Compounds similar to acyclovir. III. Synthesis of acyclic analogs of 5'-deoxynucleosides

A convenient method has been proposed for the synthesis of 1,2-dihydroxy-4-oxahex-3-yl and 1-hydroxy-4-oxahex-3-yl derivatives of guanine, adenine, thymine and cytosine, acyclic nucleoside analogues lacking the 3'--4' bond.     

Compounds similar to acyclovir. I. Synthesis of "complete" analogs of nucleosides

"Full" acyclic analogues of ribonucleosides, 1-(1,2,6-trihydroxy-4-oxahex-3-yl)thymine and -cytosine, 3- and 9-(1,2,6-trihydroxy-4-oxahex-3-yl)adenine, and 9-(1,2,6-trihydroxy-4-oxahex-3-yl)guanine, have been prepared by condensation of silylated nucleo-bases with 1,4,5,6-tetraacetoxy-3-oxahexane in the presence of Lewis acids followed by deacetylation.     

Compounds similar to acyclovir. VI. Synthesis of optically active 1',2'-seconucleosides

A convenient method is suggested of synthesis of (3R, 4R)-, (3S, 4S)- and (3R/S, 4S/R)-dihydroxy-3-hydroxymethyl-2-oxapentyl derivatives of the, cytosine, uracyl, adenine and guanine ("full" acyclic analogues of nucleosides with C1'-C2' bond cleaved) by condensation of trimethylsilyl derivatives of nucleic bases (sodium salt in case of adenine) with (3$, 4R)-, (3S )-, (3S, 4S)- and (3R/S, 4S/R)-4,5-diacetoxy-3-acetoxymethyl-1-chloro-2-oxapentanes without catalyst followed by deacetylation.     

Compounds, similar to acyclovir V. Synthesis and antiviral activity of carbethoxyalkoxymethyl derivatives of nucleic bases

Ethyl esters and amides of carboxymethoxy-, alpha- and beta-carboxyethoxy- and gamma-carboxypropoxymethyl derivatives of adenine, guanine, cytosine, uracil, thymine, 1,2,4-triazole-3- and -5-carboxamide were synthesized and their antiviral activity was studied.     

Synthesis of acyclic analogs of ribavirin

A number of ribavirin analogues were prepared in which the ribose moiety was replaced with acyclic substituents imitating some fragments of the ribose ring: 2,3-dihydroxy-prop-1-yl, 3-hydroxymethyl-4-hydroxy-2-oxabut-1-yl, 4,5-dihydroxy-2-oxapent-1-yl and 1,5-dihydroxy-3-oxapent-2-yl. These analogues were synthesized by direct alkylation of ethyl 1,2,4-triazole-3-carboxylate with suitable agents followed by ammonolysis. New convenient methods for preparing the alkylating agents were developed.     

Synthesis and properties of acyclic analogs of ribavirin

Acyclic analogues of ribavirine, viz. 1-(1-hydroxy-4-oxahex-3-yl)-, 1-(1-chloro-4-oxahex-3-yl)-, 1-(1,2-dihydroxy-4-oxahex-3-yl)-, 1-(1,6-dihydroxy-4-oxahex-3-yl)-, 1-(1-chloro-6-hydroxy-4-oxahex-3-yl)-, and 1-(1,2,6-trihydroxy-4-oxahex-3-yl)-1,2,4-triazole-3-carboxamide, with the C3'-C4' bond of the furanose ring cleaved, have been prepared by condensation of trimethylsilyl derivatives of 3-ethoxycarbonyl-1,2,4-triazole with alkylating agents in the presence of SnCl4 followed by treatment with methanolic ammonia. Convenient methods for synthesis of the alkylating agents were elaborated.     

Compounds similar to acyclovir. VII. Attempts to construct an anti-herpetic agent (6-hydroxy-2-oxa-4-hexenyl derivatives of nucleic bases

Based on the available data on the acyclovir's mechanism of action we attempted to predict the antiherpetic activity of 6-hydroxy-2-oxahexen-4-yl derivatives of nucleic bases. In terms of this model 9-(6-hydroxy-2-oxahexen-4-yl) guanine might be active. 6-Hydroxy-2-oxahexen-4-yl derivatives of adenine, guanine, cytosine, thymine, uracil, 1,2,4-triazole-3 and 1,2,4-triazole-5-carboxamide have been synthesized and their activity against herpes virus I investigated. The guanine derivative proved to possess rather high activity (chemotherapeutical index 8).     

Synthesis and biophysical studies of modified oligonucleotides containing acyclic amino alcohol nucleoside analogs.

Novel serine derivative of thymine was prepared and incorporated into oligonucleotides. These modified oligonucleotides were studied for their binding affinity with complementary DNA/RNA.     

Fluorescent analogs of acyclic S-adenosyl-L-homocysteinase inhibitors

Fluorescent analogs of S-adenosyl-L-homocysteinase inhibitors derived from acyclic nucleoside series have been synthetized by alkylation of heterocyclic bases with appropriate synthons, or by modification of preformed adenine derivatives. None of the newly prepared compounds derived from 2-aminopurine, lin-benzoadenine or 1,6-ethenoadenine significantly inhibited the above enzyme.     

