ANTITUMOUR ACTIVITY OF OPEN RING ANALOGUES OF UNGEREMINE (AT-1840)——PREPARTION OF SUBSTITUTED N-ALKYL PHENANTHRIDINIUM BROMIDES BY A PHOTOCHEMICAL REACTION

Ungeremine(I, AT-1840), an alkaloid from Ungernia minor, possesses a marked inhibiting activity against the following experimental tumour systems: EAC, L1210, P388, Lewis lung carcinoma, Yoshida sarcoma and sarcoma 180.In the present investigation, a number of its open ring analogues, 2-hyroxy-8,9-methylenedioxy-N-alkyl-phenanthridinium bromides(3) and their 8, 9-dimethoxyanalogues,(4) were prepared from bromopiperonal and bromodimethoxy-benzaldehyde through a 5-step synthesis including photochemical cyclization.Bromobenzaldehydes were converted to their Schiff bases(7) with 4-isopropoxyaniline, followed by reduction to secondary amines(8) by sodium borohydride or potassium borohydride. Phenanthridines(9) were obtained by photochemical cyclization and subsequently were transformed to their quaternary ammonium iodies(10). The final products(3a, 3b, 4a and 4b) were obtained by treating compounds(10) with a mixture of hydrobromic acid and acetic acid.From the intermediates(9a) and(9b) 2-hydroxy phenanthridines(12a), (12b) and 2-isopropxy-phenanthridinium bromides were also prepared.Compound 1 with a potential betain structure(a positive quaternary amine group and a negative phenolic group) on the one hand and a methylene N-O-O triangle on the other attracted our attention to study the contribution of these features. The above compounds were thus prepared and screened on EAC in mice. The SAR was discussed as follows:1. Compounds 9 and 12, lacking phenolic group or a quaternary amine group, can not form betaine intramolecularly and thus showed no activity. 2. Although compounds(4a and 4b) are betaines, they do not have methylene N-O-O triangle in their molecules and also showed no activity.3. Compounds such as 3a and 3b do have both betaine and methylene N-O-O triangle in their structures. But 3a exhibited marked activity while 3b did not. It has been known that ethyl group at the quaternary N-atom is much easier to be eliminated. It is reasonable to assume that 3b can be converted to 12a by eliminating the ethyl group in vivo, thus losing its betaine forming ability.4. It seems that both betaine and methylene N-O-O triangle in ungeremine may be critical for exhibiting antitumour ability. Fission of the B ring of ungeremine will not affect its betaine forming ability and the antitumour activity of the alkaloid is maintained.