The Pronucleotide Approach. II: Synthesis and Preliminary Stability Studies of Mononucleoside Glycosyl Phosphotriester Derivatives

Abstract

The synthesis and preliminary stability studies of mononucleoside phosphotriester derivatives of 3′-azido-2′,3′-dideoxythymidine (AZT) incorporating a new kind of phosphate protecting group, namely S-glycopyranosidyl-2-thioethyl (SGTE), are reported.     

SATE (Aryl) Phosphotriester Series. II. Stability Studies and Physicochemical Parameters

Abstract

The stability of phosphotriester derivatives of 3′-azido-2′,3′-dideoxythymidine (AZT) bearing a S-pivaloyl-2-thioethyl (tBuSATE) group and various aryl residues derived from L-tyrosine was evaluated in biological media. The results demonstrate that such compounds give rise to intracellular delivery of the parent mononucleotide through esterase and phosphodiesterase hydrolytic steps, successively.     

Synthesis,Biological Activity and Decomposition Studies of Amino Acid Phosphomonoester Amidates of Acyclovir

Abstract

Highly stable and water soluble amino acid phosphomonoester amidates of acyclovir (ACV) were synthesized and shown to function predominantly as prodrugs of AC V and not acyclovir monophosphate (AC V-MP) with activities within two fold of the amino acid prodrug of ACV, valaciclovir (VACV). Metabolism studies revealed that incubation of cell-free extracts of Vero cells with the L-leucine phosphomonoester amidate of ACV (3c), resulted in a burst of ACV-MP production followed by the rapid generation of ACV.     

A New Phosphorylating Agent,Di(2,2,2-Trifluoroethyl) Trimethylsilyl Phosphite. Its Application in Dna Synthesis by The Phosphotriester Approach

Abstract

A new phosphorylating agent, di(2,2,2-trifluoro-ethyl) trimethylsilyl phosphite, has been prepared and is proved to be a useful agent for the phosphorylation of the 3′-hydroxyl group of deoxyribonucleosides in the absence of coupling agents. The resulting deoxyribonucleoside 3′-(2,2,2-trifluoroethyl) phosphates are key intermediates for the synthesis of deoxyribooligonucleotides by the phospho-triester approach.     

SATE (Aryl) Phosphotriester Series. I. Synthesis and Biological Evaluation

Abstract

Synthesis and biological activities of several phosphotriester derivatives of 3′-azido-2′,3′-dideoxythymidine (AZT) bearing a S-pivaloyl-2-thioethyl (tBuSATE) group and aryl residues derived from L-tyrosine are reported. All compounds showed marked anti-HIV activity in thymidine kinase-deficient CEM cells demonstrating their ability to deliver intracellularly the parent 5′-mononucleotide.     

The Synthesis and Antiherpetic Activity of Acyclovir Phosphonate Esters

Alkyl esters of acyclovir phosphite, alkoxycarbonylphosphonate, ethoxycarbonylmethylphosphonate, and aminocarbonylphosphonate were synthesized. Most of them were shown to inhibit the replication of type 1 herpes simplex virus in Vero cell culture. The stability in phosphate buffer and human blood serum was studied for several of the derivatives. A correlation between the stability and antiviral activity of the synthesized compounds is discussed.     

Synthesis, Copper(II) Complexation, (64)Cu-Labeling, and Bioconjugation of a New Bis(2-pyridylmethyl) Derivative of 1,4,7-Triazacyclononane

A new ligand derivative of 1,4,7-triazacyclononane (TACN), 2-[4,7-bis(2-pyridylmethyl)-1,4,7-triazacyclononan-1-yl]acetic acid ( 6), has been synthesized and its complexation behavior toward Cu2+ ions investigated. The ligand 6 has been characterized by spectroscopic methods, and a molecular structure of a corresponding Cu(II) complex has been elucidated by single-crystal X-ray analysis. The suitability of 6 for conjugation to peptide substrates has been shown by amide coupling of 6 to the stabilized derivative of bombesin (BN), beta Ala-beta Ala-[Cha13, Nle14]BN(7-14), to give the conjugate 8. The free ligand 6 and the bioconjugate 8 were labeled with 64Cu2+, and the resulting complexes, 64Cu subset6 and 64Cu subset8 , were found to be stable in the presence of a large excess of a competing ligand (cyclam) or copper-seeking superoxide dismutase (SOD), as well as in rat plasma. Biodistribution studies of 64Cu subset8 in Wistar rats showed a high activity uptake into the pancreas (5.76 +/- 0.25 SUV, 5 min p.i.; 3.93 +/- 0.25 SUV, 1 h p.i.), which is the organ with high levels of gastrin-releasing peptide receptor (GRPR). This receptor is overexpressed in a large number of breast and prostate carcinomas. The novel 64Cu subset6 complex had a dominating influence on the nonspecific activity biodistribution of its BN conjugate, since the distribution data of 64Cu subset6 are similar to those of 64Cu subset8 . The 64Cu complexes exhibited a low activity accumulation in the liver tissue and an extensive renal clearance, which was distinctively different to the biodistribution of 64CuCl 2, suggesting that 64Cu subset6 does not undergo significant demetalation, but rather exhibits high in vivo stability.     

