Antitumor agents 278. 4-Amino-2H-benzo[h]chromen-2-one (ABO) analogs as potent in vitro anti-cancer agents

Abstract

4-Amino-2H-benzo[h]chromen-2-one (ABO) analogs were designed, synthesized, and evaluated for cytotoxic activity. Among all 4-substituted ABO analogs, cyclohexyl (12), N-methoxy-N-methylacetamide (14), and various aromatic derivatives (15-25 and 27) exhibited promising cell growth inhibitory activity with ED(50) values of 0.01-5.8 microM against all tested tumor cell lines. The 4'-methoxyphenyl derivative (18) and 3'-methylphenyl derivative (24) showed the most potent antitumor activity against a broad range of cancer cell lines with ED(50) values of 0.01-76 microM. Preliminary SAR results indicated that substitutions on nitrogen are critical to the antitumor potency.

Figure 1

Structures of neo-tanshinlactone (1), 4-ethyl neo-tanshinlactone (2), previously reported scaffold 3, and newly designed scaffold 4

Scheme 1

Reagents and conditions: (a) POCl₃, Et₃N, reflux, 1h; (b) aliphatic amines, EtOH, reflux, 2h; (c) 2-amino-N-methoxy-N-methylacetamide hydrobromide, Et₃N, EtOH, 55 °C; (d) aromatic amines, ethylene glycol, 160 °C, 1h.

Scheme 1

Reagents and conditions: (a) POCl₃, Et₃N, reflux, 1h; (b) aliphatic amines, EtOH, reflux, 2h; (c) 2-amino-N-methoxy-N-methylacetamide hydrobromide, Et₃N, EtOH, 55 °C; (d) aromatic amines, ethylene glycol, 160 °C, 1h.