Publications

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.

We describe the use of pharmacophore modeling as an efficient tool in the discovery of novel HIV-1 integrase (IN) inhibitors. A three-dimensional hypothetical model for the binding of diketo acid analogues to the enzyme was built by means of the Catalyst program. Using these models as a query for virtual screening, we found several compounds that contain the specified 3D patterns of chemical functions. Biological testing shows that our strategy was successful in searching for new structural leads as HIV-1 IN inhibitors.

The novel fluorinated and iodinated purine derivatives containing 9-(2-hydroxypropyl) (1a-7a and 9a-13a) and 9-(2-hydroxyethoxymethyl) (1b-3b, 5b, and 7b-12c) side chains were synthesized by a multistep synthetic route involving Baltz-Schiemann's fluorination and diazotation/iodination as key reactions. An unequivocal proof for the stereostructure of 5b was obtained by X-ray structure analysis. New compounds were evaluated for their cytostatic activity against murine leukemia (L1210); mammary carcinoma (FM3A); and human T-lymphocytes (Molt4/C8 and CEM), melanoma (HBL), cervical carcinoma (HeLa), colon carcinoma (HT29 and SW620), laryngeal carcinoma (Hep2), and pancreatic carcinoma (MiaPaCa2) as well as diploid fibroblasts (WI38). Of all the compounds, the 2-aminopurin-6-thione derivative 9a showed the most pronounced inhibitory activity against human SW620 cells. The 2-aminopurin-6-thione derivative 9b exhibited the most selective inhibitory activity against human HeLa, Hep2, SW620, and murine L1210 cell proliferation as compared to normal fibroblast (WI38) cell proliferation. None of the compounds showed inhibitory activities against HIV-1, HIV-2, HSV-1, and HSV-2, vaccinia, vesicular stomatitis, parainfluenza-3, reovirus-1, Sindbis, Coxsackie B4, or respiratory syncytial virus. The new purine derivatives, and particularly 9a and 9b, appear to demonstrate sufficient cytostatic potency and selectivity to justify further evaluation of their potential.

A novel, simple, and efficient method for the chemical resolution of epidithiodioxopiperazines is reported, which is based upon covalent formation of diastereomers. This method might be a general one for the resolution of chiral cyclic disulfides. Dithiol 5, prepared from 2 by reduction with NaBH4, was allowed to react with the disulfenyl chloride 8 to yield 9 and 10, which were separated by short-column chromatography on silica gel. From these, the optically pure enantiomers 11 and 12, respectively, were obtained by reduction with NaBH4, followed by reoxidation with I2-pyridine. In this way the precursor 7 of the resolving agent could also be recovered. The absolute configurations of 11 and 12 were derived from CD spectra. Kinetic asymmetric transformation of the gliotoxin analogue 2 with the diphosphine 6 gave a 19% enrichment in one enantiomer of the starting material. Surprisingly, both enantiomers were found to inhibit reverse transcriptase, the RNA-dependent DNA polymerase, to the same degree, indicating that there is no relation between this property of epidithiodioxopiperazines and their bridgehead configurations. From the X-ray crystal structure determination it can be seen that there is a considerable torsional and conformational strain in compound 2, which might enhance the ease of cleavage of the S-S bond. A possible relationship between this property and the biological activity of 2 is discussed.

Purpose The purpose of this paper is to assess a new powder metallurgy process to make alumina parts through indirect selective laser sintering (SLS). Density measurements, some geometrical assessments and scanning electron microscopy (SEM) microstructural analyses are performed after each stage of the process, allowing an objective overview to be provided of the challenges and possibilities for the processing of high density technical ceramic parts through SLS of ball milled alumina/polyamide powder agglomerates. Design/methodology/approach The powder production by ball milling, SLS, cold isostatic pressing (CIP) or quasi isostatic pressing (QIP), debinding and sintering (FS) stages of the powder metallurgy process were sequentially investigated. Findings Alumina parts with a density up to 94.1 per cent could be produced by a powder metallurgy process containing an SLS step. Microstructural investigation of the sintered samples reveals an alumina matrix with a grain size of ∼5 μm and two different kinds of pore morphologies, i.e. long elongated pores, which stem from the intergranular spacings during SLS, and intermediate pores, which likely originate from larger polyamide agglomerates in the ball milled powder. Also, QIPing at elevated temperatures is found to be a promising alternative for CIPing at room temperature to increase the final part density. Research limitations/implications Cracks, long elongated pores and intermediate pores remained in the sintered parts. Homogenizing the microstructure of the parts through optimizing the composite starting powder, the deposition during SLS, the SLS parameters and QIPing parameters is essential to overcome these limitations. Practical implications Homogenizing the starting powder mixture and the microstructure of the SLS material is the key issue for producing ceramic parts through indirect SLS. Originality/value Indirect SLS of ceramics has hardly been reported and the combined use of SLS and QIPing is innovative in the field of indirect SLS of ceramics.

This paper demonstrates how thermal treatments can be used to enable the laser sintering (LS) of polybutene-1 (PB-1). One of the major issues with the examined PB-1 grade is the limited thermal operating window. At temperatures slightly below 90 °C crystallisation is too fast, resulting in warpage during processing. Above 90 °C, however, the powder becomes increasingly sticky, limiting the maximum bed temperature that can be applied in a laser sintering station. In this work, the problem is remediated by annealing the powder at 115 °C, which creates a more perfect crystal structure with a sharper melting onset. An alternative treatment of melting, slowly cooling and aging the sample at room temperature creates a powder with a stabilised crystal structure, which has a sharp melting onset at 120 °C and thus also a broader thermal window. Test parts were created on an LS machine validating the increase in processability.

The four antiherpes compounds acyclovir, adenine arabinoside, bromovinyldeoxyuridine, and phosphonoformic acid showed an additive to synergistic effect with human leukocyte interferon in inhibiting focus formation by three different strains of varicella-zoster virus in human embryonic fibroblasts.