The Synthesis and Cytotoxic Activity of D-Ribofuranosides and 2-Deoxy-D-Ribofuranosides of Substituted Bis(indolyl)furan, Bis(indolyl)pyrrole, and Indolo[2,3-a]carbazole Derivatives

1-(2,3,5-Tri-O-acetyl)--D-ribofuranosyl indole, the key compound in the synthesis of glycosides with the bis(indole) aglycone, was obtained for the first time by the indoline–indole method. There were synthesized 3-(1-methylindol-3-yl)-4-(1-glycosylindol-3-yl)furan(or pyrrole)-2,5-diones containing the residue of -D-ribofuranose or 2-deoxy--D-ribofuranose and analogous glycosides of indolo[2,3-a]furano(or pyrrolo)[3,4-]carbazol-5,7-diones, which are structurally relative to the antitumor antibiotic rebeccamycin. Their cytotoxicities toward a number of human tumor cell lines were studied in vitro, and the carbazole N-glycosides were shown to be more active than the bis(indole) glycosides. At the same time, the ribofuranosides were found to be less active than the corresponding ribopyranosides synthesized previously.     

Synthesis and anti-HIV activity of some S-acyl-2-thioethyl (SATE) phosphoramidate derivatives of 3'-azido-2',3'-dideoxythymidine.

The synthesis and in vitro anti-HIV activity of tBuSATE phosphoramidate derivatives of AZT incorporating several methyl-esterified alpha-amino acids are reported. The biological evaluation strongly supports the hypothesis that such compounds exert their anti-HIV effects via intracellular delivery of the corresponding 5'-mononucleotide.     

Synthesis of 9-(2-Hydroxyethoxymethyl)guanine (Acyclovir) from Guanosine

Abstract

A convenient synthesis of 9-(2-hydroxyethoxymethyl)guanine (acyclovir) from guanosine by chemical transpurination was developed. The isomerization of the 7-isomer to the desired 9-isomer and the purification of the 9-isomer was achieved simply by concentration, heating and further crystallization.     

Synthesis and Insecticidal Activity of Lignan Analogs (III)

Ten haedoxan analogs with the bond split between 2C and 3C of the 6-methoxy-2-methoxymethyl-3-(3,4-methylenedioxy)phenyl-1,4-benzodioxan-7-yl group of haedoxans were synthesized, and their insecticidal activity was assessed on the housefly. The inactivity of an analog having a 2-methoxy-5-(2-methoxyethoxy)-4-(3,4-methylenedioxybenzyloxy)phenyI instead of the 1,4-benzodioxan-7-yl group made it evident that the benzodioxane framework is essential for the activity of haedoxans.     

The Synthesis and Biological Activity of 3,3'-Dimethyl-L-Selenocystine,a New Selenocystine Derivative

Russian Journal of Bioorganic Chemistry - Using the known synthesis of L-selenocystine,3,3'-diseleno-bis (2-aminopropionic acid), from β?chloroalanine, a structural analog of natural...     

Isolation of Two Plasticizers,Bis(2-ethylhexyl) Terephthalate and Bis(2-ethylhexyl) Phthalate,from Capparis spinosa L. Leaves

Many plants have been known to be contaminated and accumulate plasticizers from the environment, including water sources, soil, and atmosphere. Plasticizers are used to confer elasticity and flexibility to various fiber and plastic products. Consumption of plasticizers can lead to many adverse effects on human health, including reproductive and developmental toxicity, endocrine disruption, and cancer. Herein, we report for the first time that two plasticizers, bis(2-ethylhexyl) terephthalate (DEHT) and bis(2-ethylhexyl) phthalate (DEHP), have been isolated from the leaves of Capparis spinosa L. (the caper bush), a plant that is widely used in food seasonings and traditional medicine. 297 mg/kg of DEHT and 48 mg/kg of DEHP were isolated from dried and grounded C. spinosa L. leaves using column chromatography and semi-preparative high-performance liquid chromatography. Our study adds to the increase in the detection of plasticizers in our food and medicinal plants and to the alarming concern about their potential adverse effects on human health.     

Synthesis of rhodium(III), iridium(III) and osmium(III) complexes with tris(2-aminoethanethiolato)cobalt(III)

Polynuclear sulfur bridged complexes where the neutral complex tris(2-aminoethanethiolato)cobalt(III) acts as a tridentate ligand to rhodium(III), iridium(III) and osmium(III) have been prepared. These complexes have been characterized by electronic spectroscopy, vibrational spectroscopy and nuclear magnetic resonance spectroscopy. Along with the previously prepared complexes of iron(III), ruthenium(III) and cobalt(III), these complexes form two series of complexes with the group 8 and group 9 elements from all three transition series.     

