Contribution of the anomeric effect to the solution and crystal structure of [1S,2S,6S,7s]-1,6-diaza-4,9-dioxa-2,7-dimethoxycarbonylbicyclo[4.4.1]undecane, a condensation product of L-serine methyl ester with formaldehyde.

The reaction of L-serine methyl ester hydrochloride (1) with paraformaldehyde (2) in dichloromethane in the presence of triethylamine afforded a novel compound: [lS,2S,6S,7S]-1,6-diaza-4,9-dioxa-2,7-dimethoxycarbonylbicyclo[4.4.1]undecane (4) as a 2:3 adduct of 1 with 2. 1H and 13C NMR spectroscopy were unable to discriminate between two possible symmetrical structures. The latter was unambiguously proved by X-ray crystallography. The crystal structure established: (i) the existence of two identical seven-membered rings each containing a N-C-O grouping; (ii) the existence of a long C-O-C-N-C-N-C-O-C sequence in which each nitrogen belongs simultaneously to a N-C-O (oxazolidine) and to a N-C-N (aminal) motifs; (iii) the existence of a chair-like conformation for both seven-membered rings; (iv) the antiperiplanar geometry of pN-C-O and consequently the manifestation of a strong anomeric effect in both N-C-O groupings, whereas anomeric effect was virtually absent in the N-C-N sequence, as corroborated by bond distances and bond angles. Chemical shifts, coupling constants and NOE effects confirm that the conformational features of 4 are preserved in solution.

Anomeric effects in non-carbohydrate compounds: conformational differences between the oxazolidine rings of a cis-fused bicyclic system.

Tris(hydroxymethyl)aminomethane (Tris) can react with benzaldehyde (1:2 molar ratio) to produce cis-2,8-diphenyl-5-hydroxymethyl-1-aza-3,7-dioxabicyclo[3.3.0]octa ne, the structure of which has been confirmed by nuclear magnetic resonance spectroscopy and X-ray crystallography. The crystal structure showed that both oxazolidine rings A and B are puckered in opposite directions. Ring A exists in an E3 envelope form with 0-3 noticeably down (0.65 A) the plane of the remaining atoms, whereas ring B adopts the 7E envelope conformation with the 0-7 atom displaced up from the mean reference plane by 0.70 A. Comparison of bond angles and bond distances showed that both oxazolidine rings A and B exhibit cross endo-anomeric effects resulting from electron delocalization over the bond sequence O-3-C-2-N-1-C-8-O-7.

Polyanion inhibitors of HIV and other viruses. 7. Polyanionic compounds and polyzwitterionic compounds derived from cyclodextrins as inhibitors of HIV transmission.

New polyanionic compounds were obtained from radical addition of thiomalic acid and mercaptopropionic acid onto perallylated cyclodextrins (CDs) under UV irradiation with a catalytic amount of alpha,alpha'-azobis(isobutyronitrile). All these polyanions, bearing 18-48 carboxylate groups, inhibited human immunodeficiency virus type 1 (HIV-1) strain IIIB replication in MT-4 cells at a 50% inhibitory concentration (IC50) of 0.1-2.9 microM, while not being toxic to the host cells at concentrations up to 62 microM. These compounds were also active against a clinical HIV-1 isolate (HE) at >/=4-fold higher concentrations. Only some compounds showed activity against the two HIV-2 strains (ROD and EHO) but at higher concentrations than those required to inhibit HIV-1 (IIIB and HE) replication. In addition, these compounds were not active against the M-tropic HIV-1 strain BaL but were active against simian immunodeficiency virus [SIV (MAC251)]. These compounds were also inhibitory to the replication of human cytomegalovirus at an IC50 of 1-10 microM, but not herpes simplex virus (type 1 and type 2) or other (picorna-, toga-, reo-, orthomyxo-, paramyxo-, bunya-, rhabdo-, and poxvirus) viruses. Radical addition on perallylated CDs of a protected cysteine gave polyzwitterionic compounds. None of these last compounds proved inhibitory to the replication of HIV-1, HIV-2, or any of the other viruses tested.

Polyanion inhibitors of human immunodeficiency virus and other viruses. 5. Telomerized anionic surfactants derived from amino acids.

omega-Acryloyl anionic surfactants, whose polar heads are derived from amino acids, have been telomerized to prepare polyanions of a predetermined molecular weight. The main goal of this study was to verify whether the antiviral activity is influenced by the degree of polymerization of the polyanions. The oligomeric polyanions were evaluated for their activity against human immunodeficiency virus (HIV-1 or HIV-2) and various other RNA and DNA viruses. With regard to their anti-HIV activity, a minimum number of anionic groups was necessary to achieve an inhibitory effect. Moreover, to be active the overall conformation of the polyanion must be such that the anionic groups are located on the external site of the molecule. With some of the polyanions, a 50% inhibition concentration (IC50) as low as 1 microgram/ mL, or even 0.1 microgram/mL, was noted against HIV-1 in CEM-4 and MT-4 cells, respectively. The most potent polyanions also proved active against human cytomegalovirus and herpex simplex virus at concentrations of 5-10 and 20-40 micrograms/mL, respectively. No activity was observed against any of the other viruses tested (i.e., vesicular stomatitis, Sindbis, Semliki forest, parainfluenza, Junin, Tacaribe, Coxsackie, polio, reo, and vaccinia). No toxicity for the host cells was observed at concentrations up to 200 micrograms/mL.

