jm6b01565_si_006.pdb (935.51 kB)
Synthesis and Biological Evaluation of the First Triple Inhibitors of Human Topoisomerase 1, Tyrosyl–DNA Phosphodiesterase 1 (Tdp1), and Tyrosyl–DNA Phosphodiesterase 2 (Tdp2)
dataset
posted on 2017-04-18, 18:34 authored by Ping Wang, Mohamed S. A. Elsayed, Caroline B. Plescia, Azhar Ravji, Christophe E. Redon, Evgeny Kiselev, Christophe Marchand, Olga Zeleznik, Keli Agama, Yves Pommier, Mark CushmanTdp1 and Tdp2 are
two tyrosyl–DNA phosphodiesterases that
can repair damaged DNA resulting from topoisomerase inhibitors and
a variety of other DNA-damaging agents. Both Tdp1 and Tdp2 inhibition
could hypothetically potentiate the cytotoxicities of topoisomerase
inhibitors. This study reports the successful structure-based design
and synthesis of new 7-azaindenoisoquinolines that act as triple inhibitors
of Top1, Tdp1, and Tdp2. Enzyme inhibitory data and cytotoxicity data
from human cancer cell cultures establish that modification of the
lactam side chain of the 7-azaindenoisoquinolines can modulate their
inhibitory potencies and selectivities vs Top1, Tdp1, and Tdp2. Molecular
modeling of selected target compounds bound to Top1, Tdp1, and Tdp2
was used to design the inhibitors and facilitate the structure–activity
relationship analysis. The monitoring of DNA damage by γ-H2AX
foci formation in human PBMCs (lymphocytes) and acute lymphoblastic
leukemia CCRF-CEM cells documented significantly more DNA damage in
the cancer cells vs normal cells.