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S Massa

Publications and source records attributed to S Massa.

At least 19 recordsLinked to original sources
PubMed1996

Gene structure and characterization of the murine homologue of the B cell-specific transcriptional coactivator OBF-1.

The B cell-specific activity of immunoglobulin (Ig) gene promoters is to a large extent mediated by the conserved octamer motif ATTTGCAT. This requires the DNA binding octamer factors Oct-1 and/or Oct-2, as well as an additional B cell-restricted non-DNA binding cofactor. We recently cloned such a coactivator specific for Oct-1 or Oct-2 from human B cells and called it OBF-1. Here we report the isolation and characterization of the murine homologue. Full-length cDNA clones as well as genomic clones were isolated and the gene structure was determined. The deduced protein sequence shows that the mouse protein has an identical length, is likewise proline rich and shows 89% overall identity to the human protein. The OBF-1 gene is expressed in a very highly B cell-specific manner and is transcribed in cells representative of all stages of B cell differentiation, including the earliest ones. We show that OBF-1 interacts in the absence of DNA with the POU domain of Oct-1 or Oct-2 and also with the general transcription factors TBP and TFIIB. Furthermore, we demonstrate that although OBF-1 efficiently activates promoter octamer sites, it does not activate enhancer octamer sites.

Amino Acid Sequence↗
PubMed1996

Molecular modeling of azole antifungal agents active against Candida albicans. 1. A comparative molecular field analysis study.

A series of 56 azole antifungal agents belonging to chemically diverse families related to bifonazole, one of the antimycotic drugs of clinical use, were investigated using the comparative molecular field analysis (CoMFA) paradigm. The studied compounds, which have been already synthesized and reported to be active in vitro against Candida albicans, were divided into a training set and a test set. The training set consisted of 40 molecules from all the different structural classes. Due to the lack of experimental structural data on these derivatives, molecular mechanics techniques were used to obtain putative active conformations for all the compounds. the correctness of this molecular modeling work was confirmed a posteriori by comparison with structural data of the analog 2w obtained by X-ray crystallographic analysis (Massa, S.; et al. Eur. J. Med. Chem. 1992, 27, 495-502). Two different alignment rules of the training set molecules were used in this study and are based on the assumption that according to published results on azole antifungal agents, all the studied compounds exert their inhibitory activity through the coordination of their azole moiety to the protoporphyrin iron atom of the fungal lanosterol 14alpha-demethylase enzyme. The predictive ability of each resultant CoMFA model was evaluated using a test set consisting of 16 representative compounds that belong to all the different structural classes. The best 3D-quantitative structure-activity relationship model found yields significant cross-validated, conventional, and predictive r2 values equal to 0.57, 0.95, and 0.69, respectively. The average absolute error of predictions of this model is 0.30 log units, and the structural moieties of the studied antifungal agents which are thought to contribute to the biological activity were identified. The predictive capability of this model could be exploited in further synthetic studies on antifungal azoles. Furthermore, the results obtained by using two different alignments of the inhibitors suggest that the binding mode of these molecules involves both a coordination to the iron protoporphyrin atom and an additional, likewise relevant, hydrophobic interaction with the active site.

Antifungal Agents↗
PubMed1996

2-Sulfonyl-4-chloroanilino moiety: a potent pharmacophore for the anti-human immunodeficiency virus type 1 activity of pyrrolyl aryl sulfones.

The synthesis and the evaluation of cytotoxicity and anti-HIV-1 activity of new aryl pyrrolyl (8) and aryl indolyl (9) sulfones are reported. Preparation of above sulfones was achieved by reacting arylsulfonyl chlorides with substituted pyrroles and indoles or by condensing sulfonamides with 2,5-dimethoxytetrahydrofuran in glacial acetic acid according to the Clauson-Kaas method. Chemical requisites relevant to the anti-HIV-1 activity of these compounds are both a 2-sulfonyl-4-chloroanilino moiety and an alkoxycarbonyl group at position 2 of the pyrrole ring. The best activity and selectivity were obtained with ethoxycarbonyl and isopropoxycarbonyl substituents. Substitutions at the amino group of the pharmacophore moiety led to inactive products (alkylation) or weakened (acylation) anti-HIV-1 activity. Among test derivatives, 16 compounds showed EC50 values ranging between 10 and 1 microM, and five (8b',d',f',h'j') showed EC50S in the sub-micromolar range. The compounds were active against HIV-1, both wild type and AZT-resistant strains, but not against HIV-2. Moreover, in enzyme assays they potently inhibited the HIV-1 recombinant reverse transcriptase, were 10 times less active against enzymes from nevirapine- and TIBO-resistant strains, and were totally inactive against the HIV-2 recombinant enzyme. Interestingly, some compounds (8r'-y') were inactive against the recombinant reverse transcriptase while being active in tissue culture.

