Synthesis of C-6 Pyrimidine Acyclic Nucleoside Analogs as Potential Antiviral Agents

Abstract

A number of pyrimidine acyclic nucleosides in which the acyclic moiety is attached to the C-6 position rather than N-1 of the pyrimidine ring have been prepared. This was accomplished via treatment of lithiated 2,4-dimethoxy-5,6-dimethylpyrimidine, or, 2,4-dimethoxy-6-methylpyrirnidine with 1,3-bis-(benzyloxy)-2-propanone, benzyl chloromethyl ether or oxirane, respectively, to give the corresponding key intermediates 6-[3-benzyloxy-2-[(benzyloxy)methyl]-2-hydroxypropyl]-2,4-dimethoxy-5-methylpyrimidine (2a), 6-[3-Denzyloxy-2-[(benzyloxy)methyl]-2-hydroxypropyl]-2,4-dimethoxypyrimidine(2b), 6-(2-benzyloxyethyl)-2,4-dimethoxy-5-methylpyrimidine (3), and2,4-dunethoxy-6-(3-hydroxypropyl)-5-methylpyrimidine (4a). After acidic hydrolysis, followed by debenzylation with boron trichloride these key intermediates were converted to the target C-6 pyrimidine acyclic derivatives. Compounds 6–8b, 11–13, 15, 16, 20, 22, 26, and 29–32 were evaluated for activity against herpes viruses and human immunodeficiency virus. None of the compounds were active against the viruses nor were they cytotoxic at the highest concentration tested.     

Synthesis and Hybridization Studies of Oligonucleotide Sequences with Modified Fluorescent Nucleoside Analogs

Abstract

Two complementary oligodeoxynucleotide hexamers CATGAA and TTCATG and a pentamer with a fluorescent nucleoside analog viz. 9-N-(2′-deoxy-β-D-ribofuranosyl) carbazole (C*) incorporated into it, TTC*ATG were synthesized and characterised by spectroscopic and chromatographic studies. The comparative fluorescent studies of the two nucleoside analogs viz. 9-N-(2′-deoxy-β-D-ribofuranosyl) acridone and its carbazole analog (C*) have been carried out under different experimental conditions. The effect on fluorescence by incorporation of (C*) into the sequence and its subsequent hybridization with the complementary sequence have been studied.     

Synthesis and Structural Analysis of Oxadiazole Carboxamide Deoxyribonucleoside Analogs

Two novel C-linked oxadiazole carboxamide nucleosides 5-(2′-deoxy-3′,5′-β-D-erythro-pentofuranosyl)-1,2,4-oxadiazole-5-carboxamide (1) and 5-(2′-deoxy-3′,5′-β-D-erythro-pentofuranosyl)-1,2,4-oxadiazole-3-carboxamide (2) were successfully synthesized and characterized by X-ray crystallography. The crystallographic analysis shows that both unnatural nucleoside analogs 1 and 2 adapt the C2′-endo (“south”) conformation. The orientation of the oxadiazole carboxamide nucleobase moiety was determined as anti (conformer A) and high anti (conformer B) in the case of the nucleoside analog 1 whereas the syn conformation is adapted by the unnatural nucleoside 2. Furthermore, nucleoside analogs 1 and 2 were converted with high efficiency to corresponding nucleoside triphosphates through the combination chemo-enzymatic approach. Oxadiazole carboxamide deoxyribonucleoside analogs represent valuable tools to study DNA polymerase recognition, fidelity of nucleotide incorporation, and extension.

     

Synthesis and Biophysical Studies of Modified Oligonucleotides Containing Acyclic Amino Alcohol Nucleoside Analogs

Abstract

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

Synthesis of Novel Polycyclic Nucleoside Analogs

Abstract

We have synthesized polycyclic nucleoside derivatives by a novel, one pot procedure by reacting 4-0-TPS-pyrimidine nucleosides with aromatic diamines. The reaction is limited in scope but provides easy access to certain previously unknown heterocyclic ring systems.₂ 4-0-Triisopro- pylphenylsulfonyl-pyrimidine nucleosides were reacted with aromatic diamines leading to fused, polycyclic ring systems: o-phenylenediamine yielded the pyrimido[1,6-a]benzimidazole, 2.3- diaminonaphthalene gave the naphth[2′,3′:4,5]imidam [1.2-flpyrimidine and 1.8-diaminonaph- thalene led to the pyrimido[l,6-a]perimidine ring system. The reaction is unique because two connected nucleophilic centers react with the pyrimidine nucleoside to form an extended ring system. However, reactions of pyrimidine nucleosides with electrophiles are well known. E.g., reaction of cytidine and adenosine with bromoacetaldehyde yields ethenocytidine and ethenoadenosine) and on reaction of cytidine with 1′-methylthiaminium salts dipyrimido[1,6-a:4′,5′-d]pyrimidine derivatives are obtained.₄ Other polycyclic bases have been made from cytidine and adenosine by photochemical reactions₅.     

