Publications

Tat is a regulatory HIV‐1 protein, which has the particularity to be secreted very early by HIV‐infected cells. The extra cellular roles of Tat are suspected to be the main cause of the maintenance of reservoirs of HIV‐infected cells and the failure of actual AIDS therapies to eradicate HIV. This study describes the rationale used to design molecules that bind to a target area containing an hydrophobic pocket identified in the 2D‐NMR structure of Tat. Molecules were synthesized and the derivative named TDS2 was shown to be a Tat inhibitor. Fluorescence revealed that TDS2 binds in the target area, which is conserved across five different Tat variants representative of the main HIV‐1 subtypes. TDS2 inhibited in vitro HIV‐1 replication in human T‐cells. Further chemical modifications remain necessary to enhance affinity to Tat and reduce cytotoxicity.

Abstract For Abstract see ChemInform Abstract in Full Text.

The title compounds 2-mercapto-3-(substitutedmethylamino) quinazolin-4(3H)-ones were synthesized by condensing the active hydrogen atom of 3-amino group of 3-amino-2-mercapto quinazolin- 4(3H)-one with formaldehyde and the desired amines. Investigation of antimicrobial activity of the compounds was performed by agar dilution method against 6 pathogenic bacteria, 3 pathogenic fungi and antiHlV activity against replication of HIV-1 (IIIB) and HIV-2 (ROD) in MT-4 cells. The compounds exhibited significant antibacterial and antifungal activities.

Selective Laser Melting (SLM) is a promising technique for the production of biometallic scaffolds for orthopaedic applications. To produce successful scaffolds, the laser parameters should be care ...

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.

The alpha- and beta-D-xylofuranosyl analogues of the naturally occurring nucleosides, as well as other D-xylofuranosyl derivatives, have been the subject of a systematic synthesis and examination of their biological, i.e. antiviral antimetabolic, and cytostatic properties. The beta anomers were prepared by glycosylation of purine and pyrimidine aglycons with peracylated 1-O-acetyl-alpha-D-xylofuranoses, followed by removal of the blocking groups. The alpha anomers were obtained by a multistep synthesis with use of 2-amino- or 2-mercapto-alpha-D-xylofuran[1',2':4,5]-2-oxazoline as starting material. The xylofuranosyl nucleosides were tested for their activity against a variety of RNA and DNA viruses and for inhibition of cell growth and macromolecule synthesis. Three compounds, 9-(beta-D-xylofuranosyl)adenine, 9-(beta-D-xylofuranosyl)guanine, and 1-(beta-D-xylofuranosyl)cytosine, showed marked biological activity.

The diketo acid L-708,906 has been reported to be a selective inhibitor of the strand transfer step of the human immunodeficiency virus type 1 (HIV-1) integration process (D. Hazuda, P. Felock, M. Witmer, A. Wolfe, K. Stillmock, J. A. Grobler, A. Espeseth, L. Gabryelski, W. Schleif, C. Blau, and M. D. Miller, Science 287:646-650, 2000). We have now studied the development of antiviral resistance to L-708,906 by growing HIV-1 strains in the presence of increasing concentrations of the compound. The mutations T66I, L74M, and S230R emerged successively in the integrase gene. The virus with three mutations (T66I L74M S230R) was 10-fold less susceptible to L-708,906, while displaying the sensitivity of the wild-type virus to inhibitors of the RT or PRO or viral entry process. Chimeric HIV-1 strains containing the mutant integrase genes displayed the same resistance profile as the in vitro-selected strains, corroborating the impact of the reported mutations on the resistance phenotype. Phenotypic cross-resistance to S-1360, a diketo analogue in clinical trials, was observed for all strains. Interestingly, the diketo acid-resistant strain remained fully sensitive to V-165, a novel integrase inhibitor (C. Pannecouque, W. Pluymers, B. Van Maele, V. Tetz, P. Cherepanov, E. De Clercq, M. Witvrouw, and Z. Debyser, Curr. Biol. 12:1169-1177, 2002). Antiviral resistance was also studied at the level of recombinant integrase. Single mutations did not appear to impair specific enzymatic activity. However, 3' processing and strand transfer activities of the recombinant integrases with two (T66I L74M) and three (T66I L74M S230R) mutations were notably lower than those of the wild-type integrase. Although the virus with three mutations was resistant to inhibition by diketo acids, the sensitivity of the corresponding enzyme to L-708,906 or S-1360 was reduced only two- to threefold. As to the replication kinetics of the selected strains, the replication fitness for all strains was lower than that of the wild-type HIV-1 strain.

We have recently discovered that 6-aminoquinolone derivatives could be valid leads for the development of new anti-HIV agents because of their new and diversified mode of action. In fact, studies carried out on the lead WM5 showed that this derivative is able to inhibit the Tat-mediated long terminal repeat driven transcription, an essential step in the HIV-1 replication cycle. Thus, starting from lead WM5, we performed the design and synthesis of an enlarged series of 6-aminoquinolones, which permitted some very potent anti-HIV 6-amino derivatives to be obtained and the structure−activity relationship to be delineated. Some derivatives, 26c, 26e, 26i, and 26j, proved to be highly effective in inhibiting HIV replication at 50% inhibitory concentration in the range of 0.0087−0.7 μg/mL in MT-4, PBMCs and CEM cell lines coupled with positive selectivity indexes that reach values higher than 1000 on CEM cell lines for compounds 26e and 26i. Time-of-addition experiments clearly confirm that the new, potent 6-aminoquinolones interact at a postintegration step in the replication cycle of HIV.

The sulfonic acid polymers poly(2-acrylamido-2-methyl-1-propanesulfonic acid) (PAMPS), poly(4-styrenesulfonic acid) (PSS), and poly(anetholesulfonic acid) (PAS) proved to be highly potent inhibitors of angiogenesis in the chick chorioallantoic membrane (CAM) assay. PAMPS was found to achieve a dose-dependent inhibition of microvessel formation in the CAM assay ranging from 57 +/- 16% inhibition at 10 micrograms/disc to 72 +/- 15% at 150 micrograms/ disc. Also, PSS and PAS caused a strong inhibition of angiogenesis (55 +/- 19% and 48 +/- 16%, respectively, at 50 micrograms/disc), whereas poly(vinylsulfonic acid) (PVS) was found to be inactive at this dose. The compounds proved to be nontoxic for the developing chick embryo at these doses. Suramin, which was included as a reference compound, caused only a slight inhibition of vascular density, at a dose of 150 micrograms/disc, whereas pentosan polysulfate (PPS) was found to be toxic. PAMPS, PAS, and PSS, but not PVS, inhibited microvessel formation in the rat aorta-ring assay. In addition, the increased [3H-methyl]dThd uptake in endothelial cells in vitro upon stimulation with basic fibroblast growth factor (bFGF) was inhibited by PAMPS, PAS, and PSS at 20 micrograms/ml. A strong correlation (r = 0.95) was found between the antiangiogenic effect of the sulfonic acid polymers in the CAM assay and their inhibition of the bFGF-induced mitogenic response, indicating that bFGF is the target for these sulfonic acid polymers. These results suggest that sulfonic acid polymers, and in particular PAMPS, may be considered as specific, nontoxic angiogenesis inhibitors.