Acyclic Nucleoside Analogues Research Articles

Synthesis, anticancer activity, docking and computational studies of new pyridyl-glycosyl hybrids and acyclic analogs.

New pyridine-O-glycosides and their acyclic nucleoside analogues were prepared by heterocyclization and glycosylation. The anticancer activity against HCT-116, HepG2 and MCF-7 human cancer cells and BJ-1 cell revealed that the galacto- and xylopyranosyl glycosides possessing 4-bromophenyl have superior cytotoxic activities against HepG2 cell while glycosides 7-9 resulted in superior cytotoxic activities regarding MCF-7 breast cell. In case of HCT-116 colorectal carcinoma cells, two products and the derived glycosides and acyclic analogues showed potent activities. The most potent compounds were investigated for their possible binding affinities to the active site of CDK2 enzyme via in silico molecular docking simulation in addition to computational studies. The results support the antiproliferative effect and elucidate the interactions of 3a and 8 with catalytic sites.

Synthesis of acyclic nucleoside analogues through P(NMe2)3-Mediated regioselective N-alkylation

A novel and efficient approach for synthesizing acyclic nucleoside analogues with a side chain length of two carbon atoms has been established. It involves purines reacting with α-keto esters in a P(NMe2)3-mediated deoxygenation process, yielding the products in high yields and regioselectivities (22 examples, up to 93 % yield, up to >20:1 N9/N7 selectivities). This reaction features short reaction times, metal-free catalysis, mild reaction conditions, and broad substrate scope, all of which make it promising for practical applications.

Synthesis of Chiral Acyclic Pyrimidine Nucleoside Analogues from DHAP-Dependent Aldolases.

Dihydroxyacetone phosphate (DHAP)-dependent aldolases catalyze the aldol addition of DHAP to a variety of aldehydes and generate compounds with two stereocenters. This reaction is useful to synthesize chiral acyclic nucleosides, which constitute a well-known class of antiviral drugs currently used. In such compounds, the chirality of the aliphatic chain, which mimics the open pentose residue, is crucial for activity. In this work, three DHAP-dependent aldolases: fructose-1,6-biphosphate aldolase from rabbit muscle, rhanmulose-1-phosphate aldolase from Thermotoga maritima, and fuculose-1-phosphate aldolase from Escherichia coli, were used as biocatalysts. Aldehyde derivatives of thymine and cytosine were used as acceptor substrates, generating new acyclic nucleoside analogues containing two new stereocenters with conversion yields between 70% and 90%. Moreover, structural analyses by molecular docking were carried out to gain insights into the diasteromeric excess observed.

Development and Assessment of Acyclovir Gel Plaster Containing Sponge Spicules

Acyclovir is an acyclic purine nucleoside analog that is highly effective in inhibiting the herpes simplex virus. However, topical acyclovir has poor efficacy because of its low skin permeability. This study aimed to develop an acyclovir gel plaster containing sponge spicules (AGP-SS) to achieve synergistic improvements in skin absorption and deposition of acyclovir. The process of preparing the gel plaster was optimized by orthogonal experiments, while the composition of the formulation was optimized using the Plackett-Burman and Box–Behnken experimental designs. The selected formula was tested for physical properties, in vitro release, stability, ex vivo permeation, skin irritation, and pharmacokinetics. The optimized formulation exhibited good physical characteristics. In vitro release and ex vivo permeation studies showed that acyclovir release from AGP-SS was dominated by diffusion with significantly higher skin permeation (20.00 ± 1.07 μg/cm2) than that of the controls (p < 0.05). Dermatopharmacokinetic analyses revealed that the maximum concentration (78.74 ± 11.12 μg/g), area under the curve (1091.81 ± 29.05 μg/g/h) and relative bioavailability (197.12) of AGP-SS were higher than those of the controls. Therefore, gel plaster containing sponge spicules show potential for development as transdermal delivery systems to achieve higher skin absorption and deposition of acyclovir, especially in deep skin layers.

Hydrogen Bonding (Base Pairing) in Antiviral Activity.

Base pairing based on hydrogen bonding has, since its inception, been crucial in the antiviral activity of arabinosyladenine, 2'-deoxyuridines (i.e., IDU, TFT, BVDU), acyclic nucleoside analogues (i.e., acyclovir) and nucleoside reverse transcriptase inhibitors (NRTIs). Base pairing based on hydrogen bonding also plays a key role in the mechanism of action of various acyclic nucleoside phosphonates (ANPs) such as adefovir, tenofovir, cidofovir and O-DAPYs, thus explaining their activity against a wide array of DNA viruses (human hepatitis B virus (HBV), human immunodeficiency (HIV) and human herpes viruses (i.e., human cytomegalovirus)). Hydrogen bonding (base pairing) also seems to be involved in the inhibitory activity of Cf1743 (and its prodrug FV-100) against varicella-zoster virus (VZV) and in the activity of sofosbuvir against hepatitis C virus and that of remdesivir against SARS-CoV-2 (COVID-19). Hydrogen bonding (base pairing) may also explain the broad-spectrum antiviral effects of ribavirin and favipiravir. This may lead to lethal mutagenesis (error catastrophe), as has been demonstrated with molnutegravir in its activity against SARS-CoV-2.

