Substituted 4,5'-Bithiazoles as Catalytic Inhibitors of Human DNA Topoisomerase IIα.
2020
Human
type II topoisomerases, molecular motors that alter the DNA
topology, are a major target of modern chemotherapy. Groups of catalytic
inhibitors represent a new approach to overcome the known limitations
of topoisomerase II poisons such as cardiotoxicity and induction of
secondary tumors. Here, we present a class of substituted 4,5′-bithiazoles
as catalytic inhibitors targeting the human DNA topoisomerase IIα.
Based on a structural comparison of the ATPase domains of human and
bacterial type II topoisomerase, a focused chemical library of 4,5′-bithiazoles
was assembled and screened to identify compounds that better fit the
topology of the human topo IIα adenosine 5′-triphosphate
(ATP) binding site. Selected compounds showed inhibition of human
topo IIα comparable to that of the etoposide topo II drug, revealing
a new class of inhibitors targeting this molecular motor. Further
investigations showed that compounds act as catalytic inhibitors via
competitive ATP inhibition. We also confirmed binding to the truncated
ATPase domain of topo IIα and modeled the inhibitor molecular
recognition with molecular simulations and dynophore models. The compounds
also displayed promising cytotoxicity against HepG2 and MCF-7 cell
lines comparable to that of etoposide. In a more detailed study with
the HepG2 cell line, there was no induction of DNA double-strand breaks
(DSBs), and the compounds were able to reduce cell proliferation and
stop the cell cycle mainly in the G1 phase. This confirms the mechanism
of action of these compounds, which differs from topo II poisons also
at the cellular level. Substituted 4,5′-bithiazoles appear
to be a promising class for further development toward efficient and
potentially safer cancer therapies exploiting the alternative topo
II inhibition paradigm.
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