SciFinder and Scopus databases
For the period 2010 to the middle of 2015, thirty-two pyrrolo[2,1-c][1,4]benzodiazepine-related publications were retrieved, whereas for the period 1960 to the present, twenty-five pyrrolo[1,2-a][1,4]benzodiazepine and seven pyrrolo[1,2-d][1,4]benzodiazepine publications were downloaded. This is the first review on the synthesis of PBDs that includes all three structural isomers
Summary
The pyrrolo[1,4]benzodiazepine (PBD) tricyclic ring system is represented by three possible structural isomers [2,1-c][1,4] 1, [1,2-a][1,4] 2 and [1,2-d][1,4] 3 (Figure 1). The first derivative of any of these ring systems to be synthesized was a pyrrolo[2,1-c][1,4]benzodiazepine, anthramycin (4), reported by Leimgruber et al, in 1968 [1]. This is the first review on the synthesis of PBDs that includes all three structural isomers.
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