Synthesis and antitumor and antiviral properties of 5-alkyl-2'-deoxyuridines 3',5'-cyclic monophosphates, and neutral cyclic triesters

Abstract

A series of 5-alkyl-2'-deoxyuridine 3',5'-cyclic monophosphates (5-R-cdUMP's, R = Et, i-Pr, n-Pr, n-Bu, n-Pent, n-Hex, n-Oct) was prepared and tested in culture systems as antitumor and antiviral agents in comparison to the 5-alkyl-2'-deoxyuridines (5-R-dUrd's) themselves. Only the 5-Et- and 5-n-Bu-cdUMP showed appreciable cytostatic activities against murine L1210 and human lymphoblast Raji cells (ID50 range: 28-82 micrograms/mL). 5-Et-dUrd itself was much more active (ID50 = 1.6 and 2.9 micrograms/mL). The 5-i-Pr-, and 5-n-Bu-dUrd's were inactive, but activity increased again for groups with chain lengths of five carbons or greater. 5-Et-cdUMP and 5-Et-dUrd had greatly reduced activities against deoxythymidine kinase deficient (TK-) L1210 and Raji cells. 5-Et-cdUMP evidently is not an efficient prodrug source of the corresponding 5'-monophosphate where the TK- cells are concerned. Of the 5-R-cdUMP's, 5-Et-cdUMP displayed reasonably good antiviral potency against herpes simplex types 1 and 2 (MIC50, mostly 7-70 micrograms/mL) and vaccinia virus (MIC, 70 micrograms/mL). The activity was nonetheless 10- to 100-fold less than that for 5-Et-dUrd. The other 5-R-dUrd's generally showed decreasing antiviral activity with increasing 5-R chain length. Methyl and/or benzyl neutral triesters of certain 5-R-cdUMP's were inactive as antivirals and largely inactive against tumor cells in culture. In contrast to the 5'-monophosphates, the 5-R-cdUMP's failed to inhibit thymidylate synthetase from L1210 cells.

Synthesis and in vitro enzymatic and antiviral evaluation of phosphoramidate d4T derivatives as chain terminators

“…The monophosphate of d4T (d4TMP) was prepared by treatment of d4T with POCl3 as described before. 23,24 In order to avoid purification problems, this reaction was carried out using a small amount (120 mg) of d4T. The EDAC-mediated coupling of d4TMP with the primary amino function of 7 yielded the phosphoramidate methyl ester precursor (8) in 57.1 %.…”

Synthesis, cytostatic and anti-HIV evaluations of the new unsaturated acyclic C-5 pyrimidine nucleoside analogues

“…Signals of 1 H and 13 C resonances were observed which were characteristic for each of the moieties constituting structures of N1, C5-substituted pyrimidine nucleoside analogues (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). H1 0 and H4 0 protons exhibit distinct chemical shifts between 4.09 and 4.60 ppm, whereas H2 0 and H3 0 protons along C@C double bond were observed between 5.50 and 5.80 ppm (Table 1).…”

“…1 Pyrimidine nucleosides containing C-5 alkynyl groups have been shown to possess significant antiviral and/or anticancer properties. [2][3][4][5] Introduction of very rigid allenic moiety as a linker between the heterocyclic base and hydroxymethyl group led to compounds such as adenallene and cytallene which effectively inhibited the replication of HIV. [2][3][4][5] Introduction of very rigid allenic moiety as a linker between the heterocyclic base and hydroxymethyl group led to compounds such as adenallene and cytallene which effectively inhibited the replication of HIV.…”

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A series of the novel C-5 alkynyl pyrimidine nucleoside analogues (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) in which the sugar moiety was replaced by the conformationally restricted Z-and E-2-butenyl spacer between the phthalimido and pyrimidine ring were synthesized by using Sonogashira cross-coupling reaction. Cytostatic activity evaluation of the novel compounds showed that E-isomers exhibited, in general, better cytostatic activities than the corresponding Z-isomers.

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Synthesis, and in vitro Enzymatic and Antiviral Evaluation of d4T Polyphosphate Derivatives as Chain Terminators

“…-Synthesis of d4T diphosphate derivatives. The synthesis of the diphosphate derivatives of d4T (1 and 2) was carried out according to the method shown in scheme 1 [10,11]. D4T monophosphate (d4TMP) and d4T diphosphate (1) were obtained from d4T by treatment with POCl3.…”