Synthesis, Biological Activity, and Quantitative Structure-Activity Relationship Study of Azanaphthalimide and Arylnaphthalimide Derivatives Miguel F. Bran ˜ a,* ,# Ana Gradillas,* ,# Angel Go ´mez, # Nuria Acero, § Francisco Llinares, | Dolores Mun ˜ oz-Mingarro, # Cristina Abradelo, ‡ Fernanda Rey-Stolle, ‡ Mercedes Yuste, ‡ Joaquı ´n Campos, † Miguel A Ä . Gallo, † and Antonio Espinosa † Departamento de Ciencias Quı ´micas, Departamento de Ciencias Ambientales y Recursos Naturales, Departamento de Biologı ´a Celular, Bioquı ´mica y Biologı ´a Molecular, Departamento de Matema ´ ticas, Fı ´sica Aplicada y Fisicoquı ´mica, Facultad de Ciencias Experimentales y de la Salud, Universidad San Pablo CEU, Urbanizacio ´ n Monteprı ´ncipe, 28668-Boadilla del Monte, Madrid, Spain, and Departamento de Quı ´mica Farmace ´ utica y Orga ´ nica, Facultad de Farmacia, Universidad de Granada, C/Campus de Cartuja s/n, 18071 Granada, Spain Received October 24, 2003 A series of quinoline derivatives as aza analogues of the naphthalene chromophore and a series of “nonfused” tricyclic aromatic systems, in particular 5-arylquinolines and 5- or 6-aryl and heteroaryl naphthalene systems, were synthesized and evaluated for growth-inhibitory properties in several human cell lines. The analysis of quantitative structure-antitumor activity relationships for the growth-inhibitory properties is also reported. Findings suggest that these compounds may not express their cytotoxicity via interaction on DNA. Introduction DNA-intercalating antitumor drugs constitute an important class of drugs in anticancer therapy. 1 Naph- thalimides are significant examples 2 that include com- pounds in clinical trials such as the mononaphthalimide amonafide 1 3 and the bis(naphthalimide) LU 79553 (elinafide) 2. 4 Nowadays, it is accepted that the anti- tumor activity of amonafide is closely related to its ability to stabilize the DNA-intercalator-topoisomerase II ternary complex. 5 Elinafide is not a poison of topo- isomerase II (topo II). It is a strong DNA binder, but it does not stabilize the topo II-DNA complex (or binds very weakly). 6 As part of a program to broaden the scope of 1 and 2, we have recently reported 7,8 the synthesis and biological evaluation of a new series of mono- and bis-intercalating agents where heterocyclic systems have been “fused” to the naphthalimide chromophore. Previous studies have reported the consequences of appending “nonfused” aromatic systems. The results obtained by the Cheng group 9 with the “2-phenylnaph- thalene-type” structural pattern hypothesis and by Denny and co-workers with tricyclic carboxamides 10 without a completely fused chromophore encouraged us to synthesize the structures proposed herein. In the present paper we describe the synthesis of new types of structures related to 1 and 2. The first series has a quinoline nucleus as aza analogues of the naphthalene chromophore, 11-17. They were designed to determine the effect of replacing carbon with nitrogen on antitumor activity. On the other hand, several series of “nonfused” tricyclic aromatic systems, 5- or 6-aryl and hetero- arylnaphthalene systems 18-22, were also prepared. The cytotoxic activity and the quantitative structure- activity relationship (QSAR) analysis for the growth- * To whom correspondence should be addressed. For M.F.B.: phone, 34913724771; fax, 34913724009; e-mail mfbrana@ceu.es. For A.G.: phone, 34913724789; fax, 34913510496; e-mail, gradini@ceu.es. # Departamento de Ciencias Quı ´micas, Universidad San Pablo CEU. § Departamento Ciencias Ambientales y Recursos Naturales, Uni- versidad San Pablo CEU. | Departamento de Biologı ´a Celular, Bioquı ´mica y Biologı ´a Molec- ular, Universidad San Pablo CEU. ‡ Departamento de Matema ´ ticas, Fı ´sica Aplicada y Fisicoquı ´mica, Universidad San Pablo CEU. † Departamento de Quı ´mica Farmace ´ utica y Orga ´ nica, Universidad de Granada. 2236 J. Med. Chem. 2004, 47, 2236-2242 10.1021/jm0310784 CCC: $27.50 © 2004 American Chemical Society Published on Web 03/20/2004