Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide

Topoisomerase
II (TOP2) poisons as anticancer drugs work by trapping TOP2 cleavage
complexes (TOP2cc) to generate DNA damage. Repair of such damage by
tyrosyl DNA phosphodiesterase 2 (TDP2) could render cancer cells resistant
to TOP2 poisons. Inhibiting TDP2, thus, represents an attractive mechanism-based
chemosensitization approach. Currently known TDP2 inhibitors lack
cellular potency and/or permeability. We report herein two novel subtypes
of the deazaflavin TDP2 inhibitor core. By introducing an additional
phenyl ring to the N-10 phenyl ring (subtype 11) or to
the N-3 site of the deazaflavin scaffold (subtype 12),
we have generated novel analogues with considerably improved biochemical
potency and/or permeability. Importantly, many analogues of both subtypes,
particularly compounds 11a, 11e, 12a, 12b, and 12h, exhibited much stronger
cancer cell sensitizing effect than the best previous analogue 4a toward the treatment with etoposide, suggesting that these
analogues could serve as effective cellular probes.