A photochemical approach to pyridopyrroloquinoline derivatives as new potential anticancer agents.

Indoloquinoline alkaloid cryptolepine and pyridocarbazole alkaloid ellipticine are of great interest because in vitro and in vivo studies revealed their good cytotoxic properties. In order to obtain some biologically active analogs of these compounds, we developped a synthesis based on the photocyclisation of tertiary N-methylated enaminones derived from cyclopentane-1,3-dione and 3 or 6-aminoquinoline. The angular cyclised compounds thus obtained were submitted to Beckmann rearrangement, preceded by the formation of a Z oxime. Finally, the delta-lactame ring was oxidized using 10% palladium/carbon in diphenylether and pyridopyrroloquinolines were obtained. These compounds and the intermediate lactams and cyclopentanopyrroloquinolines were tested in vitro on K 562 cells and A 2780 doxorubicine sensitive and resistant cells. All compounds were less effective than doxorubicine in sensitive cells but their activity wasn't decreased by MDR resistance.

In vitro and in vivo pharmacological characterisation of the antitumour properties of pyrido[1',2':1,2]imidazo[4,5-h]quinazoline.

The anti-tumour activity of pyrido[1',2':1,2]imidazo[4,5-h]quinazoline (PIQ) was investigated in vitro and in vivo with a human tumour model. In vitro PIQ cytotoxicity was evaluated on two different human parental-sensitive cancer cell lines (HL60S and A2780S) and their multidrug-resistant variant sublines (HL60R and A2780R). Proliferation was assessed using the MTT assay and PIQ showed activity, particularly with resistant cell lines. Drug activity was not affected by MDR resistance. After LD50 determination using Swiss mice, in vivo activity with A2780 ovarian carcinoma was carried out using xenografted Swiss nude mice. We performed either a weekly intra-peritoneal injection of 64 mg.kg-1 PIQ or an intra-venous injection of 10 mg.kg-1 PIQ during 2 months. After 60 days of treatment, no toxicologically meaningful differences were observed in macroscopic and microscopic parameters compared to controls. Both regimens demonstrated efficacy against xenografted tumours. However, the decrease in tumoural volume of the xenografted mice was significant only in the PIC i.v. injection group. Pharmacokinetics and the accumulation of PIQ in normal and tumour tissues were also assessed using a chromatographic method. The lack of activity using the i.p. route was explained by the four-fold reduction of its AUC in comparison to the i.v. route. After an i.v. injection, the highest concentrations of PIQ were accumulated in the tumour and spleen. Drug analysis has shown that PIQ intercalates into DNA. PIQ derivatives are effective new antitumour agents in cancer chemotherapy.