Tricyclic indenopyridazine derivatives: synthesis, cytotoxic activity and DNA-binding properties

2,4,4a,5-Tetrahydro-3H-indeno [1,2-c]pyridazin-3-one (1) has been submitted to a series of modifications in order to obtain a new class of potential intercalating agents. In particular, insertion of a 4-4a double bond (2) and of a flexible cationic side-chain in the pyridazine moiety as well as introduction of substituents in several positions of the benzene ring have been considered. The dihydro analog 3 has been submitted to similar modifications. The new compounds have been tested for their cytotoxic activity on LoVo and LoVo/DX human colon carcinoma cell lines and on L1210 and L1210/CDPP murine leukemia cell lines, in comparison with cisplatin, melphalan and doxorubicin. Finally, to verify their intercalating properties, DNA-binding studies have been performed. Available evidence seems to indicate that the double bond in position 4-4a is essential for activity and that compounds derived from 2 are more potent than the corresponding compounds obtained from 3. Moreover, while a side-chain in position 2 led to active compounds, the 3-substituted indenopyridazines (8, 9) were inactive. The 2-[2-(dimethylamino)ethyl]2,5-dihydro-3H-indeno[1,2-c]pyridazin-3-one (5a) and its 8-methoxy derivative (5d) were found to compare favourably with cisplatin and melphalan, against resistant and both sensitive and resistant cell lines, respectively.