Polyanion inhibitors of human immunodeficiency virus and other viruses. 6. Micelle-like anti-HIV polyanionic compounds based on a carbohydrate core.

A new class of polyanionic compounds, inhibitors of human immunodeficiency virus, was obtained from radical addition of mercapto acid or mercapto ester on a perallylated carbohydrate under UV irradiation with a catalytic amount of AIBN. Unlike the polyanions that we have previously prepared by polymerization reactions, the compounds are structurally well defined. Polyanions bearing 16 carboxylate groups showed a 50% inhibitory concentration (IC50) of 0.1-4.1 micrograms/mL against HIV-1 in MT-4 cells while not being toxic to the host cells at concentrations up to 125 micrograms/mL. The most potent polyanions also proved active against human cytomegalovirus at concentrations of 1-14 micrograms/mL. No activity was observed against any of the other viruses tested (i.e., herpes simplex virus, vesicular stomatitis virus, Sindbis, Semliki forest, parainfluenza-3, Junin, Tacaribe, Coxsackie B4, polio-1, reo-1, or vaccinia virus).

Synthesis and biological activity of acylated and telomerized peptides as potential HIV-fixation inhibitors.

In order to inhibit the gp 120-CD4 glycoprotein interaction, a key step of the HIV-infection, we have synthesized a series of N-acylated peptides containing sequences identified in both the viral and lymphocytic proteins, (SDFR, SDAR, RFDSAARFDS, DRADSRRS, PSKLNDRADSRRSLWD, ASTTTNYT). An hydrophobic moiety (capryloyl, palmitoyl acrylamidoundecanoyl) was introduced in the last step of interactive synthesis, in homogeneous or solid phase. The acrylogyl-containing compounds were then telomerized under UV irradiation (DPn observed: 2 to 6). The biological evaluation shown an antiviral effect in vitro for telomerized peptides containing amino diacids such as Glu and Asp.

Polyanion inhibitors of human immunodeficiency virus and other viruses. Part 2. Polymerized anionic surfactants derived from amino acids and dipeptides.

A series of new polyanions was synthesized via gamma-polymerization, in aqueous micellar solution, of omega-unsaturated anionic surfactants whose polar head was derived from amino acids or dipeptides. The obtained polyanions were evaluated for their activity against human immunodeficiency virus (HIV-1, HIV-2) and various other RNA and DNA viruses. All the test compounds proved active against HIV-1 and HIV-2, their 50% inhibitory concentration (IC50) being in the range of 0.04-7.5 micrograms/mL, while they were not toxic to the host cells (CEM-4 or MT-4) at concentrations up to 100 micrograms/mL or higher. The HIV-inhibitory effect increased with the hydrophilic character of the amino acid moiety. The compounds were found to interact with both the viral envelope glycoprotein gp120 and the cellular CD4 receptor, thus blocking virus-cell binding and virus-induced syncytium formation. These polyanions also proved active against human cytomegalovirus at about the same IC50 as for HIV. In addition, they were also active, albeit at somewhat higher IC50 values (0.8-20 micrograms/mL), against other enveloped viruses such as respiratory syncytial virus and arenaviruses (Junin and Tacaribe). At yet higher IC50 values ( > or = 20 micrograms/mL), some of the compounds showed activity against influenza A virus. No activity was observed with any of the compounds against vesicular stomatitis virus, Sindbis virus, Semliki forest virus, influenza B, parainfluenza type 3, and the nonenveloped viruses Coxsackie type B4, polio type 1, and reovirus type 1.

Polyanion inhibitors of human immunodeficiency virus and other viruses. 1. Polymerized anionic surfactants.

A series of polyanionic compounds was synthesized and evaluated for their activity against human immunodeficiency virus (HIV-1, HIV-2) and various other RNA and DNA viruses. Several compounds, i.e., 2p, 3p, 8p, 13p, 14p, 15p, 17p, 18p, and 19p, proved active against HIV-1 within the concentration range of 0.1-3 micrograms/mL while not being toxic to the host cells (CEM, MT-4) at concentrations up to 100 micrograms/mL or higher. As a rule, these polyanionic compounds proved also active, albeit at somewhat higher concentrations than those required for HIV-1 inhibition, against a number of other enveloped viruses, including HIV-2, human cytomegalovirus, influenza A virus, respiratory syncytial virus, and arenaviruses (Junin and Tacaribe). Among the most potent HIV-1 inhibitors ranked compounds 18p and 19p, the sodium salts of N-methylamides obtained by polymerization of monomers prepared starting from 10-undecenoyl chloride and omega-aminoalkanoic acids.