Bioorganic and Medicinal Chemistry Letters p. 512 - 517 (2016)
Update date:2022-08-10
Topics:
?arlauskas, Jonas
Pe?iukaityte-Alksne, Milda
Misevi?iene, Lina
Maroziene, Audrone
Polmickaite, Evelina
Staniulyte, Zita
?enas, Narimantas
Anusevi?ius, ?ilvinas
Naphtho[1′,2′:4,5]imidazo[1,2-a]pyridine-5,6-diones (NPDOs), a new type of N-heterocycle-fused o-quinones, have been synthesized. They have been found to be efficient electron-accepting substrates of NADPH-dependent single-electron-transferring P-450R and two-electron transferring NQO1, generating reactive oxygen species (ROS) with a concomitant decrease in NADPH, which is consistent with redox-cycling. The reactivity of NPDOs toward P-450R (in terms of kcat/Km) varied in the range of 106-107 M-1 s-1, while their reduction by NQO1 proceeded much faster, approaching the diffusion control limit (kcat/Km ~ 108-109 M-1 s-1). NPDOs exhibited relatively high cytotoxic activity against human lung carcinoma (A-549) and breast tumor (MCF-7) cell lines (LC50 = 0.1-8.3 μM), while promyelocytic leukemia cells (HL-60) were less sensitive to NPDOs (LC50 ≥ 10 μM). 3-Nitro-substituted NPDO (11) revealed the highest potency against both A-549 and MCF-7 cell lines, with LC50 of 0.12 ± 0.03 μM and 0.28 ± 0.08 μM, respectively. Dicoumarol partly suppressed the activity of the compounds against A-594 and MCF-7 cell lines, suggesting that their cytotoxic action might be partially influenced by NQO1-mediated bioreductive activation.
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