Synthesis of uracil nucleotide analogs with a modified,acyclic ribose moiety as P2Y2 receptor antagonists

A series of new uracil nucleotide analogs (monophosphates, triphosphates, and phosphonates) was synthesized, in which the ribose moiety was replaced by acyclic chains, including branched or linear alkyl or dialkylether linkers. 1-ω-Bromoalkyluracil derivatives (2) were converted to the corresponding alcohols by treatment with sodium hydroxide and subsequently phosphorylated using phosphorus oxychloride followed by hydrolysis to yield the monophosphates, or by coupling with diphosphate to form the triphosphates. Reaction of 2 with triethyl phosphite followed by deprotection with trimethylsilyl bromide led to the ω-phosphonylalkyluracil derivatives. These products could be further phosphorylated by converting them into their imidazolides and subsequent treatment with diphosphate yielding the corresponding UTP analogs. Nucleoside analogs with an oxygen atom in the 2′-position, which are more similar to the natural ribosides, were synthesized from silylated uracil and trimethylsilyl iodide-treated 1,3-dioxolane, or 1,3-dioxane, respectively, and subsequently phosphorylated by standard procedures. The nucleotide analogs were investigated in a functional assay at NG108-15 cells, a neuroblastoma × glioma hybrid cell line which expresses the UTP- and ATP-activated nucleotide receptor subtype P2Y₂. The acyclic nucleotide analogs were generally weaker ligands than UTP, and—in contrast to UTP—they were antagonistic. The most potent compound was diphosphoric 5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pentylphosphonic anhydride (5c) with an IC₅₀ value of 92 μM showing that the replacement of the α-phosphate by phosphonate, which leads to enhanced stability, was well tolerated.     

Mechanisms of nickel carcinogenesis. Interaction of Ni(II) with 2'-deoxynucleosides and 2'-deoxynucleotides

Interactions of Ni(II) with the base moieties of 2'-deoxynucleosides and 2'-deoxynucleotides were studied by means of UV difference spectroscopy in order to elucidate the mechanisms of site-specific enhancement by Ni(II) of DNA base oxidation with active oxygen species, observed previously (Kasprzak et al., Cancer Res., 49 (1989) 5964; Carcinogenesis, 11 (1990) 647). The interactions were generally weak and could be quantitated only at pH 7.2-7.9. The resulting coordination binding of Ni(II) was stronger with the purine derivatives, especially these of guanine, than with pyrimidine derivatives. Also, Ni(II) interacted more strongly with the bases of 2'-deoxynucleotides than with the bases of 2'-deoxynucleosides. The apparent stability constants for the interactions calculated with the use of a non-linear regression method, equalled 102 +/- 14, 159 +/- 30 and 290 +/- 70 M-1 for Ni(II) coordinated by 5'dAMP, 5'dADP and 5'dATP, respectively, and 305 +/- 73, 191 +/- 54, and 270 +/- 28 M-1 for 5'dGMP, 5'dGDP and 5'dGTP, respectively. Stability constant for the dG Ni(II) interaction was 39 +/- 7 M-1. Interactions of Ni(II) with the bases of dA, dC, dT and the dC- and dT- mono-, di- and tri-phosphates were too weak for meaningful quantitation. The strongest relative Ni(II) interaction with dG may explain high sensitivity of the dG site at the DNA molecule to Ni(II)-mediated oxidation observed in vitro and in vivo. The present results contrast with Ni(II)-directed site specific cleavage of DNA with H2O2 that occurs preferentially at the pyrimidine bases (Kawanishi et al., Carcinogenesis, 10 (1989) 2231).     

Conformationally locked nucleosides. Synthesis and hybridization properties of oligodeoxynucleotides containing 2',4'-C-bridged 2'-deoxynucleosides.

A conformationally locked, 2',4'-C-bridged 2'-deoxyribofuranoside2 was condensed with silylated pyrimidines to give 2',4'-C-bridged bicyclonucleosides, which were converted to the phosphoramidites and incorporated into oligodeoxynucleotides (ODNs). The hybridization data of the modified ODNs to DNA and RNA are presented.     

New analogs of acyclovir substituted at the side chain

A series of novel analogs of acyclovir, substituted with an alkyl (methyl, ethyl, n-butyl) or phenyl group at the positions 1', 4', and/or 5', has been obtained in a direct one-pot coupling reaction of guanosine and the respective 1,3-dioxolanes. The new acyclonucleosides were essentially inactive in antiviral (HSV, VV, VSV, HBV) evaluation in vitro.     

Synthesis and properties of novel acyclic nucleotides.

Acyclic adenosine and thymidine analogs derived from L- and D-threonie were synthesised and incorporated into oligonucleotides by automated protocols using a standard phosphoramidite method. UV melting experiments with thus obtained oligonucleotides showed that incorporation of those acyclic nucleosides did not destabilize the hybrid duplexes and that the stabilities of them are influenced by the stereochemical structures of acyclic analogs. Modification of 3'-end of oligonucleotide with acyclic analogs protected the oligonucleotide against 3'-exonuclease.     

