Abstract:
A number of perimidine derivatives have been prepared which bear flexible cationic sidechains either at nitrogen, or attached at C2 through a heteroatom or an amide group. These compounds, together with the imide (704) provide a range of simple perimidine derivatives appropriate for testing as potential antineoplastic agents.
It has been demonstrated that the formation of derivatives of permidine by structural modification of naphthalo[1,8-cd]pyran-1,3-dione (195) is a viable procedure. Moreover, a novel route has been developed to naphtho[1,8-de]-1,3-thiazines (e.g. 508), involving cyclisation of an 8-halo-1-isothiocyanatonaphthalene.
The preparation of the "azaperimidines" (800) and (801) has been accomplished in several steps from quinoline and isoquinoline respectively. The synthesis of the third azaperimidine (802) was attempted but not accomplished. Moreover, a number of routes to the pyrimido[4,5,6-de]phthalazine and pyrimido[4,5,6-de]quinazoline ring system have been investigated, although no derivatives of either system were isolated, and a novel route to the pyrimido[3,4,5-ij]naphthyridine ring system has been developed.
A number of the perimidines prepared were found to possess cytotoxic activity, although none was active against P388 leukaemia in vivo. It is suggested that the perimidine chromophore provides a lower limit for intercalative binding to DNA, as evidenced by the fact that derivatives substituted at C2 intercalate, and are active in vitro, whereas those substituted at nitrogen do not intercalate and are inactive.
