Synthesis and Biological Evaluation of Diaryl Ether Linked DC-81 Conjugates as Potential Antitumor Agents
M. Janaki Ramaiah,
J. N.S.R.C. Murty,
E. Vijaya Bharathi,
S. N.C.V.L. Pushpavalli,
Manika pal Bhadra.
A series of new diaryl ether linked pyrrolobenzodiazepine (PBD) conjugates (4a-i, 5a-i and 6a-f) was synthesized and
evaluated for their anticancer activity against a panel of 11 human cancer cell lines. These conjugates exhibited significant anticancer
activity with GI50 values in the range of 0.1-3.88 μM. Some of the potent conjugates (4b, 4h, 5h, 6b, 6c and 6e) were further investigated
on cell cycle distribution. FACS analysis showed the accumulation of cells in G0 phase indicating the apoptosis inducing nature of these
conjugates. Moreover, compound 6b caused a decrease in the mitochondrial membrane potential, which indicates the apoptotic nature of
the compound through mitochondrial mediated pathway. Further conjugates 4b, 4h and 6b induce the activation of caspase and PARP
proteins, followed by apoptotic cell death in MCF7 cell line.
Keywords: Anticancer activity, apoptosis, caspase, diaryl ether, mitochondrial membrane potential, poly-(ADP-ribose) polymerase,
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