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1-Hydroxyphenazine 5,10-dioxide showed antitumor properties against mouse leukemia P388. It also participated in biochemical mechanisms of quinoid antitumor agents, as indicated by inhibition of radiolabeled DNA-RNA precursors in cultured leukemia L1210 cells and by stimulation of oxygen consumption in mammalian microsomes. This suggests that the isosteric di-N-oxide system may be a biologically active substitute for 1,4-quinone, and that di-N-oxides of tetrahydrobenzo[b]phenazines can be explored as anthracyclinone N-isosteres. As potential synthetic intermediates, 7,8,9,10-tetrahydro-6,11-dihydroxybenzo[b]-phenazines have been prepared by 1) Diels-Alder addition of phenazine-1,4-quinone and 1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene to give isolable but labile adducts and 2) condensation of 6,7-diamino-1,2,3,4-tetrahydro-2-hydroxy-5,8-dimethoxy-2-naphthoic acid with 3-methoxy-1,2-quinone. Attempts at N-oxidation gave instead oxidation of the 6,11-hydroquinone ring to quinone, regardless of hydroxyl protection. Despite previous literature indications, we have been unable to synthesize the 1,4-dihydroxyphenazine 5,10-dioxide system. We conclude that this hydroxyl substitution pattern (1,4) in an adjacent ring must be avoided in the redesign of anthracyclinone isosteres that have di N-oxide in place of quinone.

1,4-Dimethyldibenzothiophene (VII) was synthesized and was converted with butyl dichloromethyl ether to the 2-aldehyde (VIII). The structure was confirmed by an independent synthesis of the 2-ester (XI) derived from it. The 2-aldehyde (VIII) with aminoacetaldehyde diethylacetal formed the Schiff′s base (IX), and Pomeranz-Fritsch cyclization with 105% superphosphoric acid then formed thia-ellipticine (II), an isostere of the antitumor alkaloid, ellipticine.

Condensation of bis-(2-chloroethyl)phosphoramidic dichloride with 3′-amino-3′-deoxy-N,N-dimethyladenosine afforded the 2′,3′-cyclicphosphorodiamidate (III). By an improved synthesis, methyl 3-amino-3-deoxy-β-D-ribofuranoside was obtained as a model compound for conversion to the analogous 2,3-cyclicphosphorodiamidate (XII). Existence of the latter as two diastereomers due to phosphorus asymmetry was shown by nmr analysis, using comparison with the 5-(O-p-nitrobenzoate) (XIII) as a basis for assignments.

Nitration of 2,5-dimethylbenzoic acid was only 29% at the meta2 position vs. 41% at the ortho, in contrast to sulfonation which was 85% meta vs. 15% para. Identity of the products (and of their derived amino esters and phenolic esters) was determined from the nuclear magnetic resonance spectra and confirmed by chemical means.

Oxaellipticine has been synthesized from 1,4-dimethyldibenzofuran, by converting it to the 2-aldehyde, forming the Schiff's base with aminoacetaldehyde diethyl acetal, and cyclizing this with 105%superphosphoric acid. Alternatively, tetrahydrodimethyldibenzofuran was formylated mainly at the 3-position, and the 3-(2-nitrovinyl) derivative of the 3-aldehyde, by hydride reduction, then Bischler-Napieralski cyclization of the 3-(2-formamidoethyl) derivative, afforded hexahydrooxaellipticine, which could be aromatized only in poor yield. Isooxaellipticine, the pyrido-A' positional isomer, was similarly prepared from the nitrovinyl derivative of 1,4-dimethyl-2-dibenzofurancarboxaldehyde, through cyclization of the formamidoethyl intermediate and aromatization of the dihydro product. Likewise, isothiaellipticine was obtained from 1,4-dimethyl-2-dibenzothiophenecarboxaldehyde.

Oxidation with perbenzoic acid derivatives in neutral organic solvents of 11-desmethylellipticine (at the pyrido-N) and oxa-ellipticine afforded the corresponding N-Oxides. Thia-ellipticine afforded the sulfone N-oxide, which underwent N-deoxygenation with triphenylphosphine to yield thia-ellipticine sulfone.

Viene confermato che la struttura dell'agente dolcificante perillartina e quella di unasim ossima. Il tentativo di ottenere l'isomeroanti per azione dell'acido cloridrico ha condotto invece all'addotto tra HCl e gruppo isopropenilico, mentre il trattamento con trifluoruro di boro ha provocato solo la migrazione del doppio legame per formare l'analogo derivato dell'1, 3-cicloesadiene.