Synthesis and Biological Evaluation of a Novel C8-Pyrrolobenzodiazepine (PBD) Adenosine Conjugate. A Study on the Role of the PBD Ring in the Biological Activity of PBD-Conjugates
Here we sought to evaluate the contribution of the PBD unit to the biological activity
of PBD-conjugates and, to this end, an adenosine nucleoside was attached to the PBD A-ring C8
position. A convergent approach was successfully adopted for the synthesis of a novel C8-linked
pyrrolo(2,1-c)(1,4)benzodiazepine(PBD)-adenosine(ADN) hybrid. The PBD and adenosine (ADN)
moieties were synthesized separately and then linked through a pentynyl linker. To our knowledge,
this is the first report of a PBD connected to a nucleoside. Surprisingly, the compound showed no
cytotoxicity against murine cells and was inactive against Mycobacterium aurum and M. bovis strains and
did not bind to guanine-containing DNA sequences, as shown by DNase I footprinting experiments.
Molecular dynamics simulations revealed that the PBD–ADN conjugate was poorly accommodated
in the DNA minor groove of two DNA sequences containing the AGA-PBD binding motif, with
the adenosine moiety of the ligand preventing the covalent binding of the PBD unit to the guanine
amino group of the DNA duplex. These interesting findings shed further light on the ability of
the substituents attached at the C8 position of PBDs to a ect and modulate the biological and
biophysical properties of PBD hybrids