Synthesis, metabolism and in vitro cytotoxicity studies on novel lavendamycin antitumor agents

Abstract

A series of lavendamycin analogues with two, three or four substituents at the C-6, C-7 N, C-2', C-3' and C-11' positions were synthesized via short and efficient methods and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. The compounds were prepared through Pictet-Spengler condensation of the desired 2-formylquinoline-5,8-diones with the required tryptophans followed by further needed transformations. Metabolism and toxicity studies demonstrated that the best substrates for NQO1 were also the most selectively toxic to NQO1-rich tumor cells compared to NQO1-deficient tumor cells.

Scheme 1

Scheme 2^a

^aReagents and conditions: (a) see ref 16; (b) succinic anhydride, NaOAc, Na₂SO₃, DMF, Ar, 18 h, rt, 82%; (c) K₂Cr₂O₇, CH₃COOH, 20 h, rt, 44%; (d) SeO₂, 1,4-dioxane, H₂O, 11 h, reflux, 57%.

Scheme 3^a

^aReagents and conditions: (a) CH₃CH=N(CH₃)_2, CH₃COOH, toluene, 4 days, 5 °C, 38%; (b) NaCH₂CH₃CO₂CH₃, Et₃N, toluene, Ar, 1 h, rt, then 9 h at 103–105 °C, 97%; (c) H₂, Pd-C 10%, CF₃COOH, 21 h, rt, 93%.

Scheme 4^a

^aReagents and conditions: (a) H₂N(CH₂)₂OH for 73, H₂NCH₂CHOHCH₂OH for 74, N(CH₂CH₂)₂NBn for 75, CHCl₃, Et₃N, alcohol, Ar, 29 h for 73, 24 h for 74, and 48 h for 75, rt; (b) HCOONH₄, Pd-C 10%, isopropanol for 30, 32 and methanol for 31, Ar, 4.5 h for 30, 30 min for 31 and 32, rt.

Scheme 5