Chem. Pharm. Bull. 55(5) 734—738 (2007)

secondary metabolites present in plants and microorganisms generally arise from oxidative coupling and/or pericyclic reactions. In the field of alkaloids, such compounds often exhibit biological activities dramatically increased, when compared with the corresponding monomeric units, as illustrated by anticancer heterodimeric bisindole alkaloids vinblastine and vincristine, and curarizing homodimeric bisindole and bisisoquinoline alkaloids toxiferine and tubocurarine. As far as DNA interacting agents are concerned, the idea of mimicking Nature led to conceive dimeric synthetic systems, which also display significantly enhanced biological activity when compared to the parent monomeric entities. Ditercalinium (1), resulting from the dimerization of two pyridocarbazole units related to natural alkaloids ellipticine (2) and olivacine (3) is an excellent example of this approach. Benzo[b]acronycine derived antitumor derivatives, developed from the model of natural acronycine (4), are exemplified by diacetate 5, currently under phase I clinical trials under the code S23906-1. These compounds displayed a particularly impressive broad antitumor spectrum, when evaluated against aggressive orthotopic models of human ovarian, lung, and colon cancers. The mechanism of action of these compounds has been recently shown to imply alkylation of the 2-amino group of DNA guanine residues. In this context, benzo[b]acronycine dimers appeared us as possible drug candidates. The linkage of the two monomeric units was envisaged through their C-6 positions, since acronycine and benzo[b]acronycine derivatives modified at this position had been previously shown to exhibit cytotoxic activities in vitro and antitumor properties in vivo comparable or superior to those of the parent compounds. Chemistry A flexible a ,w-alkyl ether linkage was envisaged to tether the two benzo[b]acronycine units, since the use of this type of spacer recently resulted in dimers with significantly enhanced DNA-binding affinities when compared to the corresponding monomers in the cytotoxic pyrrolo[2,1-c][1,4]benzodiazepine and berberine series. Coupling of 6-hydroxy-3,3-14-trimethyl-3,14-dihydro-7Hbenzo[b]pyrano[3,2-h]acridin-7-one (6) with a ,w-diiodoalkanes of varying length under alkaline conditions, according to a method essentially similar to that initially introduced by Marvel and Tannenbaum, provided the desired dimers 7—10 in 10—32% yield. Halogenated ethers 11—14, arising from monoalkylation at O-6, were also isolated in 9—34% yield from the reaction mixtures. They were accompanied by minute amounts of intramolecular cyclization products at C5, illustrated by the fused pyran 15, oxepine 16, and oxocine 17, when 1,3-diiodopropane, 1,4-diiodobutane, and 1,5-diiodopentane were used as alkylating agents, respectively. In addition, compounds resulting from C-alkylation at C-5 and olefins obtained through hydrogen iodide elimination, 18—22, were obtained in small yield, particularly in the course of the reaction involving 1,3-diiodopropane. Pharmacology The study of the cytotoxic properties of the benzo[b]acronycine dimers 7—10 and of halogenated ethers 11—14 was carried out in vitro on the L1210 murine leukemia cell line. The results (IC50) are reported in Table 1, in comparison with acronycine (4), benzo[b]acronycine (23), and 6-hydroxy-3,3-14-trimethyl-3,14-dihydro-7H-benzo[b]734 Vol. 55, No. 5