Publications

Continuing our study on the structural features of geiparvarin (1), responsible for cytostatic activity, a series of 4,5-dihydro-3(2H)-furanones 10a-f and of 3(2H)-furanones 11a-f as well as 2",3"-dihydrogeiparvarin (14) have been designed and synthesized. Their cytostatic activity was evaluated against proliferation of murine (L1210, FM3A) and human (Raji, Molt/4F, and MT4) tumor cells. Modifications in the region of the olefinic double bond by introduction of the characteristic alkenyl side chain of ascofuranone (compounds 10a-f and 11a-f) markedly decreased the cytostatic activity as compared to geiparvarin itself, but this effect does not seem to be correlated to the presence of the furanone moiety linked to the alkenyl chain or to the ability to afford Michael type adducts. Replacement of the coumarin portion by other aromatic rings did not alter the cytostatic activity. The essential inactivity of 2",3"-dihydrogeiparvarin (14) points to the importance of the 3(2H)-furanone ring system in the cytostatic activity; consequently, this moiety may be considered as the determinant pharmacophore for antitumor activity, while the side chain plays a rather modulatory role.

No abstract is provided for this article.

A series of N2-acyl isonicotinic acid hydrazides (1-17) was synthesized and tested for its in vitro antimycobacterial activity against Mycobacterium tuberculosis and the results indicated that the compound, isonicotinic acid N'- tetradecanoyl-hydrazide (12) was more active than the reference compound isoniazid. The results of antimicrobial activity of the synthesized compounds against S. aureus, B. subtilis, E. coli, C. albicans and A. niger indicated that compounds with dichloro, hydroxyl, tri-iodo and N2 –tetradecanoyl substituent were the most active ones. The antiviral activity studies depicted that none of the tested compounds were active against DNA or RNA viruses. The multi-target QSAR model was found to be effective in describing the antimicrobial activity of N2-acyl isonicotinic acid hydrazides. Keywords: Antimicrobial, Antitubercular, Antiviral, N2-acyl Isoniazid, QSAR

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.

4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)amino]-N(4,6-dimethyl-2-pyrimidiny)-benzene Sulphonamide and its derivatives were evaluated for antibacterial activity, antifungal activity, antiviral activity against ten pathogenic viruses in E6SM, Vero and HeLa cells and anticancer activity against CNS, breast and lung cancer. The N-acetyl and 5-methyl derivatives showed a minimum inhibitory concentration (MIC) of 48 I¼g/ml against herpes simplex virus type-2 and respiratory syncytial virus, without toxicity at a concentration upto 400 I¼g/ml. The test compounds showed comparable antibacterial activity to that of the parent sulphadimidine, except for the 5-bromo and N-acetyl derivatives.

Sonogashira coupling of 5-iodouracil (2) and trimethylsilylacetylene gave 5-(trimethylsilylethynyl)uracil (3), which was deprotected to give 5-ethynyluracil (4). Copper(I)-catalyzed cyclization of 4 gave furo[2,3-d]pyrimidin-2(3H)-one (5). Tosylation of 2 and 4 gave the 1-(p-toluenesulfonyl) derivatives 6 and 7, respectively. The tosylated compound 6 and trimethylsilylacetylene did not undergo Sonogashira coupling, and copper(I)-catalyzed cyclization of 7 did not occur. Coupling of 2 with several terminal alkynes gave 5-(alkyn-1-yl)uracil derivatives (9), which underwent tosylation to produce the targeted 5-(alkyn-1-yl)-1-(p-toluenesulfonyl)uracil compounds (11). Copper(I)-catalyzed cyclization of 9 gave the respective furopyrimidines (10) in low yields. Again, cyclization did not occur with the tosyl derivatives (11). Activity against varicella-zoster virus (VZV) was observed with longer-chain analogues of 9 and 11, and compound 7 showed activity against human cytomegalovirus (HCMV) at near cytotoxic levels.Key words: antiviral screening, furo[2,3-d]pyrimidin-2(3H)-one derivatives, Sonogashira coupling, 1-(p-toluenesulfonyl)pyrimidine derivatives.

A novel 6-substituted acyclouridine derivative, 5-ethyl-1-ethoxymethyl-6-(phenylthio)uracil (E-EPU), has recently proved to be a highly potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) in vitro. Combinations of 3'-azido-2',3'-dideoxythymidine (AZT) and E-EPU synergistically inhibit the replication of HIV-1 in MT-4 cells, whereas the cytotoxic effects of AZT and E-EPU on mock-infected MT-4 cells are not enhanced by the drug combination. Synergistic inhibition of HIV-1 replication has also been observed in peripheral blood lymphocytes. These results indicate that the combination of AZT and E-EPU should be further pursued in the treatment of AIDS.

(E)-5-(2-bromovinyl)-2'-deoxyuridine 5'-triphosphate (BVdUTP), known as a specific inhibitor of herpes simplex virus (type 1)-DNA polymerase, was found to be a potent inhibitor of the activity of terminal deoxynucleotidyltransferase (TdT) from calf thymus. BVdUTP was not an efficient substrate of TdT, but it inhibited the incorporation of normal deoxynucleotide substrates in competitive fashion at the nucleotide binding site of TdT molecule. The Ki value for BVdUTP (5 microM) was much less than the Km value for dGTP (83 microM), indicating stronger affinity of the inhibitor to TdT than that of the substrate. These results indicate the usefulness of BVdUTP as a potent inhibitor of TdT for elucidation of the reaction mechanism of this enzyme.