Synthesis and Antiviral Evaluation of Ribavirin Congeners Containing a Hexitol Moiety

Abstract

Several ribavirin congeners containing a hexitol moiety were prepared via ring opening of two different epoxides with the methylcarboxylate ester of triazole and further elaboration. Unfortunately, none of the newly synthesized compounds displayed appreciable antiviral activity.     

Synthesis and Antiviral Evaluation of Analogs of Adenosine-N 1-Oxide and 1-(Benzyloxy)Adenosine

Abstract

The activity of a series of compounds related to adenosine-N ¹-oxide (1) and 1-(benzyloxy)adenosine (42) against vaccinia virus has been determined both in vitro and in a vaccinia mouse tailpox model. Significant activities have been found both in vitro and in vivo for a number of the synthetic compounds.     

Synthesis of New Nucleoside Analogues Comprising a Geminal Difluorocyclopropane Moiety as Potential Antiviral/Antitumor Agents

Abstract

Geminal difluorocyclopropane analogues of nucleosides 7a–7e were synthesized. Compounds 7a and 7c–7e were obtained by alkylation of nucleic acid bases or their appropriate precursors with (cis)-1-benzyloxymethyl-2-bromomethyl-3,3-difluorocyclopropane (8). Analogue 7b was prepared by hydrolysis of 2-amino-6-chloropurine derivative 7e. Compounds 7a–7d did not exhibit any antiviral activity against HCMV, HSV-1, HSV-2, EBV, VZV, HBV and HIV-1 or antitumor effects against murine leukemia L1210, mouse tumors PO3 or C38 and human tumor H15.     

Organometallic Intermediates in the Synthesis of Nucleoside Analogs

Abstract

The common nucleosides, modified or derivatized in some way at the heterocyclic ring carbons, include examples of structures which a r e useful as biological probes and chemotherapeutic agents. Like previous authors, we will use the term “nucleoside analog” for structures related to one of the common naturally occurring nucleosides. Nucleosicle analogs can be derivatives which differ by such minor modification as replacement of hydrogen by a single atom or derivatives which are grossly modified at both the carbohydrate and the base. Examples of the former include 5-fluoro-2′-deoxyuridine, an inhibitor of thymidylate synthetase as its 5′-phosphate, and 5′-iodo-2′-deoxyuridine, a clinically useful antiviral agent. Larger groups have frequently been linked to nucleoside as probes for enzymatic processes. Side chains in “nonrestricted positions” may be used to carry spectroscopic or chemically reactive probes, or provide the means to attach a molecule to an affinity column. Ultimately with positions of bulk tolerance defined, it may be possible to design “active site directed irreversible enzyme inhibitors” as defined by B.R. Baker. Nucleoside structures in which a side chain is attached at a pyrimidine or purine carbon will undoubtedly, in some instances be the most appropriate structure. Yet, these have typically been more difficult to synthesize than analogs with side chains attached to heteroatoms.     

Synthesis and Incorporation of Pyrrole Carboxamide Nucleoside Triphosphates by DNA Polymerases

Abstract

We have synthesised and examined the enzymatic incorporation properties of the 5′-triphosphates of 2′-deoxyribosyl pyrrole 3-monocarboxamide (dMTP) and 2′-deoxyribosyl pyrrole 3,4-dicarboxamide (dDTP). These analogues we had hoped would behave as ambivalent base analogues in that they can present two alternative hydrogen-bonding faces either by rotation about the carboxamide group or about the glycosidic bond. The two pyrrole derivatives, dMTP and dDTP, exhibit a preference for incorporation with Klenow polymerase. They are preferentially incorporated as either A or C.     

Enantiospecific Synthesis of Carbocyclic Aminoimidazole Carboxamide Ribonucleotide (C-AICAR), Succinoaminoimidazole Carboxamide Ribonucleotide (C-SAICAR), and a New Intermediate for SAICAR Analogs

Abstract

The (-)-enantiomer of the carbocyclic analogs of aminoimidazole carboxamide ribonucleotide (C-AICAR¹, 7), and succinoaminoimidazole carboxamide ribonucleotide (C-SAICAR, 14) have been prepared. En route, a new intermediate (19) for the preparation of SAICAR analogs was developed.     

Synthesis,Antiproliferative, and Antiviral Evaluation of Certain Acyclic 6-Substituted Pyrrolo[2,3-D]-pyrimidine Nucleoside Analogs Related to Sangivamycin and Toyocamycin

