Several 5 (or 4)-(3-alkyl-3-methyl-l-triazeno)imidazole-4 (or 5)-carboxamides (111-X) were prepared from 5-diazoimidazole-4-carboxamide and the appropriate N-alkyl methylamine. Most of these derivatives significantly increased the life span of leukemic (L1210) mice. Inhibition of the growth of sarcoma 180, adenocarcinoma 755, and Walker carcinosarcoma 256 was observed, but inhibition of solid tumors was generally accompanied by large, adverse, host-weight changes. Qualitative observations of the sensitivity to light of aqueous alcoholic solutions of the dimethyltriazeno (NSC-4 5 388) and the butylmethyltriazeno derivatives indicate a pronounced variation in stability with the kind of light exposure. EPRESENTATIVES OF BOTH disubstituted-
The action of adenosine deaminase on racemic carbocyclic analogues of 6-aminopurine nucleosides was investigated. When either racemic carbocyclic adenosine [(+/-)-C-Ado] or the racemic carbocyclic analogue [(+/-)-C-2,6-DAP-2'-dR] of 2,6-diaminopurine 2'-deoxyribofuranoside was incubated with this enzyme, approximately half of the material was deaminated rapidly. From the resulting solution, the D isomers of the deaminated carbocyclic analogues (D-carbocyclic inosine, D-C-Ino, or D-carbocyclic 2'-deoxyguanosine, D-2'-CDG) and the L isomers of the undeaminated carbocyclic analogues were isolated. At higher concentrations of the enzyme, deamination of L-C-Ado and L-C-2,6-DAP-2'-dR proceeded slowly, thus also making the other enantiomers accessible. In tests in vitro against herpes simplex virus, types 1 and 2, D-2'-CDG was as active and potent as (+/-)-2'-CDG, whereas L-2'-CDG displayed only modest activity. In contrast to the previously reported high activity and potency of (+/-)-C-2,6-DAP-2'-dR against these two viruses, L-C-2,6-DAP-2'-dR was inactive.
The carbocyclic analogues of 5-fluoro-2'-deoxyuridine (5-FdUrd, 1), 5-fluorouridine, and 5-fluoro-3 alpha-deoxyuridine were prepared by fluorination of the uracil nucleoside analogues with elemental fluorine. The 5-FdUrd analogue (C-5-F-2'-dUrd, 6) was enzymatically phosphorylated to the analogue of 5-FdUrd 5'-phosphate and inhibited the incorporation of 2'-deoxyuridine into DNA of murine colon 26 tumor cells and L-1210 cells in culture. Biochemical studies also indicated that C-5-F-2'-Urd (6) was a less potent inhibitor of DNA synthesis in tumor cells than was 5-FdUrd (1). C-5-F-2'-dUrd was cytotoxic (ED50 = 2.5 mcg/mL) to L-1210 cells in culture; the other two analogues were less cytotoxic. C-5-F-2'-dUrd was inactive--or, at best, borderline active--in tests against P-388 leukemia in vivo.
N-(all-trans-Retinoyl)amino acids were synthesized via all-trans-retinoyl chloride and an ester of the amino acid. The retinoyl derivatives of leucine, phenylalanine, alanine, tyrosine, and glutamic acid were prepared. The 13-cis-retinoyl derivatives of leucine, phenylalanine, alanine, and glycine were prepared similarly from 13-cis-retinoic acid. In assays of the retinoylamino acids for reversal of squamous metaplasia in hamster trachea organ cultures, these compounds were less active than retinoic acid, but the leucine, alanine, and phenylalanine derivatives were similar in activity to several retinamides that suppress bladder carcinogenesis in vivo. Two of the retinoylamino acids, as well as two simple retinamides, were shown to be moderately cytotoxic to murine leukemia and human epidermoid carcinoma cells in culture.
The carbocyclic analogue of the antiviral agent 5-ethyl-2'-deoxyuridine (EDU) was synthesized by two routes. The pivotal step in the first route is the reaction of lithium dimethylcuprate with the carbocyclic analogue of 5-(bromomethyl)-2'-deoxyuridine dibenzoate (6). The second route is based on the synthesis of the carbocyclic analogue of 5-ethynyl-2'-deoxyuridine (12) by a coupling reaction catalyzed by bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide, a method reported recently (Robins and Barr) for the synthesis of the true nucleoside 5-ethynyl-2'-deoxyuridine (1b). The carbocyclic analogue of EDU inhibits the replication of type 1 and type 2 herpes simplex viruses in Vero cells. The carbocyclic analogue of 5-ethynyl-2'-deoxyuridine has modest activity against herpes simplex virus, types 1 and 2.
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