Publications

(E)-5-(2-Iodovinyl)-2'-deoxyuridine (IVDU), its 2'-fluoro-substituted derivatives IVFRU (with fluorine in the ribo configuration), IVFAU (with fluorine in the ara configuration), and the corresponding 3'-chemical delivery system (CDS), or 3'-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)- substituted derivatives IVDU-CDS, IVFRU-CDS and IVFAU-CDS were evaluated for their cytostatic activity against wild-type (FM3A/O), thymidine kinase (TK)-deficient (FM3A/TK-), and herpes simplex virus type 1 (HSV-1) or HSV-2 thymidine kinase (tk) gene-transfected murine mammary carcinoma FM3A cells (FM3A TK-/HSV-1 TK+ and FM3A TK-/HSV-2 TK+). The test compounds proved highly inhibitory to the proliferation of HSVtk gene-transfected FM3A cells. Their cytostatic activity was within the 0.002 to 0.80 microM range, a compound concentration that is 1000- to 10,000-fold lower than that required to inhibit proliferation of wild-type FM3A/O cells. The target for the cytostatic activity of the test compounds is the cellular thymidylate synthase. In contrast to the parent IVDU compound, IVFRU and IVFAU and their CDS-substituted derivatives proved resistant to phosphorolytic cleavage by human and bacterial thymidine phosphorylase and should be considered as promising candidate compounds for further evaluation for combined gene/chemotherapy of HSVtk gene-transfected tumor cells in animal models.

A series of 3,4,5-trisubstituted isothiazoles has been screened against HIV-1 (III B ) and HIV-2 (ROD) at sub-toxic concentrations in acutely infected MT-4 cells. Among the tested compounds, only 3-mercapto-5-phenyl-4-isothiazolecarbonitrile was found to inhibit the replication of HIV-1 (III B ) and HIV-2 (ROD) at 50% effective concentrations (EC 50 ) of 7.8 and 9.7 μg/ml, respectively. The presence of a thioalkyl chain or dialkylamino function in the 3-position caused a loss of anti-HIV activity. New 4-cyano-5-phenylisothiazoles with other substituents in the 3-position have also been synthesized and studied as potential anti-HIV agents. Our results have demonstrated that 5-phenyl-3-(4-cyano-5-phenylisothiazol-3-yl) disulphanyl-4-isothiazolecarbonitrile and S-(4-cyano-5-phenylisothiazol-3-yl)- O-ethyl thiocarbonate are effective against both HIV-1 (III B ) (EC 50 =13.6 and 15.2 μg/ml, respectively) and HIV-2 (ROD) (EC 50 =17.4 and 13.4 μg/ml, respectively).

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Background In 2009, the Care Trajectory (CT) project - a nation-wide quality improving program enabling the reimbursement of self monitoring of Blood Glucose, patient education and structured shared care between generalist and specialist care - was set up in Belgium. Patients with Diabetes Mellitus Type 2 (T2DM), HbA1c > 7% (53 mmol/l) and in need for insulin or incretin therapy were allowed to enroll in a CT. The ongoing computerized primary care based morbidity registration network ‘Intego’, part of the Ambulatory Care …

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.

In our continued efforts to discover more active and less toxic HIV-1 non-nucleoside reverse transcriptase inhibitors, we recently designed a novel series of piperidine-linked pyridine analogues on the basis of diarylpyrimidine derivatives, among which two drugs-etravirine and rilpivirine-are approved for use by the US FDA. The title compounds were evaluated for activity against wild-type and resistant mutant strains of HIV-1 as well as HIV-2 in MT-4 cells. The highly potent compound BD-c1 (EC50 =10 nM, CC50 ≥146 μM, SI≥14 126) displays lower cytotoxicity and higher selectivity than etravirine (EC50 =2.2 nM, CC50 =28 μM, SI=12 884) against wild-type HIV-1. Compound BD-e2 (EC50 =5.1 nM) shows greater antiviral efficacy against wild-type HIV-1 than do the four reference drugs nevirapine, delavirdine, efavirenz, and zidovudine. Many compounds were also found to be active against the frequently observed drug-resistant double mutant (K103N+Y181C) HIV-1 strain. Herein we report the design, synthesis, anti-HIV evaluation, preliminary structure-activity relationships, and molecular simulations of novel piperidine-linked pyridine analogues.

Mice bearing sarcoma 180 tumors were irradiated by 3000-MHz microwave at a power density of 40 mW/cm/sup 2/ for 2 h daily during 14 consecutive days. The irradiation resulted in an increase of rectal temperature of 3-4/spl deg/C. Hyperthermal treatment was started on the second day after tumor-cell transplantation. Some of the animals also received daily injections of polyhiboinosinic acid-polyribocytidylecacid (poly I-poly C), 2 mu g/g, or of mouse interferon (100 IU/g), or of both. Survival of the animals, mass of the tumors, incorporation of tritiated thymidine, uridime and glycine into the tumor tissue, and intracellular levels of cyclic AMP were determined. Microwave hyperthermia resulted in a prolongation of the survival of tumor-bearing mice, a regression of tumors in 12 out of 24 mice, and a decreased incorporation of thymidine and glycine. The inhibitory effect of microwave hyperthermia was enhanced by simultaneous treatment with poly I-poly C and mouse interferon. Combination of microwave hyperthermia and poly I-poly C and interferon treatment resulted in a regression of sarcoma 180 tumors in 16 out of 24 animals. No tumor regression was observed in the control group.

Synthesis of 1,2,4,6-thiatriazine 1,1-dioxide nucleosides is now reported for the first time. In order to know the conformation of the nucleosides, a NMR study has been carried out. Anti-HIV-1 and HIV-2 properties of the nucleosides have been tested. These compounds have not shown activity at subtoxic concentrations.