Publications

CCDC 192239: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

ChemInform Abstract: (D)‐ and (L)‐Cyclohexenyl‐G, a New Class of Antiviral Agents: Synthesis, Conformational Analysis, Molecular Modeling, and Biological Activity

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Structure-Directed Expansion of Biphenyl-Pyridone Derivatives as Potent Non-Nucleoside Reverse Transcriptase Inhibitors with Significantly Improved Potency and Safety

Synthesis, Antiviral and Cytostatic Activities of Carbocyclic Nucleosides Incorporating a Modified Cyclopentane Ring. Part 2:¹Adenosine and Uridine Analogues

Six new carbocyclic nucleosides were prepared by mounting a purine (compounds 5-7), 8-azapurine (compounds 9 and 10) or pyrimidine (compound 13) base on the amino group of (1R,cis)-3-(aminomethyl)-1,2,2-trimethylcyclopentylmethanol (2). The antiviral activity of compounds 5-7, 10 and 13, and their cytostatic activity, were evaluated. At subtoxic concentrations, the compounds showed no or marginal antiviral activity. Compound 5 showed moderate inhibition on tumor cell proliferation.

Antiviral activity of the adenosine analogue BCX4430 against West Nile virus and tick-borne flaviviruses

Intestinal metabolism and permeability of bis-pivaloyloxymethyl-PMEA in an in vitro cell culture system of the intestinal mucosa

Synthesis and antiviral activity of acyclic nucleosides with a 3(S),5-dihydroxypentyl or 4(R)-methoxy-3(S),5-dihydroxypentyl sidechain

Optically pure acyclic nucleoside analogues with a 3(S),5-dihydroxypentyl or 4(R)-methoxy-3(S),5-dihydroxypentyl side chain were synthesized starting from 2-deoxy-D-ribose. The acyclic nucleosides were obtained by alkylation of the bases with the mesylates 16 and 17. Of these series of novel nucleoside analogues only 9-[3(S),5-dihydroxypent-1-yl]guanine (6d) showed marked antiviral activity. It inhibited the cytopathogenicity of herpes simplex virus type 1 (HSV-1) at a concentration of 0.4-0.6 microgram/mL, which thus points to a greater antiviral activity than recently reported for the mixture of the R and S enantiomers (12.5 micrograms/mL). In contrast with 6d, its 4(R)-methoxy derivative 7d did not show antiviral activity, which implies that the 4'-methoxy group is unable to mimic the 1',4'-oxygen bridge of the normal furanose ring.

Viral Entry as the Primary Target for the Anti-HIV Activity of Chicoric Acid and Its Tetra-Acetyl Esters

ChemInform Abstract: Synthesis and anti‐HIV Activity Evaluation of 2‐(4‐(Naphthalen‐2‐yl)‐1,2,3‐thiadiazol‐5‐ylthio)‐N‐acetamides as Novel Non‐Nucleoside HIV‐1 Reverse Transcriptase Inhibitors.

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Efficacy of oral 9‐(2‐phosphonylmethoxyethyl)‐2,6‐diaminopurine (PMEDAP) in the treatment of retrovirus and cytomegalovirus infections in mice

9-(2-Phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) is a broad-spectrum antiviral agent with potent activity against DNA viruses and retroviruses. We now demonstrate that PMEDAP is highly efficacious when given orally to mice infected with either Moloney murine sarcoma virus (MSV), Friend leukemia virus (FLV), or murine cytomegalovirus (MCMV). PMEDAP markedly delayed MSV-induced tumor initiation when administered orally at 50, 100, or 250 mg/kg/day during 5 subsequent days. At the highest dose (250 mg/kg/day), PMEDAP completely prevented tumor formation in the MSV-infected animals. PMEDAP also caused 84-96% inhibition of FLV-induced splenomegaly when given orally to FLV-infected mice at 50-250 mg/kg/day. These PMEDAP treatment regimens were also markedly effective in increasing the survival rate of MCMV-infected mice. Intraperitoneal PMEDAP achieved a comparable antiviral activity at 2- to 5-fold lower doses than oral PMEDAP. However, the therapeutic index (ratio of the toxic dose to the antivirally effective dose) of oral PMEDAP was substantially higher than that of intraperitoneal PMEDAP. Oral PMEDAP at doses of 100, 250, or 500 mg/kg resulted in plasma PMEDAP levels of 0.5-2.5 micrograms/ml, which were sustained for 3 or 6 hours after administration and may account for the high antiviral efficacy achieved.

