10.1021/acs.jmedchem.6b01565.s007
Ping Wang
Ping
Wang
Mohamed S. A. Elsayed
Mohamed
S. A. Elsayed
Caroline B. Plescia
Caroline B.
Plescia
Azhar Ravji
Azhar
Ravji
Christophe E. Redon
Christophe
E. Redon
Evgeny Kiselev
Evgeny
Kiselev
Christophe Marchand
Christophe
Marchand
Olga Zeleznik
Olga
Zeleznik
Keli Agama
Keli
Agama
Yves Pommier
Yves
Pommier
Mark Cushman
Mark
Cushman
Synthesis and Biological
Evaluation of the First Triple
Inhibitors of Human Topoisomerase 1, Tyrosyl–DNA Phosphodiesterase
1 (Tdp1), and Tyrosyl–DNA Phosphodiesterase 2 (Tdp2)
American Chemical Society
2017
Tdp 2 inhibition
Tdp 2
cancer cells vs
7- azaindenoisoquinolines
cancer cell cultures
PBMC
Tdp 2. Molecular modeling
Tdp 2. Enzyme
γ- H 2AX foci formation
lymphoblastic leukemia CCRF-CEM cells
DNA damage
lactam side chain
topoisomerase inhibitors
First Triple Inhibitors
2017-04-18 18:34:00
Dataset
https://acs.figshare.com/articles/dataset/Synthesis_and_Biological_Evaluation_of_the_First_Triple_Inhibitors_of_Human_Topoisomerase_1_Tyrosyl_DNA_Phosphodiesterase_1_Tdp1_and_Tyrosyl_DNA_Phosphodiesterase_2_Tdp2_/4887071
Tdp1 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.