Novel Lavendamycin Analogues as Antitumor Agents:  Synthesis, in Vitro Cytotoxicity, Structure−Metabolism, and Computational Molecular Modeling Studies with NAD(P)H:Quinone Oxidoreductase 1

Abstract

Novel lavendamycin analogues with various substituents were synthesized and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. Pictet-Spengler condensation of quinoline- or quninoline-5,8-dione aldehydes with tryptamine or tryptophans yielded the lavendamycins. Metabolism studies with recombinant human NQO1 revealed that addition of NH2 and CH2OH groups at the quinolinedione-7-position and indolopyridine-2'-position had the greatest positive impact on substrate specificity. The best and poorest substrates were 37 (2'-CH2OH-7-NH2 derivative) and 31 (2'-CONH2-7-NHCOC3H7-n derivative) with reduction rates of 263 +/- 30 and 0.1 +/- 0.1 micromol/min/mg NQO1, respectively. Cytotoxicity toward human colon adenocarcinoma cells was determined for the lavendamycins. The best substrates for NQO1 were also the most selectively toxic to the NQO1-rich BE-NQ cells compared to NQO1-deficient BE-WT cells with 37 as the most selective. Molecular docking supported a model in which the best substrates were capable of efficient hydrogen-bonding interactions with key residues of the active site along with hydride ion reception.

Analysis of quinolinequinone reactivity, cytotoxicity, and anti-HIV-1 properties

“…Notably, the 5,8-quinolinequinone, streptonigrin and its derivatives have demonstrated anti-cancer activities (1). Similar 5,8-quinolinequinones have been reported to have anti-bacterial, anti-malarial, anti-fungal, and anti-inflammatory activities (2–7). Another quinolinequinone, LY83583 (6-anilino-5,8-quinolinequinone), has been shown to inhibit soluble guanylate cyclase and leukotriene synthesis with IC50 concentrations in the 1–2 micromolar range (8–9).…”

“…Notably, streptonigrin and its derivatives have been studied for more than five decades as potential anti-cancer agents (1). The structurally related lavendamycin has been the subject of investigation for both its anti-cancer and antibiotic activities (2–3). Similar quinolinequinones have been reported to have potent anti-inflammatory and anti-fungal properties (1–9), and LY83583 has been identified as a specific inhibitor of soluble guanylate cyclase (7–9).…”

Synthesis of New Quinolinequinone Derivatives and Preliminary Exploration of their Cytotoxic Properties

“…Although unusual, higher rates for acetylated analogues have been observed in other series. 6, 11 With regard to the aromatic substituents at the quinoline-2-position, no clear trend in reduction rates was observed except that bulkier groups generally decreased reduction rates. Oxygen consumption is a measure of the ability of the reduced quinone (hydroquinone) to redox cycle following reduction by NQO1.…”

Self-assembly of 2-aldehyde-8-hydroxyquinolinate-based lanthanide complexes and NIR luminescence

“…2-Aldehyde-8-hydroxyquinoline (ahq) was synthesized according to the reported method [22], and tris(hydroxymethyl)aminomethane (tris) was commercially purchased. The ligands N-(2-(8-hydroxylquinolinyl)methylene)(trishydroxymethyl)methylamine (Hnhm) and 2,8-bis(2-(8-hydroxylquinolinyl))-1-aza-5-hydroxymethyl-3,7-dioxabicyclo[3.3.0]octane (H 2 baho) were in-situ formed.…”

“…Especially, it is recently reported that 2-aldehyde-8-hydroxyquinoline could efficiently sensitize Yb 3+ ions, where intriguing NIR photoluminescence has been observed [15][16][17][18]. We have reported the syntheses, structures and NIR luminescence of a series of Nd 3+ and Yb 3+ complexes coordinated with 2-(2 0 -hydroxyphenyl)benzimidazole, and salen-type ligands, respectively [19][20][21][22]. As a continuing attempt for NIR property, we herein present the syntheses, structures of a series of mononuclear lanthanide complexes Ce(baho) 2 ÁEt 2 O (1), Dy(nhm) 2 ClÁ0.5H 2 O (2) and Ln(nhm) 2 ClÁ0.5C 6 H 14 (Ln = Ho (3), Er (4), Yb (5)) ( Fig.…”