acyclovir and Leukemia-P388

A series of new 5-(1-hydroxy-2-iodoethyl)-2'-deoxyuridine and uridine compounds (11, 16) was synthesized by the regiospecific addition of HOI to the vinyl substituent of 5-vinyl-2'-deoxyuridine (10a), 5-vinyl-2'-fluoro-2'-deoxyuridine (10b), 5-vinyluridine (10c), and (E)-5-(2-iodovinyl)-2'-deoxyuridine (4b). Treatment of the iodohydrins 11a-c with methanolic sulfuric acid afforded the corresponding 5-(1-methoxy-2-iodoethyl) derivatives (12a-c). In contrast, reaction of 5-(1-hydroxy-2-iodoethyl)-2'-deoxyuridine (11a) with sodium carbonate in methanol afforded a mixture of 5-(1-hydroxy-2-methoxyethyl)-2'-deoxyuridine (13) and 2,3-dihydro-3-hydroxy-5-(2'-deoxy-beta-D-ribofuranosyl)- furano[2,3-d]pyrimidin-6(5H)-one (14). The most active compound, 5-(1-methoxy-2-iodoethyl)-2'-deoxyuridine (12a, ID50 = 0.1 micrograms/mL), which exhibited antiviral activity (HSV-1) 100-fold higher than that of the 5-(1-hydroxy-2-iodoethyl) analogue (11a), was less active than IVDU or acyclovir (ID50 = 0.01-0.1 micrograms/mL range). The C-5 substituent in the 2'-deoxyuridine series was a determinant of cytotoxic activity, as determined in the in vitro L1210 screen, where the relative activity order was CH(OH)CHI2 (16) greater than CH(OMe)CH2I (12a) greater than CH(OH)CH2I (11a) congruent to CH(OH)CH2OMe (13). The 2'-substituent was also a determinant of cytotoxic activity in the 5-(1-hydroxy-2-iodoethyl) (11a-c) and 5-(1-methoxy-2-iodoethyl) series of compounds, where the relative activity profile was 2'-deoxyuridine greater than 2'-fluoro-2'-deoxyuridine greater than uridine (11a greater than 11b greater than or equal to 11c; 12a greater than 12b greater than 12c). The most active cytotoxic agent (16), possessing a 5-(1-hydroxy-2,2-diiodoethyl) substituent (ED50 = 0.77 micrograms/mL), exhibited an activity approaching that of melphalan (ED50 = 0.15 micrograms/mL). All compounds tested, except for 13 and 14, exhibited high affinity (Ki = 0.035-0.22 mM range relative to deoxyuridine, Ki = 0.125) for the murine NBMPR-sensitive erythrocyte nucleoside transport system, suggesting that these iodohydrins are good permeants of cell membranes.

Topics: Animals; Antimetabolites, Antineoplastic; Antiviral Agents; Biological Transport; Cell Survival; Chemical Phenomena; Chemistry; Deoxyuridine; In Vitro Techniques; Leukemia L1210; Leukemia P388; Mice; Tumor Cells, Cultured; Uridine; Vinyl Compounds

Cyclopentenylcytosine (CPE-C, 2), a pyrimidine analogue of the fermentation derived carbocyclic nucleoside neplanocin A, has been synthesized from the optically active cyclopentenylamine 3b by two synthetic routes. CPE-C demonstrates significant antitumor activity against both the sensitive and ara-C resistant lines of L1210 leukemia in vivo. Multiple long term survivors are produced in both tumor models. The compound also gives 100% growth inhibition of the solid human A549 lung and MX-1 mammary tumor xenografts grown in athymic mice. Good activity is also observed against a third human tumor xenograft model, metastatic LOX melanoma. CPE-C has significant activity against both DNA and RNA viruses in vitro. Potent activity is observed against HSV-1 (TK+ and TK-), HSV-2, vaccinia, cytomegalovirus, and varicella-zoster virus. Good activity is also found against a strain of influenza virus (Hong Kong flu), vesicular stomatitis virus, Japanese encephalitis virus, and Punta Toro virus.

Topics: 3-Deazauridine; Animals; Antineoplastic Agents; Antiviral Agents; Chemical Phenomena; Chemistry; Cytidine; DNA Viruses; Humans; Leukemia L1210; Leukemia P388; Lung Neoplasms; Mammary Neoplasms, Experimental; Melanoma; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Orthomyxoviridae; RNA Viruses; Sarcoma, Experimental; Viruses

(+/-)-(1 alpha,2 beta,3 alpha,5 alpha)-3-[(2,5-Diamino-6-chloro-4- pyrimidinyl)amino]-5-(hydroxymethyl)-1,2-cyclopentanediol (7) was synthesized from 2-amino-4,6-dichloropyrimidine and the carbocyclic xylofuranosylamine (+/-)-(1 alpha,2 beta,3 alpha,5 alpha)-3-amino-5-(hydroxymethyl)-1,2-cyclopentanediol (2) by subsequent preparation of the 5-[(4-chlorophenyl)azo] derivative of the resulting pyrimidine and reduction of the azo moiety with zinc and acetic acid. The carbocyclic analogue of 2-amino-4-chloropurine xylofuranoside (8) and the corresponding 8-azapurine 11 were prepared from 7. The carbocyclic analogues xylofuranosylguanine (9), xylofuranosyl-2,6-diaminopurine (10), xylofuranosyl-8-azaguanine (13), and xylofuranosyl-8-aza-2,6-diaminopurine (14) were prepared from 8 and 11. Compounds 9 and 13 were active against herpes simplex virus (types 1 and 2), with 9 being the more potent against both viruses. Analogue 9 also exhibited potent activity against human cytomegalovirus and varicella-zoster virus.

Topics: Animals; Antiviral Agents; Leukemia P388; Purines; Simplexvirus

Acyclic neplanocin analogues were prepared by condensation of adenine or N2-acetylguanine with (E)-1,4-dichlorobut-2-ene and subsequent hydrolysis. The N-9-substituted product 9-[(E)-4-hydroxybut-2-enyl]adenine was obtained when adenine was employed as the starting purine, while N2-acetylguanine yielded both the N-7 and N-9 isomers. Cell-culture studies revealed that only the chloro-substituted intermediate 9-[(E)-4-chlorobut-2-enyl]adenine exhibited significant cytotoxicity against P-388 mouse lymphoid leukemia cells, while the N-9-substituted guanine analogue 9-[(E)-4-hydroxybut-2-enyl]guanine inhibited replication of herpes simplex viruses type 1 and type 2.

Topics: Adenine; Animals; Antineoplastic Agents; Antiviral Agents; Drug Evaluation, Preclinical; Guanine; Indicators and Reagents; Leukemia P388; Magnetic Resonance Spectroscopy; Mice; Simplexvirus; Spectrophotometry, Infrared; Structure-Activity Relationship