7-Nitrobenzofurazan (NBD) derivatives of 5'-N-ethylcarboxamidoadenosine (NECA) as new fluorescent probes for human A(3) adenosine receptors.

New fluorescent ligands for adenosine receptors (ARs), obtained by the insertion, in the N(6) position of NECA, of NBD-moieties with linear alkyl spacers of increasing length, proved to possess a high affinity and selectivity for the A(3) subtype expressed in CHO cells. In fluorescence microscopy assays, compound 2d, the most active and selective for human A(3)-AR, permitted visualization and localization of this human receptor subtype, showing its potential suitability for internalization and trafficking studies in living cells.

Design, synthesis, and characterization of the antitumor activity of novel ceramide analogues.

A deficiency in apoptosis is one of the key events in the proliferation and resistance of malignant cells to antitumor agents; for these reasons, the search for apoptosis-inducing drugs represents a valuable approach for the development of novel anticancer therapies. In this study we report the first example of conformationally restrained analogues of ceramide (compounds 1-4), where the polar portion of the molecule has been replaced by a thiouracil (1, 3) or uracil (2, 4) ring. The evaluation of their biologic activity on CCRF-CEM human leukemia cells demonstrated that the most active was compound 1 followed by compound 2 (mean 50% inhibition of cell proliferation [IC(50)] 1.7 and 7.9 microM, respectively), while compounds 3 and 4 were inactive, as were uracil, thiouracil, and 5,6-dimethyluracil, the pyrimidine moieties of compounds 1-4. For comparison, the IC(50) of the reference substance, the cell-permeable C2-ceramide, was 31.6 microM. Compounds 1 and 2 and C2-ceramide were able to trigger apoptosis, as shown by the occurrence of DNA and nuclear fragmentation, and to release cytochrome c from treated cells. The treatment of female CD-1 nu/nu athymic mice bearing a WiDr human colon xenograft with the most active compound 1 at 2, 10, 50, and 200 mg/kg ip daily for 10 days resulted in an antitumor effect that was equivalent at 50 mg/kg or superior (200 mg/kg) to that of cyclophosphamide, 20 mg/kg ip daily, delivered on the same schedule, with markedly lower systemic toxicity. In conclusion, the present study demonstrates that the new ceramide analogues 1 and 2 are characterized by in vitro and in vivo antitumor activity and low toxicity.

Stereoselective synthesis of 2-hydroxy-alpha-mannopyranosides from glucal donors.

[figure: see text] Direct synthetic access to 2-hydroxy-alpha-mannopyranosides from glucal donors is accomplished via a one-pot stereoselective oxidative glycosylation reaction, employing the reagent combination of dibenzothiophene bis(triflate) and dibenzothiophene-5-oxide.

Synthesis and antiviral properties of novel analogues of monophosphate and diphosphate bioactive forms of acyclovir.

New analogues (compounds 6, 7 and 9) of the mono- (8) and diphosphate (10) bioactive forms of the antiherpes drug acyclovir are described. In compound 6, the monophosphate moiety of 8 was replaced by an aminosulfonyloxy group, while in compounds 7 and 9, a phosphonoacetamidoxy and an O-ethyl phosphonoacetamidoxy moiety are, respectively present instead of the diphosphate one of 10. None of the compounds synthesized proved to possess an appreciable activity on herpes simplex virus (HSV) or human immunodeficiency virus (HIV).

Synthesis and antiviral properties of 9-[(2-methyleneaminoxyethoxy)methyl]guanine derivatives as novel Acyclovir analogues.

This paper reports the synthesis and the antiviral properties of a series of 9-[(2-methyleneaminoxyethoxy)methyl]guanine derivatives, which can be viewed as analogues of the antiherpes drug Acyclovir (ACV) from which they differ in the replacement of its hydroxy group with variously substituted methyleneaminoxy moieties. Some of the newly synthesized compounds proved to possess a certain activity against HSV-1, albeit lower than that of ACV.

Acetamidoglycosylation with Glycal Donors: A One-Pot Glycosidic Coupling with Direct Installation of the Natural C(2)-N-Acetylamino Functionality.

Nitrogen transfer to glycals: A new method for direct C2-aza-glycosylation with glycal donors has been developed (see scheme), employing the new reagent combination of thianthrene-S-oxide and trifluoroacetic anhydride for glycal activation, in an overall one-pot procedure.

Mutagenicity of hexahydrophenanthrenes and their oxirane derivatives.

The mutagenicity of some hexahydrophenanthrenes and their corresponding arene oxides was assayed in histidine-dependent mutants of Salmonella typhimurium TA98 and TA100. All the arene epoxides examined were devoid of mutagenic activity, although some of them could alkylate nicotinamide. By contrast, the 1,2,3,9,10, 10a-hexahydrophenanthrene, trans-1,2,3,4,4a,10a-hexahydrophenanthrene, 9-methyl-, 6-methoxy-trans-1,2,3,4,4a,10a-hexahydrophenanthrene, 7-bromo-trans-1,2,3,4,4a,10a-hexahydrophenanthrene and 9-methyl-trans-1,2,3,4,4a,10a-hexahydrophenanthrene were active as mutagens in the presence of S9 mix. A negative result was obtained with octahydrophenanthrene, suggesting that the benzylic double bond is a prerequisite for the mutagenic activities of hexahydrophenanthrenes. Thus, probably a very reactive intermediate (aryloxirane) formed by a secondary metabolism following the primary oxidation of the benzylic double bond by S9 mix could be responsible for the mutagenicity of the hexahydrophenanthrenes.

An 1,2,3-triazole derivative bioisoster of a potent in vitro prostaglandin synthesis inhibitor: preparation and biological activity.

This paper reports the preparation of the triazole ester 10, a methylenic bioisoster of an oxygenated compound A, effective inhibitor of the prostaglandin synthesis in vitro. Biological evaluation of 10 and of the corresponding acid 9 shows that the compounds maintain a good enzymatic inhibitory activity compared with indomethacin and aspirin.