Topical Bromovinyldeoxyuridine Treatment of Herpes Simplex Keratitis

Impact of 9‐(2‐phosphonylmethoxyethyl)adenine on (deoxy)ribonucleotide metabolism and nucleic acid synthesis in tumor cells

Following exposure to 9-(2-phosphonylmethoxyethyl)adenine (an inhibitor of the cellular DNA polymerases alpha, delta and epsilon), human erythroleukemia K562, human T-lymphoid CEM and murine leukemia L1210 cells markedly accumulated in the S phase of the cell cycle. In contrast to DNA replication, RNA synthesis (transcription) and protein synthesis (mRNA translation) were not affected by 9-(2-phosphonylmethoxyethyl)-adenine. The ribonucleoside triphosphate pools were slightly elevated, while the intracellular levels of all four deoxyribonucleoside triphosphates were 1.5-4-fold increased in 9-(2-phosphonylmethoxyethyl)adenine-treated K562, CEM and L1210 cells. The effect of 9-(2-phosphonylmethoxyethyl)adenine on de novo (thymidylate synthase-mediated) and salvage (thymidine kinase-mediated) dTTP synthesis was investigated using radio-labelled nucleoside precursors. The amount of thymidylate synthase-derived dTTP in the acid soluble pool was 2-4-fold higher in PMEA-treated than in untreated K562 cells, which is in accord with the 3-4-fold expansion of the global dTTP level in the presence of 9-(2-phosphonylmethoxyethyl)adenine. Strikingly, 2-derived dTTP accumulated to a much higher extent (i.e. 16-40-fold) in the soluble dTTP pool upon 9-(2-phosphonylmethoxyethyl)adenine treatment. In keeping with this finding, a markedly increased thymidine kinase activity could be demonstrated in extracts of 9-(2-phosphonylmethoxyethyl)adenine-treated K562 cell cultures. Also, in the presence of 200 microM 9-(2-phosphonylmethoxyethyl)adenine, 14-fold less thymidylate synthase-derived but only 3-fold less thymidine kinase-derived dTTP was incorporated into the DNA of the K562 cells. These data show that thymidine incorporation may be inappropriate as a cell proliferation marker in the presence of DNA synthesis inhibitors such as 9-(2-phosphonylmethoxyethyl)adenine. Our findings indicate that 9-(2-phosphonylmethoxyethyl)adenine causes a peculiar pattern of (deoxy)ribonucleotide metabolism deregulation in drug-treated tumor cells, as a result of the metabolic block imposed by the drug on the S phase of the cell cycle.

3,5-Bis(Phenylmethylene)-1-(N-arylmaleamoyl)-4-piperidones: A Novel Group of Cytotoxic Agents

A series of novel 3,5-bis(phenylmethylene)-1-(N-arylmaleamoyl)-4-piperidones 3 have been synthesized which displayed potent cytotoxicity towards human Molt 4/C8 and CEM T-lymphocytes as well as murine P388 and L1210 leukemic cells. In contrast, the related N-arylmaleamic acids 4 possessed little or no cytotoxicity in these four screens. Molecular modeling revealed certain interplanar and bond angles and interatomic distances which were perceived to contribute to the observed bioactivity as well as providing suggestions for future structural modifications of the piperidones 3. Evaluation of representative compounds in series 3 and 4 on the activity of human N-myristoyltransferase revealed that, at the maximum concentration utilized, namely 250 microM, only weak inhibiting properties were displayed by some of the compounds in series 4. Various members of series 3 and 4 were well tolerated in mice.

An Erosion Index for Wire Electrode Materials in EDM

In this paper, the authors propose an erosion index for wire materials or wire coatings. In sinking EDM research and practice, an erosion index is commonly available. In wire EDM few efforts have been made to identify possible electrode materials from the point of view of cutting speed. The index is based on physical understanding of the process and uses thermal properties of the electrode material, as is the case for the sinking EDM erosion index. The most important materials used as a coating for wire electrodes, like Zn, Cu, W and Mo, are analyzed and the proposed index is in good correlation with experimental cutting data, both from literature reports and own experiments. The theory can also be applied to alloys, such as brass (Cu-Zn) with different amounts of zinc.

ChemInform Abstract: Synthesis and Antiviral Activity of Deoxy Analogs of 1‐((2‐ Hydroxyethoxy)methyl)‐6‐(phenylthio)thymine (HEPT) as Potent and Selective Anti‐HIV‐1 Agents.

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Synthesis and Biological Evaluation of Some Acyclic α‐(1H‐Pyrazolo[3,4‐d]pyrimidin‐4‐yl)thioalkylamide Nucleosides.

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Stereospecific Synthesis and Antiviral Activities of β‐L‐2′,3′‐Dideoxy‐5‐chloropyrimidine Nucleoside Derivatives

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Molecular simulation of 5,6-substituted 1-[(2-hydroxyethoxy)methyl]uracils with anti-HIV-1 activity