Antitumor agents 281. Design, synthesis, and biological activity of substituted 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one analogs (ATBO) as potent in vitro anticancer agents

Abstract

In our exploration of new biologically active chemical entities, we designed and synthesized a novel class of antitumor agents, substituted 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one (ATBO) analogs. We evaluated their cytotoxic activity against seven human tumor cell lines from different tissues, and established preliminary structure-activity relationships (SAR). All analogs, except 8, 9, and 25-27, displayed potent tumor cell growth inhibitory activity. Especially, compounds 15 and 33 with a 4-methoxyphenyl group at position C-4 were extremely potent with ED(50) values of 0.008-0.064 and 0.035-0.32 μM, respectively. Compound 15 was the most potent analog compared with structurally related neo-tanshinlactone (e.g., 1) and 4-amino-2H-benzo[h]chromen-2-one (ABO, e.g., 4) analogs, and thus merits further exploration as an anti-cancer drug candidate.

Figure 1

Structures of neo-tanshinlactone (1), 4-ethyl neo-tanshinlactone (2), previously reported scaffold 3 and its analog 4, and newly designed scaffold 5

Scheme 1

Reagents and conditions: (a) POCl₃, Et₃N, reflux, 1h; (b) aliphatic amines, EtOH, reflux, 2h; (c) aromatic amines, ethylene glycol, 160 °C, 1h.