A series of DNA-intercalating 9-anilinoacridines, namely 9-phenoxyacridines, 9-(phenylthio)acridines, and 9-(3',5'-disubstituted anilino)acridines, were synthesized as potential antitumor agents with inhibitory effects on DNA topoisomerase II. Unlike amsacrine (m-AMSA), these agents were designed to avoid the oxidative metabolic pathway. These acridine derivatives were, therefore, expected to have long half-life in plasma. Both 9-phenoxyacridines and 9-(phenylthio)acridines were found to have moderate cytotoxicity against mouse leukemia L1210 and human leukemic HL-60 cell growth in culture. Among 9-(3',5'-disubstituted anilino)acridines, 3-(9-acridinylamino)-5-(hydroxymethyl)aniline (AHMA) was found to be a potent topoisomerase II inhibitor and exhibited significant antitumor efficacy both in vitro and in vivo. Chemotherapy of solid-tumor-bearing mice with 10, 10, and 5 mg/kg (QD x 4, ip) AHMA, VP-16, and m-AMSA, respectively, resulted in more tumor volume reduction by AHMA than by VP-16 or m-AMSA for E0771 mammary adenocarcinoma and B-16 melanoma. For Lewis lung carcinoma, AHMA was as potent as VP-16 but more active than m-AMSA. Structure-activity relationships of AHMA derivatives are discussed.
The syntheses of several new pyrrolo[3,2-dlpyrimidine (9-deazapurine) C-nucleosides (3-5) and an improved synthesis of 9-deazainosine (1) are described. 9-Deazaguanosine 5 was obtained from the blocked 4-ribosylated 3-amino-2-carbethoxypyrrole key intermediate loa by its initial conversion to thiourea derivative 23 followed by S-methylation, ring closure with ammonia, and deprotection in acid. 9-Deazainosine 1 was also obtained from intermediate 10s by pyrimidine ring closure with formamidine acetate and final deprotection in acid. The 4-thiono and methylthio derivatives 3 and 4 were prepared via the corresponding 3-amino-2-cyanopyrrole 5 by its Conversion to thioamide 16 and cyclization with triethyl orthoformate. (14) This relationship between the chemical shifts of H-1' for several a+ epimeric pairs of N-nucleosideslh and C -n u c l e o s i d e~~J~~ has served as a reliable criterium for the epimeric assignment at C-1': (a) Townsend, L. B. 'Weigele, M. Ibid. 1976, 41, 287. (15) (a) Imbach, J.-L.; Kam, B. L. J. Carbohydr. Nucleosides, Nucleotides 1974, l , 271 and references therein. (b) The "relative" A6 value of isopropylidene methyls has been found useful in the configurational assignment of several C-glycosides substituted at C-5'; see ref 17a. Sokolova, T. N.; Yartseva, I. V.; Preobrazhenskaya, M. N. Carbohydr. Res. The development of a new cyclohexenone annulation reaction of general scope which utilizes a,p-unsaturated aldehydes and (3-carbethoxy-2-oxopropylidene)triphenylphosphorane is reported.
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