Synthesis and Bioactive Studies of Complex 8-Hydroxyquinolinato-Bis-(Salicylato) Yttrium (III)

This paper reports the synthesis of a new bioactive complex, 8-hydroxyquinolinato-bis-(salicylato) yttrium (III) (HSAY), whose composition and structure were characterized by elemental analysis, IR spectra, thermogravimetric analysis, and X-ray diffraction. The power-time curves of the compounds HSAY, C(7)H(6)O(3), C(9)H(7)NO, and YCl(3)·6H(2)O on the growth metabolism of Schizosaccharomyces pombe (S. pombe) were determined at 32.00°C, respectively. The corresponding thermokinetics parameters, which include the microbial growth rate constant (κ), inhibition ratio (I), and half inhibition concentration (IC(50)), were also derived. The results showed that the generation time was 168.2 min, and all the compounds HSAY, C(7)H(6)O(3), C(9)H(7)NO, and YCl(3)·6H(2)O possessed good bioactivities on the growth metabolism of S. pombe, with the values of IC(50) being 0.055, 3.57, 0.057, and 1.35 mmol L(-1), respectively. The inhibition ability of these compounds above on the growth of the S. pombe has been observed to decrease in the order HSAY>C(9)H(7)NO>YCl(3)·6H(2)O>C(7)H(6)O(3).     

Synthesis of Phosphonic Acid Analogs of Acyclovir (ACV) and Canciclovir (DHPG)

Abstract

Isosteric Phosphonic acid analogs of acyclovir and ganciclovir have been synthesized for evaluation for antiviral activity.     

Studies Designed to Increase the Stability and Antiviral Activity (HCMV) of the Active Benzimidazole Nucleoside,TCRB

Abstract

The potent activity of 2,5,6-trichloro-1-(ß-D-ribofuranosyl)benzimidazole (TCRB) against Human Cytomegalovirus with the concomitant low cellular toxicity at concentrations that inhibit viral growth prompted considerable interest in this research area. This interest was moderated by the pharmacokinetic studies of TCRB in rats and monkeys that revealed the instability of TCRB in vivo. These studies suggested that the instability was due to a cleavage of the glycosidic bond in vivo which released the heterocycle (2,5,6-trichlorobenzimidazole) into the bloodstream. This prompted us to initiate synthetic studies designed to increase the stability of the glycosidic bond of TCRB and BDCRB. Several synthetic approaches to address this and other problems are presented.     

Synthesis,Stability, and Biological Evaluation of 1,3-Dihydrobenzo[c]furan Analogue of d4T and Its SATE Pronucleotide

Abstract

The anti-HIV activity and stability studies of 1,3-dihydrobenzo[c]furan analogue of d4T are reported. The corresponding mononucleoside phosphotriester derivative bearing a S-pivaloyl-2-thioethyl (tBuSATE) group, as biolabile phosphate protection, is also studied.     

Synthesis of Bis (1, 2, 4-triazoles, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles) and Related Compounds

Reaction of malonylhydrazide with different isothiocyanates yields corresponding bisthiosemicarbazides which are transformed into bis[5-mercapto-4-aryl-l,2,4-triazol-3-yl] methane, bis[5-arylamino-l,3,4-oxadiazol-2-yl]methane and bis[5-arylamino-1,3,4-thiadiazol-2-yl]methane under different reaction conditions. Mercapto compounds react with alkyl halides, and give the corresponding sulphides, some of the sulphides are converted into sulphones with aqueous potassium permanganate. Some of the compounds are evaluated as pesticides.     

NMR Studies of Backbone-Alkylated DNA: Duplex Stability,Absolute Stereochemistry,and Chemical Shift Anomalies of Prototypal Isopropyl Phosphotriester Modified Octanucleotides, (Rp,Rp)- and (Sp,Sp)-{d-[GGA(iPr)ATTCC]}2 and - {d- [GGAA(iPr)TTCC]}2

Abstract

The DNA octamer {d-[GGAATTCC]}₂ and four alkylated analogues, (Rp)-{d-[GGA(iPr)ATTCC]}₂, (Sp)-{d-[GGA(iPr)ATTCC]}₂, (Rp)-{d-[GGAA(iPr)TTCC]}₂, and (Sp)-{d-[GGAA(iPr)TTCC]}₂ have been examined using ¹H and ³¹P NMR spectroscopies. Duplex stability, as monitored by both NMR and optical measurements, is shown to be a function of both site and stereochemistry of the phosphotriester moiety. Chemical shift changes relative to the native octamer indicate that there are long-range perturbations in the isopropylated molecules. ¹H NMR is shown to be a general means by which stereochemistry at phosphorus can be determined.