Publications

To develop effective non-nucleoside reverse transcriptase inhibitors (NNRTIs) with improved antidrug resistance profiles and drug-like properties, a series of novel diarylpyrimidine derivatives targeting the hydrophobic domain of the NNRTI-binding pocket was strategically designed, synthesized, and evaluated. Following structural optimization, <b>18e</b> (EC₅₀ = 5.06-54.0 nM) emerged as the most potent inhibitor against wild-type and NNRTI-resistant strains, comparable to ETR (EC₅₀ = 3.79-51.8 nM). In particular, for Y188L and RES056 mutant strains, <b>18e</b> (EC_50(Y188L) = 24.2 nM, RF = 4.79/EC_50(RES056) = 54.0 nM, RF = 10.7) showed improved antiresistance profiles versus ETR (EC_50(Y188L) = 23.4 nM, RF = 6.18/EC_50(RES056) = 51.8 nM, RF = 13.7). Molecular simulation studies indicated that the 1,3,4-oxadiazolylpyridine motif was essential for binding to reverse transcriptase. Moreover, <b>18e</b> exhibited promising pharmacokinetic properties (<i>T</i>_1/2 = 2.35 h, <i>F</i> = 14.4%) and safety (LD₅₀ < 2000 mg/kg), positioning it as a promising anti-HIV-1 drug candidate.

In an attempt to determine some of the structural features of geiparvarin (1) that account for its cytostatic activity in vitro, a series of geiparvarin analogues (10a-i, 1, 12, and 14-16) which contain novel modifications in the region of the olefinic double bond and of the coumarin moiety have been designed and synthesized. Among the derivatives containing a carbamate moiety, only the analogues containing a carbamate group linked to an alkyl moiety 10b-i were endowed with potent cytostatic activity, whereas the corresponding benzene derivative 10a was devoid of any antiproliferative activity. 6-Methoxygeiparvarin 101 proved equally effective as geiparvin (1), while compounds containing an additional double bond at the side chain (12 and 14-16) were invariably 5-100-fold less effective than geiparvarin. Diene derivative 15, bearing a coumarin moiety, was essentially inactive against murine (L1210, FM3A) tumor cells but exhibited good activity against human (Molt/4F, MT-4) tumor cells.

The new pyrimidine derivatives of 2,3-O, O-dibenzyl-6-deoxy-L-ascorbic acid (8-10) were synthesized by condensation of uracil and its 5-fluoro- and 5-trifluoromethyl-substituted derivatives with 4-(5,6-epoxypropyl)-2, 3-O,O-dibenzyl-L-ascorbic acid (7), while pyrimidine derivatives of 4,5-didehydro-5,6-dideoxy-L-ascorbic acid (14-17) with free C-2' and C-3' hydroxy groups in the lactone ring were obtained by debenzylation of 11-13 with boron trichloride. Z-Configuration of the C4'=C5' double bond and position of the benzyl group in the lactone ring of 14 were deduced from their (1)H and (13)C NMR spectra and connectivities in COSY, ROESY, and HMBC spectra. The exact stereostructure of 13 was confirmed by its X-ray crystal structure analysis. Of all the compounds in the series, compound 16 containing a 5-fluoro-substituted uracil ring showed the most significant antitumor activities against murine leukemia L1210/0 (IC(50) = 1.4 microg/mL), murine mammary carcinoma FM3A/0 (IC(50) = 0.78 microg/mL), and, to a lesser extent, human T-lymphocyte cells Molt4/C8 (IC(50) = 31.8 microg/mL) and CEM/0 cell lines (IC(50) = 20.9 microg/mL).

No abstract is provided for this article.

This work investigates the feasibility of a novel method to simultaneously alloy and reinforce a low alloyed Al alloy (i.e., Al6061) during selective laser melting (SLM) via in situ decomposition of zinc oxide (ZnO). Based on Gibbs free energy calculations, an Al6061+6wt%ZnO powder mixture is designed and prepared. The thermal decomposition of ZnO, resulting in the formation of Al oxide and free Zn, simultaneously alloys and reinforces the Al matrix. This also provides extra thermal energy that alters the dynamics of the melt pool and necessitates a completely different set of optimised SLM parameters compared to traditional Al alloys. After SLM, it is shown that this method can successfully reinforce the Al matrix with numerous nanometer sized oxide particles (typically ~ 50-120 nm). Despite this clear success to manufacture in situ reinforced Al composites by SLM, the applied method could not avoid partial Zn evaporation (limiting in situ alloying) and could not successfully suppress the cracking that also occurs after SLM of unreinforced Al6061.

Abstract As part of a synthetic program on cyclic oligomers of DNA, the cyclic dimer of 5-fluoro-2′-deoxyuridylic acid (FdUMP) was synthesized. The fully protected dimer 5 was obtained following Catlin and Cramer′s phosphotri-ester strategy. Autocondensation and deprotection then afforded the title compound 9 [cyclo(5FdUp5FdUp)] in excellent yield. In vitro, 9 proved slightly less active than FdUrd in inhibiting the proliferation of various murine and human tumor cells, but, in vivo, 9 was equally effective, and less toxic than 5-FdUrd in inhibiting adenocarcinoma tumor growth in mice.

A number of adamantaneketoxime ethers and an acetylenic adamantaneketoxime iododerivative have been prepared and tested as potential antifungal agents. They were also examined for their antibacterial and antiviral effects. Most of them proved active against the tested fungi. Their antimicrobial activity was generally low, while they did not exhibit a "specific" antiviral activity against any of the viruses tested.