Publications

Abstract 2-(2-Deoxy-D-erythro-pent-1-enofuranosyl)pyridine and its methyl analogues have been prepared by treatment of the corresponding 2′,3′-O-isopropylidene-D-ribofuranosyl derivatives with several bases such as sodium amide, tert.BuOK, EtONa, lithium tetramethylpiperidide (LTMP) and phenyl lithium (PhLi). PhLi and tert.BuOK gave the best results. The products thus obtained showed cytostatic activity against human tumor cell lines, in particular MT-4, a human T-lymphocyte cell line. No antiviral activity was noted at subtoxic concentrations.

The synthesis of original imidazo[1,2-a]pyridines bearing a thioether side chain at the 3 position and their antiviral activity are reported. From the synthesized compounds, 4, 15, and 21 were highly active against human cytomegalovirus with a therapeutic index superior to 150. These compounds also showed pronounced activity against varicella-zoster virus. Their structure-activity relationship is discussed.

Several purine and purine-modified analogues of the new lead anti-HIV-1 agent [[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl] thymine]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole 2'',2''-dioxide) (TSAO-T) have been prepared and evaluated as inhibitors of HIV-1-induced cytopathicity. Reaction of O-mesylcyanohydrins of furanos-3'-ulosyladenine with Cs2CO3 afforded beta-D-xylo- and ribofuranosyladenine 3'-spiro nucleosides. Reaction of 1,2-di-O-acetyl-5-O-benzoyl-3-C-cyano-3-O-mesyl-D-ribofuranose with purine bases, followed by treatment with Cs2CO3, stereoselectively afforded beta-D-ribofuranosyl 3'-spiro nucleosides. 2',5'-O-Deacylation and subsequent treatment with tert-butyldimethylsilyl chloride gave the required TSAO derivatives. The 3'-spiro nucleosides with a xylo configuration did not show any anti-HIV activity. However, the purine ribo 3'-spiro nucleosides were potent and selective inhibitors of HIV-1 with a 50% effective concentration in the range of 0.1-1 microM and a selectivity index ranging from 2 to 3 orders of magnitude. Introduction of an alkyl function at N-1 of the purine moiety markedly decreased cytotoxicity without affecting antiviral activity.

Selective laser melting (SLM) is an additive manufacturing technique which enables fabrication of three dimensional objects by selectively melting successive layers of metallic powder. By utilizing a high energy density laser, complex geometries of even refractory metals like tungsten can be realized. However, due to its intrinsic properties (high melting point, good thermal conductivity, high ductile-to-brittle transition temperature and high surface tension) SLM of tungsten is a challenging task, mainly resulting in cracked and/or porous parts. In order to overcome these drawbacks, the influence of the SLM processing parameters on the melting and solidification behavior of tungsten and tungsten alloys was investigated. The best results were obtained with a high energy density of the laser and lowest oxygen level in build chamber of the ProX® DMP 320, where the optimal processing conditions resulted in parts with closed porosity. Microstructural development, crack formation as well as the resulting texture in the finished parts was evaluated with respect to the material composition and the used scanning strategy.

Hemangiomas represent the most frequent tumors of infancy. However, the pathogenesis of these tumors is still largely unknown, and current treatment of juvenile hemangiomas remains unsatisfactory. Here we present a novel animal model to study proliferating hemangiomas and to evaluate the effect of angiostatic compounds on their growth. Intraperitoneal (i.p.) infection of 4-day-old rats with murine polyomavirus resulted in the development of multiple cutaneous, intramuscular (i.m.), and cerebral hemangiomas with 100% frequency. Histological examination of the brain revealed the formation of immature lesions as soon as 4 days postinfection (p.i.). The subsequent exponential growth of the hemangiomas, both in number and size, was associated with severe hemorrhage and anemia. The cerebral, cutaneous, and i.m. lesions consisted of blood-filled cysts, histologically similar to human cavernous hemangiomas and stained positive for proliferating cell nuclear antigen, urokinase-type plasminogen activator, and vascular endothelial growth factor. Mature cerebral hemangiomas also expressed von Willebrand factor. Cerebral lesions caused death of the untreated animals within 19.2 +/- 1.1 days p.i. Remarkably fewer and smaller hemangiomas developed in animals that had been treated s.c. with the angiogenesis inhibitor TNP-470. Accordingly, TNP-470 (50 mg/kg), administered twice a week from 3 days p.i., significantly delayed tumor-associated mortality [mean day of death, 28.2 +/- 3.3 (P < 0.001)]. Even if therapy was initiated when cerebral hemangiomas were already macroscopically visible (i.e., 9 days p.i.), a significant delay in hemangioma-associated mortality was observed. Also, the IFN-inducer polyinosinic-polycytidylic acid caused a delay of 9 days (P < 0.005) in tumor-associated mortality when administered i.p. at 5 mg/kg, twice a week, starting at day 3 p.i. The model described here may be useful for investigating (a) the angiogenic mechanism(s) underlying hemangioma progression; and (b) the effect of anti-angiogenic compounds on vascular tumor growth.

The principal objective of this study was the examination of the theory of cytotoxic synergism. In this exploratory study, we tested the hypothesis that doubling the number of sites available for thiol alkylation in a series of candidate cytotoxins increases potency more than two-fold. This concept was verified in one-third of our comparisons using human Molt 4/C8 and CEM T-lymphocytes and murine L1210 cells. In addition, the significant potencies of various members of our compound series justified further studies. Molecular modeling revealed that relative locations of the amidic groups correlate with cytotoxicity. A potent cytotoxic compound, 1,2-bis(3,5-dibenzylidene-4-oxo-piperidin-1-yl)ethane-1,2-dione (1a) inhibited the growth of a large number of human tumor cell lines and displayed greater toxicity toward certain non-adherent cells than toward adherent neoplasms or fibroblasts. The mode of action of 1a includes induction of apoptosis and necrosis.

Starting from (±)-trans- and (±)-cis-3-hydroxymethyl-1-indanol, novel 6-substituted purinylcarbanucleoside derivatives of indan (5, 6, 9, 10, 15 and 17) were synthesized through a key coupling reaction with 6-chloropurine under Mitsunobu conditions. Suzuki–Miyaura reactions of the protected 6-chloropurine derivative with different arylboronic acids afforded the corresponding 6-arylpurinylcarbanucleoside derivatives. Finally, three new 5-halouracilcarbanucleosides (19, 20 and 21) were prepared by reaction of uracilcarbanucleoside 18 with different N-halosuccinimides. All of the new analogues were evaluated for antiviral activity against a wide variety of viruses.

The metal additive manufacturing industry is rising and so is the interest in new lattice structures with unique mechanical properties. Many studies have already investigated lattice structures with different geometries and their influence on mechanical properties, but little is known about the effect of specific processing characteristics that are inherent to metal additive manufacturing. Therefore this study investigates the effect of two crucial steps in the manufacturing process: the build orientation selection and heat treatment. In total the microstructure and static mechanical properties of five different orientations and three heat treatment conditions were evaluated using Ti6Al4V diamond like lattice structures. The results show a significant decrease in mechanical strength for samples that are built diagonally and a transformation of the microstructure after a HIP (hot isostatic pressing) treatment, resulting in a lower maximum strength, but higher ductility. In general, horizontal struts should be avoided during manufacturing, unless the applied load after manufacturing can be properly supported by other struts. Both a stress relief heat treatment and a HIP treatment can be used in statically loaded applications, whereas a HIP treatment is believed to be beneficial for dynamically loaded applications. This study enables an appropriate selection of build orientation and heat treatment of lattice structures for different applications.