Improvement of Entrapment and Ocular Permeability of Ganciclovir Nanostructured Lipid Carriers Using Various Conditions of Preparations

Ganciclovir (GCV) is a drug included in BCS-Class III, having high solubility and low permeability. It is a synthetic acyclic nucleoside analog of 2′-deoxyguanosine, considered a potent inhibitor of herpes viruses and cytomegalovirus (CMV) infection. Herpes simplex virus (HSV) infections are very common and are also considered a major cause of corneal blindness. This study intended to advance a pioneering nanostructured lipid carriers (NLCs) system for improving the ocular permeability of GCV. Several procedures were used for the preparation. Cold homogenization, solvent injection, and emulsifi cationultrasonication methods. A mixture of palmitic acid (PA) and oleic acid (OA) as a lipid matrix, cremophore EL, and transcutol HP were used as emulsifi ers. To evaluate the optimum method, the particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment effi ciency (EE), and drug loading (DL%) were determined for the prepared NLCs. Due to the decreased particle size value, the polydispersity index, and the high value of EE%, emulsifi cation/ultrasonication outcomes were more practical than cold homogenization and solvent injection procedures. The fi ndings demonstrated that the preparation procedure had a substantial impact on the EE%.The emulsifi cation method can prepare the NLCs of GCV successfully.

“All-Aqueous” Tandem Boc-Deprotection and Alkylation of N-Bocbenzimidazole Derivatives under Visible Light with Alkyl Aryl Diazoacetates: Application to Site-Selective Insertion of Carbenes into the N–H Bond of Purines

Herein, we have reported a blue LED-induced tandem Boc-deprotection and NH-alkylation of benzimidazole derivatives with methyl aryl diazoacetates. The reactions occur in water at room temperature. The desired products are obtained in good to excellent yields. The putative mechanism of this reaction is discussed based on control experiments and supported by DFT studies. Additionally, the strategy is used to alkylate various purine derivatives via site-selective N1-alkylation to generate acyclic nucleoside analogues.

Method Development, Stability, and Pharmacokinetic Studies of Acyclovir-Loaded Topical Formulation in Spiked Rat Plasma

Acyclovir (ACV) is a synthetic acyclic nucleoside analogue active against herpes simplex virus type 1 and 2 (HSV-1 and HSV-2). The current research entails optimization, development, and validation of the sensitive, accurate, and precise high performance liquid chromatography-photo-diode array detector (HPLC-PDA) bioanalytical method for quantification of ACV in rat plasma. The central composite design (CCD) of Design Expert (quality by design tool) was employed for identification of significant attributes (flow rate and concentration of buffer), which affected the performance of the developed method. The elution of ACV was achieved by separating the XBridge C18 column and the mobile phase comprising of the potassium dihydrogen phosphate buffer (pH-6.8) and acetonitrile in a 90:10 v/v ratio pumped at a flow rate of 1.0 mL/ min. The method was validated as per International Council for Harmonization (ICH) guidelines in terms of selectivity, linearity, recovery, accuracy, and precision. The values of the lower limit of detection and the lower limit of quantification were found to be 30 and 100 ng/mL, respectively. Conclusively, the study showed superior performance with high robustness, sensitivity, and specificity of the developed bioanalytical method. The developed quantification method was applied for estimating pharmacokinetic (PK) parameters of ACV loaded vesicular systems (ethosomes, elastic liposomes, colloidal solution, and solution) transdermally applied to rat skin (using a previously published report). The method was successful in quantifying PK profiles for comparative assessment with a high robustness, re-validity, re-transferable, and simplicity approach.

Heteroatom-Assisted Regio- and Stereoselective Palladium-Catalyzed Carboxylation of 9-Allyl Adenine.

Strategy for the synthesis of acyclic nucleoside analogs of biological relevance via highly regio- and stereoselective C-H functionalization employing heteroatom-assisted palladium-catalyzed carboxylation of 9-allyl adenine is disclosed. Substrate scope with different carboxylic acids was performed giving decent to good yields of the desired products. The method also allowed for the synthesis of deuterated analogs.

