Dithiocarbamate/piperazine bridged pyrrolobenzodiazepines as DNA-minor groove binders: Synthesis, DNA-binding affinity and cytotoxic activity

• C8-linked dithiocarbamate/piperazine-PBD conjugates (5a–c, 6a,b) were synthesized.
• The conjugates 5a and 5b have been screened for their cytotoxicity by NCI.
• The compounds 5c and 6a,b have been also exhibited significant in vitro cytotoxicity.
• Molecular modeling studies predict that 6b exhibits superior than other compounds.

A new series of C8-linked dithiocarbamate/piperazine bridged pyrrolo[2,1-c][1,4]benzodiazepine conjugates (5a–c, 6a,b) have been synthesized and evaluated for their cytotoxic potential and DNA-binding ability. The representative conjugates 5a and 5b have been screened for their cytotoxicity against a panel of 60 human cancer cell lines. Compound 5a has shown promising cytotoxic activity on selected cancer cell lines that display melanoma, leukemia, CNS, ovarian, breast and renal cancer phenotypes. The consequence of further replacement of the 3-cyano-3,3-diphenylpropyl 1-piperazinecarbodithioate in 5b and 5c with 4-methylpiperazine-1-carbodithioate yielded new conjugates 6a and 6b respectively. In addition, the compounds 5c and 6a,b have been evaluated for their in vitro cytotoxicity on some of the selected human cancer cell lines and these conjugates have exhibited significant cytotoxic activity. Further, the DNA-binding ability of these new conjugates has been evaluated by using thermal denaturation (ΔTm) studies. The correlation between structure and DNA-binding ability has been investigated by molecular modeling studies which predicted that 6b exhibits superior DNA-binding ability and these are in agreement with the experimental DNA-binding studies.

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