Abstract

A number of 6-substituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine and 7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3-d]pyrimidine derivatives related to the nucleoside antibiotics toyocamycin and sangivamycin were prepared and tested for their biological activity. Treatment of 2-amino-5-bromo-3,4-dicyanopyrrole (2) with triethylorthoformate, followed by alkylation via the sodium salt method with either 2-(acetoxyethoxy)methyl bromide or (1,3-diacetoxy-2-propoxy)methyl bromide, furnished the corresponding N-substituted pyrroles 3a and 3b. These compounds were then smoothly converted to the requisite deprotected 4-amino-6-bromopyrrolo[2,3-d]-pyrimidine-5-carbonitriles 5a and 5b (toyocamycin analogs) by methanolic ammonia. The 6-amino-derivatives were obtained by a displacement of the bromo group with liquid ammonia. Conventional functional group transformations involving the 5-cyano group furnished the 5-carboxamide (sangivamycin) and 5-thioamide analogs. Compounds substituted at the 7-position with a ribosyl moiety were active against human cytomegalovirus (HCMV) at micromolar concentrations, but the apparent activity was not selective. The 7-ribosyl compounds also had no activity against human immunodeficiency virus (HIV), though they were all cytotoxic. The new compounds were also evaluated against HCMV, herpes simplex virus type I (HSV-1), HIV, and also for their ability to inhibit the growth of L1210 murine leukemic cells in vitro. None of these compounds with (2-hydroxyethoxy)methyl substituents or 7-(1,3-dihydroxy-2-propoxy)methyl substituent at N-7 showed significant cytotoxicity toward L1210, or toward uninfected human foreskin fibroblasts (HFF cells), and KB cells. Nor were they cytotoxic in human lines CEM or MT2. Only compound 4a was found to be active against HCMV, having an IC₅₀ of 32 μM.     

Synthesis of Acyclic Nucleoside Analogs Related to Barbituric Acid

Abstract

The syntheses of the pyrimidine analogs 5,5-dihydroxymethyl-2,4,6-pyrimidineytrione I, 2-amino-5,5-dihydroxymethyl-4,6-pyrimidinedione II, 5,5-di(2-hydroxyethyl)-2,4,6-pyrimidinetrione III, and 2-amino-5,5-di(2-hydroxyethyl)-4,6-pyrimidinedione IV are described.     

Synthesis of Tetrazole Oxathiolane Nucleoside Analogues and Their Evaluation as HIV-1 Antiviral Agents

Abstract

The synthesis of The synthesis of 2-hydroxymethyl-5-[N₂-(5′-carboxamido tetrazolyl)]-1,3-oxathiolane (6a and 6b) and 2-hydroxymethyl-5-[N₂-(5′-aminotetrazolyl)]-1,3-oxathiolane (7a and 7b) is described. It involved the preparation of suitable 1,3-oxathiolane precursors via cyclocondensation between benzoyloxyacetaldehyde and 2-mercaptoacetaldehyde di-[2-methoxyethyl] acetal, followed by condensation of adequately substituted tetrazoles using trimethylsilyltriflate or titanium tetrachloride as acid catalysts. In a preliminary in vitro study these new tetrazole oxathiolane nucleoside analogues were found inactive against HIV-1 retrovirus.     

Synthesis of Carbocyclic 2-Substituted Adenine Nucleoside and Related Analogs

2-Iodonoraristeromycin, 2-iodoaristeromycin and related analogs were synthesized to investigate their inhibitory activities against human and Plasmodium falciparum S-adenosyl-L-homocysteine hydrolases.     

Synthesis and Properties of Bacteriorhodopsin Analogs Containing Electron-Density Labels in the Chromophore Moiety

A method for synthesis of retinal analogs labeled with electron-density groups is suggested. The interaction of these polyene compounds with bacterioopsin in apomembrane of Halobacterium salinarum was tested. A retinal analog containing a crown-ether receptor group is able to interact readily with bacterioopsin giving rise to rapid formation of a pigment with absorption maximum at 460 nm. This pigment is capable of undergoing cyclic photoconversion. The crown-bacteriorhodopsin photocycle is extremely slow and its quantum efficiency is very low (3% of that in native bacteriorhodopsin). This photocycle includes an M-like intermediate with a differential absorption maximum at 380 nm. A retinal analog in which the -ionone ring is replaced by ferrocene moiety forms a stable chromoprotein with the main absorption band at 483 nm and a shoulder near 590-610 nm.     

Synthesis and Antiviral Activity of 2-Substituted Analogs of Triciribine

Abstract

Triciribine (TCN) and triciribine monophosphate (TCN-P) have antiviral and antineoplastic activity at low or submicromolar concentrations. In an effort to improve and better understand this activity, we have conducted a structure-activity relationship study to explore the effect of substitutions at the 2-position of triciribine. 2-Methyl-(2-Me-TCN), 2-ethyl-(2-Et-TCN), 2-phenyl-(2-Ph-TCN), 2-chloro-(2-Cl-TCN), and 2-aminotriciribine(2-NH₂-TCN) were designed and synthesized to determine the effects of substitutions at the 2-position which change the steric, electronic, and hydrophobic properties of TCN, while maintaining the integrity of the tricyclic ring system. These compounds were evaluated for activity against human immunodeficiency virus (HIV-1), herpes simplex virus type 1 (HSV-1), and human cytomegalovirus (HCMV) and were found to be either less active than TCN and TCN-P or inactive at the highest concentrations tested, 100 µM. We conclude that substitutions at the 2-position of triciribine adversely affect the antiviral activity most likely because these analogs are not phosphorylated to active metabolites.