From 5-Azapyrimidine Chemistry to Thiadiazoles

The review is devoted to 5-aza- and 6-azapyrimidine nucleosides with emphasis on antileukemic agents 5‑azacytidine and 2′-deoxy-5-azacytidine (decitabine), mechanism of their action as inhibitors of DNA methylations in tumour suppressor genes and current trends in the search for their stabilized analogues. A significant contribution to 5-azacytosine chemistry is synthesis of 5-aza­cytosine acyclic nucleosides phosphonates and their prodrugs, identified as potent and selective anti-DNA viral agents. Application of 5-amino-1,2,4-thiadiazol-3-(2H)-one moiety to acyclic nucleoside analogues was inspired by hypothesis that this heterocyclic base could work as a cytosine mimic and, moreover, the reactive N-S bond could be able to attack strong nucleophiles such as the cysteine thiol group of enzymes (similarly as 5‑azacytosine). A series of prepared 1,2,4-thiadiazole derivatives provided several inhibitors of Cathepsin K and glycogen synthase kinase 3β effective in the low micromolar range.

Synthesis and Anticancer Activity of New Pyrimidine and Oxadiazole Acyclic Nucleoside Analogs and Thiazolopyrimidine Derivatives

Synthesis and Anticancer Activity of New Pyrimidine and Oxadiazole Acyclic Nucleoside Analogs and Thiazolopyrimidine Derivatives

Synthesis of Novel Acyclic Nucleoside Analogue Starting From 6-Aminouracil as Potent Antimicrobial Agent

6-Aminouracil and 2-bromoethyl amine were prepared, as starting materials to be introduced as an alkylating reagent with sodium carbonate as a catalyst. Acyclic nucleoside was prepared for the first time, the expected structure of the final new compound 3 was determined based on IR, NMR, and mass spectroscopy, with safe and mild reaction conditions. The synthesized acyclic nucleoside has a potent and efficient antimicrobial activity compared to reference drugs particularly as an antibacterial agent, and can be used as an alternative to the commonly used antibiotics after performing the necessary biological research for its validation.

Synthesis and Cytotoxic Activity of New Substituted Pyrazolo[3,4-b]pyridine Derivatives and Their Acyclic Nucleoside Analogs

As an important strategy, including incorporation of more than active core in one molecule, for finding potent candidates against cancer cells, a number of functionalized pyrazolopyridin derivatives linked to oxadiazole, dioxolane, acyclic sugar and fluorene ring systems, were synthesized through heterocyclization reactions. The derived sugar hydrazone and the corresponding acyclic C-nucleoside analog in addition to acyclic N-nucleoside were also prepared. The behavior of the afforded compounds as possible cytotoxic agents against human HTC116 and MCF7 cancer cells was investigated and the results showed that compounds 11-13 showed the highest activities against the two cancer cells. Other compounds revealed a type of selectivity toward one cancer cell while the activity was relatively lost against the other cancer cell line.

Diarylborinic Acid-Catalyzed Regioselective Ring Openings of Epoxy Alcohols with Pyrazoles, Imidazoles, Triazoles, and Other Nitrogen Heterocycles.

A method for regioselective ring openings of 3,4- and 2,3-epoxy alcohols with ambident nitrogen heterocycles is described. Using a diarylborinic acid catalyst, a single regioisomer is favored in couplings of nucleophile and electrophile partners that display low regioselectivity under conventional conditions. The method provides access to aromatic heterocycles bearing stereochemically defined, functionalized alkyl substituents, a product class similar in structure to medicinally relevant compounds such as the acyclic nucleoside analogues.

Chemo- and regioselective ring-opening of donor-acceptor oxiranes with N-heteroaromatics.

The first ring-opening of D-A oxiranes with N-heteroaromatics in a chemoselective C-C bond cleavage manner was achieved. In the presence of 5 mol% of Y(OTf)3 as the catalyst, diverse N-heteroaromatics, including benzotriazoles, purines, substituted benzimidazole, imidazole and pyrazole, reacted well with various D-A oxiranes, providing acyclic nucleoside analogues containing a N-glycosidic bond in up to 97% yield and up to >95 : 5 regioselectivity. Through simple transformation, the Ganciclovir analogue could also be obtained.

A Tenofovir-Loaded Glycyrrhetinic Acid-Modified Cationic Liposome for Targeted Therapy of Hepatitis B Virus.

