Publications

A series of new ether lipid-3'-azido-3'-deoxythymidine (AZT) conjugates (11a-g) were synthesized and evaluated for anti-HIV activity. The effect of chirality on the antiviral activity was examined through the synthesis of AZT conjugates bearing alkoxypropanols in the lipid portion of the molecule (11a-d). In addition, the long alkyl chain of alkoxyethyl ether lipid-AZT analogs was replaced with aromatic groups (11e-g), and the effect of this structural modification on activity is reported. The results of the biological tests indicate that analogs with a methyl group alpha to the phosphate moiety (11c,d) exhibit a marked degree of stereoselectivity with regard to their anti-HIV activity. Also, replacement of the long alkyl chain with aromatic groups in the oxyalkyl ether phospholipid-AZT conjugates leads to substantially more potent compounds (11e-g) with an anti-HIV activity comparable to that of AZT.

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A series of 2-(4-methylbenzyl)-5,6-substituted-imidazo[2,1-b][1,3,4]thiadiazole derivatives were synthesized, characterized and evaluated for antiproliferative activity and cancer chemopreventive activity. Results showed that molecules with formyl and thiocyanate substiments at the 5 position exhibited an increase in activity against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions. Derivative 22 displayed significant in vino anticancer activity against colon cancer (MID GI₅₀ = 0.75 μM). The cancer chemopreventive effect of 19 (IC₅₀ = 489 nM) was almost equipotent to standard oleanolic acid (IC₅₀ = 449 nM).

After laser powder bed fusion (LPBF) of an ultra-strong in situ TiC whisker reinforced β-Ti composite, this paper investigates the evolution of microstructure and mechanical properties in response to heat treatment at different temperatures. Using in depth nano-SEM and TEM analyses, it is shown that ageing at 400 °C rounds the whiskers, annihilates the strain fields and grows Mo segregated nano-cells, but without improving the ductility. In contrast, ageing at 600 °C enables the transformation of metastable β to a lamellar β + α, leading to a dual phase matrix embedding TiC particles. This is in such a manner that extra ageing at 600 °C coalesces the nano-lamellar α + β microstructure to form a coarser micro-lamellar α + β matrix. This microstructure achieves 66 % of the compressive deformation of Cp-Ti, and over 1400 MPa compressive strength after 1 h of ageing at 600 °C. Despite this success under compression, hard and stiff TiC particles may still cause large spherical fractured voids, severely limiting the plastic deformation under tension.

In 1988, the World Health Assembly launched the Global Polio Eradication Initiative, which aimed to use large-scale vaccination with the oral vaccine to eradicate polio worldwide by the year 2000. Although important progress has been made, polio remains endemic in several countries. Also, the current control measures will likely be inadequate to deal with problems that may arise in the postpolio era. A panel convoked by the National Research Council concluded that the use of antiviral drugs may be essential in the polio eradication strategy. We here report on a comparative study of the antipoliovirus activity of a selection of molecules that have previously been reported to be inhibitors of picornavirus replication and discuss their potential use, alone or in combination, for the treatment or prophylaxis of poliovirus infection.

5-Formyl-2'-deoxyuridine (2a), an effective inhibitor of herpes simplex virus type 1 or 2 (HSV-1, HSV-2) and vaccinia virus, was converted to the oxime (3a) and dithiolane (4a) derivatives. The oxime (3a) was equally as potent as the formyl compound against HSV-1, but one-fifth as active against HSV-2, 100 times less effective against vaccinia, and 25 times less toxic for the host cells. In addition, compound 3a was about 10 times less active than 2a in inhibiting thymidylate synthetase in vivo (as reflected by a differential inhibition of dThd and dUrd incorporation into host cell DNA). The dithiolane (4a) did not exert an appreciable effect on either virus multiplication or dThd or dUrd incorporation, nor was it cytotoxic. All these compounds as their 5'-phosphate derivatives were potent in vitro inhibitors of thymidylate synthetase (Lactobacillus casei). The inhibition was competitive with substrate with Ki/Km ratios of 0.05 for the formyl 2b, 0.5 for the oxime 3b, and 0.2 for the dithiolane 4b. Thus, 3b was 10 times less active than 2b as an in vitro inhibitor of thymidylate synthetase, which appears to corroborate the in vivo findings.

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) are part of the combination therapy currently used to treat HIV infection. Based on analogy with known HIV-1 NNRT inhibitors, 18 novel alkenyldiarylmethanes (ADAMs) containing 5-chloro-2-methoxyphenyl, 3-cyanophenyl, or 3-fluoro-5-trifluoromethylphenyl groups were synthesized and evaluated as HIV inhibitors. Their stabilities in rat plasma have also been investigated. Although introducing 5-chloro-2-methoxyphenyl or 3-fluoro-5-trifluoromethylphenyl groups into alkenyldiarylmethanes does not maintain the antiviral potency, the structural modification of alkenyldiarylmethanes with a 3-cyanophenyl substituent can be made without a large decrease in activity. The oxazolidinonyl group was introduced into the alkenyldiarylmethane framework and found to confer enhanced metabolic stability in rat plasma.

Long-term treatment with ritonavir is associated with the emergence of multiple mutations in the HIV-1 protease gene. The mutations L10I, I54V, L63P, A71V, V82A/F and I84V correspond to known drug-resistance mutations for ritonavir and other protease inhibitors. Phenotypic resistance to ritonavir was detected in a majority of ritonavir-treated patients at 1 year of treatment. In addition, long-term ritonavir treatment selects for cross-resistance to the protease inhibitors indinavir and saquinavir. This argues against sequential therapy with several protease inhibitors. Delayed resistance in one patient was accompanied with a prolonged increase in CD4 cell count and decrease in viral load suggesting a temporary benefit of treatment.