Synthesis of Novel Pyrido[3',2':5,6]thiopyrano[3,2-b]indol-5(6H)-ones and 6H-Pyrido[3',2':5,6]thiopyrano[4,3-b]quinolines, two New Heterocyclic Ring Systems Antonio Da Settimo, Anna Maria Marini*, Giampaolo Primofiore, Federico Da Settimo, Silvia Salerno, Francesca Simorini, Gianluca Pardi, Concettina La Motta, and Daniele Bertini Dipartimento di Scienze Farmaceutiche, Via Bonanno 6, 56126 Pisa, Italy Received February 14, 2002 The synthesis of new pyrido[3',2':5,6]thiopyrano[3,2- b]indol-5(6H)-ones was accomplished by the Fischer-indole cyclization of some 2,3-dihydro-3-phenylhydrazonothiopyrano[2,3-b]pyridin-4(4H)-ones, obtained from the 2,3-dihydro-3-hydroxymethylenethiopyrano[2,3- b]pyridin-4(4H)-one, by the Japp- Klingemann reaction. 6H-Pyrido[3',2':5,6]thiopyrano[4,3-b]quinolines were obtained by reaction of 2,3-dihydrothiopyrano- [2,3-b]pyridin-4(4H)-ones with o-aminobenzaldehyde or 5-substituted isatins. The preparation of some derivatives, functionalized with an alkylamino-substituted side chain, is also described. J. Heterocyclic Chem., 39, 1001(2002). In the ongoing search for new effective antitumor agents, a wide variety of new derivatives with completely different chemical structures have been prepared and tested. Among them, polycondensed nitrogen heterocycles having a planar structure are effective moieties for drugs endowed with antineoplastic activity. Their mechanism of action is correlated with the capacity to intercalate with the macromolecule of DNA [1-4], and to interfere with the activity of Topoisomerases I and II, two enzymes capable of modifying the topological state of DNA [5-9]. On the basis of these considerations, a large part of our studies was directed towards the design and synthesis of planar heteropolycyclic derivatives, structurally related to biologically active drugs, as new potential antitumor agents. In the last few years we have reported the synthesis of several new compounds, bearing benzimidazole or purine moieties, which exhibited interesting antiprolifera- tive activity, because of their ability to form a complex with DNA and to inhibit the Topoisomerase II [10-11]. In the present paper we wish to report the synthesis of derivatives of two new tetracyclic heteroaromatic systems of general formula A and B. They were prepared starting from the 2,3-dihydro- thiopyrano[2,3-b]pyridin-4(4H)-ones 2a-b [12,13], by known reactions employed in the literature for the obtain- ment of analogous tetracyclic systems [14-18]. Compounds 2a-b revealed to be versatile intermediates as, recently, they were used for the synthesis of new pyridoth- iopyrano[4,3-b]indole system 1 [12], which is structurally related to the novel heterocycle A. Notwithstanding the undoubted importance of the planar aromatic ring systems, the addition of groups or side chains which project from one or both the grooves of the DNA double helix and which interact like external binder moiety, appears to be crucial for drug activity. Indeed, a large number of anti-tumor compounds have been modi- fied by linking to a DNA intercalator a suitable basic side chain, thus modulating the biological properties and increasing solubility under physiological conditions [19- 21]. More recently, in the literature, it is also reported that flexible basic side chains, linked to the chromophore moi- ety by a carbonyl spacer, play an important role in enhanc- ing DNA-binding properties [22,23]. Taking it into account, we accomplished the synthesis of two derivatives of B, in which a carboxamidodimethylaminoalkyl side chain has been inserted in the 7 position of the heterotetra- cyclic system. Results and Discussion. Scheme 1 shows the synthetic procedure used to afford the title pyrido[3',2':5,6]thiopyrano[3,2- b]indol-5(6H)- ones of general formula A. The preparation of the interme- diate 2,3-dihydro-3-hydroxymethylenethiopyrano[2,3-b]- pyridin-4(4H)-one 3 was accomplished from 2,3-dihy- drothiopyrano[2,3-b]pyridin-4(4H)-one 2a, by reaction Sep-Oct 2002 1001