Tenofovir (TFV), an acyclic nucleoside analog, exhibits potent anti-HBV activity. However, poor bioavailability, nephrotoxicity and bone toxicity limit its further clinical application. In this work, a novel tenofovir-loaded glycyrrhetinic acidmodified cationic liposome (TGCL) was prepared for targeted therapy of HBV. The TGCL had an average particle size of 107.39 ± 1.21 nm and an entrapment efficiency of 89.83 ± 2.70% with a positive zeta potential of 37.63 ± 1.22 mV. The results of in vitro indicated that the inhibitory effects on HBsAg, HBeAg and HBV cccDNA of TGCL in HepG2.2.15 cells were significantly better than that of free TFV and non-targeted cationic liposome. In the DHBV-infected duck model, TGCL showed remarkably suppression on DHBV DNA than that of free TFV. Overall, TGCL is a promising formulation of TFV for targeted therapy of HBV.

Treatment of patients with herpetic infection on the principles of evidence-based medicine

The article summarizes modern approaches to the treatment of patients with herpetic infection based on the principles of evidence-based medicine. The use of technologies and drugs in daily medical practice with proved effectiveness is the main objective of such treatment. The effectiveness of various therapeutic approaches, scientifically based principles of the treatment for patients with this pathology has been analyzed. Combined therapy of herpetic infection should be active, long and include several stages. It is important to take into account the sensitivity of different types of herpes viruses to etiotropic agents and the patient's immune response. Reducing the active replication of the virus, minimizing the likelihood of active virions transmission to the regional ganglia through the use of antiviral therapy, reduction of toxicity, elimination of additional antigenic loads are the main objectives of this treatment. Antiviral drugs - acyclovir and its analogues are used at the first stage. Prolonged intake of acyclovir in suppressive doses within 2–12 months, depending on the disease severity is initiated at the second stage of the treatment. It is also advisable to use immunotherapeutic agents, in particular, preparations of immunoglobulins, recombinant interferons, interferon inducers, while their effectiveness requires further study in modern conditions.Conclusions. Acyclic nucleoside analogues remain one of the important components of modern treatment for patients with herpetic infection. Randomized studies have shown that three antiviral drugs (acyclovir, valacyclovir and famciclovir) are clinically effective. Systemic antiviral drugs partially control the symptoms of genital herpes in primary and recurrent episodes, and are effective as suppressive therapy. Considering the chronic recurrent nature of this infection, its complications and consequences, the combined use of replacement immunotherapy with etiotropic antiviral drugs is possible.

Synthesis and Cytotoxic Activity of New Thiazolopyrimidine Sugar Hydrazones and Their Derived Acyclic Nucleoside Analogues.

New thienyl- or chlorophenyl-substituted thiazolopyrimidine derivatives and their derived sugar hydrazones incorporating acyclic d-galactosyl or d-xylosyl sugar moieties in addition to their per-O-acetylated derivatives were synthesized. Heterocyclization of the formed sugar hydrazones afforded the derived acyclic nucleoside analogues possessing the 1,3,4-oxadiazoline as modified nucleobase via acetylation followed by the cyclization process. The cytotoxic activity of the synthesized compounds was studied against human breast cancer MCF7 and MDA-MB-231 cell lines as well as human colorectal cancer HCT 116 and Caco-2 cell lines. High activities were revealed by compounds 1, 8, 10, 11, and 13 against Caco-2 and MCF7 cells in addition to moderate activities exhibited by other compounds against HCT116 or MDA-MB-231 cells.

Synthesis and anti-H5N1 virus activity of triazole- and oxadiazole-pyrimidine hybrids and their nucleoside analogs

New 1,2,3-triazole glycosides and 1,2,4-thioglycosides incorporating a substituted pyrimidinedione ring system were synthesized via click dipolar cycloaddition and heterocyclization of hydrazine-1-carbodithioate derivatives, respectively. The sugar hydrazine derivatives linked aminodimethyluracil were also prepared. In addition, the oxadiazoline substituted with acyclic sugar moieties linked to the pyrimidinedione as acyclic nucleoside analogs were synthesized. The antiviral activity of the synthesized compounds against avian influenza H5N1 virus was investigated and compounds 18, 13 and 19 showed good activities against the virus strains.

Synthesis and Anticancer Activity of New ((Furan-2-yl)-1,3,4-thiadiazolyl)-1,3,4-oxadiazole Acyclic Sugar Derivatives.

New sugar hydrazones incorporating furan and/or 1,3,4-thiadiazole ring systems were synthesized by reaction of the corresponding hydrazide with different aldose sugars. Heterocyclization of the formed hydrazones afforded the derived acyclic nucleoside analogues possessing the 1,3,4-oxadiazoline as modified nucleobase via acetylation followed by the heterocyclization process. The anticancer activity of the synthesized compounds was studied against human liver carcinoma cell (HepG-2) and at human normal retina pigmented epithelium cells (RPE-1). High activities were revealed by compounds 3, 12 and 14 with IC50 values near to that of the reference drug doxorubicin.