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 subm itted to a series of modifications in order to obtain a new class of p otential intercalating agents. In particular, insertion of a 4-4a doub le bond (2) and of a flexible cationic side-chain in the pyridazine mo iety as well as introduction of substituents in several positions of t he benzene ring have been considered. The dihydro analog 3 has been su bmitted to similar modifications. The new compounds have been tested f or 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 veri fy their intercalating properties, DNA-binding studies have been perfo rmed. Available evidence seems to indicate that the double bond in pos ition 4-4a is essential for activity and that compounds derived from 2 are more potent than the corresponding compounds obtained from 3. Mor eover, while a side-chain in position 2 led to active compounds, the 3 -substituted indenopyridazines (8, 9) were inactive. The )ethyl]2,5-di hydro-3H-indeno[1,2-c]pyridazin-3-one (5a) and its 8-methoxy derivativ e (5d) were found to compare favourably with cisplatin and melphalan, against resistant and both sensitive and resistant cell lines, respect ively.