Discovery, Synthesis, and Evaluation of Oxynitidine Derivatives as Dual Inhibitors of DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1), and Potential Antitumor Agents

Tyrosyl–DNA
phosphodiesterase 1 (TDP1) is a recently discovered
enzyme repairing DNA lesions resulting from stalled topoisomerase
IB (TOP1)–DNA covalent complex. Inhibiting TDP1 in conjunction
with TOP1 inhibitors can boost the action of the latter. Herein, we
report the discovery of the natural product oxynitidine scaffold as
a novel chemotype for the development of TOP1 and TDP1 inhibitors.
Three kinds of analogues, benzophenanthridinone, dihydrobenzophenanthridine,
and benzophenanthridine derivatives, were synthesized and evaluated
for both TOP1 and TDP1 inhibition and cytotoxicity. Analogue 19a showed high TOP1 inhibition (+++) and induced the formation
of cellular TOP1cc and DNA damage, resulting in cancer cells apoptosis
at nanomolar concentration range. In vivo studies indicated that 19a exhibits antitumor efficiency in HCT116 xenograft model. 41a exhibited additional TDP1 inhibition with IC50 value of 7 μM and synergistic effect with camptothecin in
MCF-7 cells. This work will facilitate future efforts for the discovery
of natural product-based TOP1 and TDP1 inhibitors.