Synthesis and antimetabolic properties of 4,5-substituted pyrimidine 2'-deoxynucleosides and their 5'-monophosphates

Reaction of the reagent of Lawesson, 2,4-bis(p-methoxyphenyl)-1,3,4-dithiadiphosphatane-2,4-disulfide, with blocked uracil nucleosides in dioxane leads to quantitative thionation at C(4). With the bases, thionation occurs at C(4) and, with two equivalents of the reagent, at C(2) and C(4). Enzymatic phosphorylation of 4-thio-FdUrd gave the 5'-monophosphate, which was further converted with NH2OH to N4-hydroxy-FdCMP. Both nucleotides were examined as potential inhibitors of thymidylate synthase, and 4-thio-FdUrd for cytotoxic activities vs monkey and human leukemic cell lines.     

Cyclic peptides. XXVI. Synthesis of AM-toxin II analogs by cyclization through ester bond formation

In order to explore the route for the preparation of cyclodepsipeptide by cyclization through an ester bond formation, two analogs of AM-toxin II, cyclotetradepsipeptide, were synthesized. As a preliminary experiment, synthesis of [L-Phe3, L-Ser(Bzl)4]-AM-toxin II, containing L-Phe and L-Ser(Bzl) in place of L-App (2-amino-5-phenyl-pentanoic acid) and delta Ala (alpha, beta-dehydroalanine), respectively, was attempted. Cyclization of H-L-Hmb-L-Phe-L-Ser(Bzl)-L-Ala-OH in CH2Cl2 at 10 mM concentration using water-soluble carbodiimide (EDC) and 4-dimethylaminopyridine (DMAP) successfully gave a cyclic monomer in 16% yield. Cyclization of H-L-Hmb-L-App-L-Ser(Bzl)-L-Ala-OH under the same conditions also afforded a cyclic monomer, [L-Ser(Bzl)4]AM-toxin II, in 19% yield. Analytical parameters of these cyclic monomers obtained were identical to those of the authentic samples obtained by cyclization through a peptide bond formation.     

New acyclic quinoxaline nucleosides. Synthesis and anti-hiv activity

A series of acyclonucleosides substituted 1-(4,5-dihydroxypentyl) (13-8) and 2-(4,5-dihydroxypentyloxy)quinoxalines (19-24) were synthesized by the sharpless asymmetric dihydroxylation of the derivatives 1-6 and 7-12, respectively. Treatment of the quinoxaline base 26 with (R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl-p-toluenesulfonate (27) in the presence of NaH/DMF furnished 28. Acid hydrolysis of 28 gave 1-(2,3-dihydroxypropyl)-6,7-dimethyl-quinoxaline-2-one (29). Alternatively, 29 was prepared by sharpless dihydroxylation of 30. All the compounds were evaluated for their in vitro anti-HIV-1 and HIV-2 in MT-4 cell and found inactive, except 29, which showed inhibition of HIV-1 with EC50 value of 0.15 +/- 0.1 microg/ml and a therapeutic index (SI) of 73.     

Synthesis and anti-HSV-1 activity of quinolonic acyclovir analogues.

Several 1-[(2-hydroxy-ethoxy)methyl]-3-carbethoxy-4(1H)quinolones (2a-l) and l-[(2-hydroxy-ethoxy)methyl]-4(1H)quinolone-3-carboxylic acids (3a-j and 3l) were synthesized and 2a-j, 2l and 3a-j, 3l were evaluated against herpes simplex virus type 1 (HSV-1), employing a one-pot reaction: silylation of the desired quinolone (BSTFA 1% TMCS) followed by equimolar amount addition of 1,3-dioxolane, chlorotrimethylsilane and KI, at room temperature. The acyclonucleosides 2a-l were obtained in 40-77% yields. The esters 2a-j and 2l were subsequently converted into the corresponding hydroxyacids 3 in 40-70% yields. Attempts of hydrolysis of 2k produced only a mixture of degradation products. Antiviral activity of 2 and 3 on HSV-1 virus infection was assessed by the virus yield assay. Except for compounds 2i and 3e, the acyclonucleosides were found to reduce the virus yield by 70-99% at the concentration of 50 microM, being the acids, in general, more effective inhibitors than their corresponding esters. Compounds 3j and 2d exhibited antiviral activity against HSV-1 virus with EC50 of 0.7+/-0.04 and 0.8+/-0.09 microM, respectively. Both compounds were not toxic towards the Vero cell line.     

Synthesis and antimitotic activity of novel 2-methoxyestradiol analogs. Part III

The syntheses and antimitotic activity of several novel analogs of 2-methoxyestradiol are described. Structural modifications include ring-D homologation, aromatization of the six-membered ring-D to a chrysine type molecule, and introduction of unsaturation in five-membered ring-D along with substitution of alkyl and ethynyl groups for the 17beta-hydroxy function. Of nine analogs synthesized, five have demonstrated superior antiproliferative activities compared to 2-methoxyestradiol.