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The novel l- and d-amino acid derivatives of hydroxyurea 5a−o were prepared by aminolysis of N-(1-benzotriazolecarbonyl)amino acid amides 4a−o with hydroxylamine. The hydantoin derivatives 6a−e,m,p were synthesized by base-catalyzed cyclization of amides 4, common precursors for 5 and 6. X-ray crystal structure analysis shows that the C5 atom in 6e possesses the S configuration, which is consistent with the configuration of the starting reagent, l-leucine. Among l-amino acid derivatives of hydroxyurea, 5h and 5i inhibited specifically murine leukemia and human T-lymphocytes (IC50 = 10−19 μM) and showed selectivity with respect to normal human fibroblasts (WI 38). d-Amino acid derivatives of hydroxyurea 5m and 5o inhibited the growth of all tumor cell lines (IC50 = 4.8−83.9 μM), but not the growth of normal fibroblasts (WI 38; IC50 > 100 μM). Results on antiviral evaluations showed that N-(1-benzotriazolecarbonyl)amino acid amide 4m and hydantoin 6m had marked activity against the Davis strain of CMV (4m, EC50 = 3.2 μg/mL; 6m, EC50 = 4.0 μg/mL). However, these compounds showed also rather expressed cytotoxicity (4m, CC50 = 43.4 μg/mL; 6m, CC50 = 12.5 μg/mL^-1).

The novel fluorinated and iodinated purine derivatives containing 9-(2-hydroxypropyl) (1a−7a and 9a−13a) and 9-(2-hydroxyethoxymethyl) (1b−3b, 5b, and 7b−12c) side chains were synthesized by a multistep synthetic route involving Baltz−Schiemann's fluorination and diazotation/iodination as key reactions. An unequivocal proof for the stereostructure of 5b was obtained by X-ray structure analysis. New compounds were evaluated for their cytostatic activity against murine leukemia (L1210); mammary carcinoma (FM3A); and human T-lymphocytes (Molt4/C8 and CEM), melanoma (HBL), cervical carcinoma (HeLa), colon carcinoma (HT29 and SW620), laryngeal carcinoma (Hep2), and pancreatic carcinoma (MiaPaCa2) as well as diploid fibroblasts (WI38). Of all the compounds, the 2-aminopurin-6-thione derivative 9a showed the most pronounced inhibitory activity against human SW620 cells. The 2-aminopurin-6-thione derivative 9b exhibited the most selective inhibitory activity against human HeLa, Hep2, SW620, and murine L1210 cell proliferation as compared to normal fibroblast (WI38) cell proliferation. None of the compounds showed inhibitory activities against HIV-1, HIV-2, HSV-1, and HSV-2, vaccinia, vesicular stomatitis, parainfluenza-3, reovirus-1, Sindbis, Coxsackie B4, or respiratory syncytial virus. The new purine derivatives, and particularly 9a and 9b, appear to demonstrate sufficient cytostatic potency and selectivity to justify further evaluation of their potential.

The new pyrimidine derivatives of 2,3-O,O-dibenzyl-6-deoxy-l-ascorbic acid (8−10) were synthesized by condensation of uracil and its 5-fluoro- and 5-trifluoromethyl-substituted derivatives with 4-(5,6-epoxypropyl)-2,3-O,O-dibenzyl-l-ascorbic acid (7), while pyrimidine derivatives of 4,5-didehydro-5,6-dideoxy-l-ascorbic acid (14−17) with free C-2‘ and C-3‘ hydroxy groups in the lactone ring were obtained by debenzylation of 11−13 with boron trichloride. Z-Configuration of the C4‘&dbd;C5‘ double bond and position of the benzyl group in the lactone ring of 14 were deduced from their ¹H and ¹³C NMR spectra and connectivities in COSY, ROESY, and HMBC spectra. The exact stereostructure of 13 was confirmed by its X-ray crystal structure analysis. Of all the compounds in the series, compound 16 containing a 5-fluoro-substituted uracil ring showed the most significant antitumor activities against murine leukemia L1210/0 (IC50 = 1.4 μg/mL), murine mammary carcinoma FM3A/0 (IC50 = 0.78 μg/mL), and, to a lesser extent, human T-lymphocyte cells Molt4/C8 (IC50 = 31.8 μg/mL) and CEM/0 cell lines (IC50 = 20.9 μg/mL).

The novel pyrimidine derivatives 1−6 of 2,3-dibenzyl-4,5-didehydro-5,6-dideoxy-l-ascorbic acid were synthesized by the condensation of pyrimidine bases with 5,6-diacetyl-2,3-dibenzyl-l-ascorbic acid (DDA). Both N-9 (7) and N-7 (8) regioisomers were obtained in the reaction of 6-chloropurine with 5-acetyl-6-bromo-2,3-dibenzyl-l-ascorbic acid (ABDA), while the reaction of 6-(N-pyrrolyl)purine with ABDA afforded exclusively the N-9 isomer 9. Structures of all newly prepared compounds were deduced from the chemical shifts in ¹H and ¹³C NMR spectra, as well as connectivities in 2D homo- and heteronuclear correlation spectra. An unambiguous proof of the structure and conformation of 7 was obtained by X-ray crystallographic analysis. Compounds 1−9 were found to exert cytostatic activities against malignant cell lines:  pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), murine leukemia (L1210/0), murine mammary carcinoma (FM3A), and human T-lymphocytes (Molt4/C8 and CEM/0), as well as antiviral activities against varicella-zoster virus (TK⁺VZV and TK^-VZV) and cytomegalovirus (CMV). The compound 6 containing a trifluoromethyl-substituted uracil ring exhibited marked antitumor activity. The N-7-substituted purine regioisomer 8 had greater inhibitory effects on the murine L1210/0 and human CEM/0 cell lines than the N-9 isomer 7. Compound 9 with the 6-purine-substituted pyrrolo moiety had a more pronounced selective cytostatic activity against human (Molt4/C8 and CEM/0) cell lines than murine (L1210/0 and FM3A/0) and human (MiaPaCa2, MCF7, HeLa, and Hep2) tumor cell lines and normal fibroblasts (Hef522). The compound 6 exhibited the most potent antiviral activities against TK⁺VZV, TK^-VZV, and CMV, albeit at concentrations that were only slightly lower than the cytotoxic concentrations.