Antiviral Agents↗
PubMed1996

Polygenic control of antibody production and correlation with vaccine induced resistance to rabies virus in high and low antibody responder mice.

The amplification of "high" (H) and "low" (L) multispecific antibody responses achieved respectively by H and L lines of selection GP represents a valuable tool in the genetic study of host-infection interactions. These lines were obtained by bidirectional selective breeding for high (HGP) or low (LGP) antibody production to natural complex antigens. HGP and LGP parental lines and reciprocal F1 hybrids, as well as their F2 segregants and backcrosses were submitted to immunization and challenge with rabies virus CVS strain. Acquired resistance was 1000-fold higher in HGP than LGP mice, with a dominance effect to low antibody production observed in F1 hybrids. An association between high antibody response and acquired resistance (P < 0.001) in F2 segregant mice was noticed. The genetic study was performed in these several populations, with a single dose of 104.5-fold LD50 CVS. We could demonstrate 3 independent loci regulating the anti-rabies antibody production, that are distinct, at least in part, from the 10 genes controlling the antigen selection response (sheep erythrocytes) of selection GP.

Animals↗
PubMed1996

5H-pyrrolo[1,2-b] [1,2,5]benzothiadiazepines (PBTDs): a novel class of non-nucleoside reverse transcriptase inhibitors.

With the aim of developing novel inhibitors of human immunodeficiency virus, various derivatives (10-17) related to 5H-pyrrolo[1,2-b] [1,2,5]benzothiadiazepine (PBTD) were prepared and tested in vitro. The title tricyclic derivatives were obtained by intramolecular cyclization of the open-chain intermediate arylpyrrylsulfones, followed by N-alkylation at position 10. Among test derivatives some 10-alkyl-5H-pyrrolo[1,2-b] [1,2,5]benzothiadiazepin-11(10H)-one-5,5-dioxides were found to exert potent and specific activity against HIV-1. In particular, 7-chloro derivatives 11i and j showed a potency comparable to that of nevirapine. However, when the chloro atom was shifted to the 8 position, the related products were scarcely active or totally inactive. Replacement of the pyrrole with pyrrolidine led to inactive products and the reduction of SO2 to S strongly diminished the antiviral potency. PBTD derivatives active in cell cultures were also inhibitory to the recombinant HIV-1 RT in enzyme assays, thus allowing the conclusion that PBTDs are a new class of non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Anti-HIV Agents↗
PubMed1996

Investigation on QSAR and binding mode of a new class of human rhinovirus-14 inhibitors by CoMFA and docking experiments.

A 3-D QSAR study has been carried out on a new class of potent and selective human rhinovirus-14 (HRV-14) inhibitors. In particular, the CoMFA (comparative molecular field analysis) technique has been applied to develop a model able to explain and predict the anti-HRV-14 activity of a class of compounds 4 and potentially helpful to design new and more potent antirhinovirus agents. Docking experiments have also been performed with the aim of elucidating the possible binding mode of these inhibitors. These two approaches are combined to highlight a single, highly favoured mode of interaction of the compounds with the viral capsid proteins.

Antiviral Agents↗
PubMed1996

Synthesis and anti-HIV activity of 10,11-dihydropyrrolo [1,2-b][1,2,5]benzothiadiazepine-11-acetic acid 5,5-dioxide derivatives and related compounds.

The synthesis and the in vitro anti-HIV-1 activity of novel pyrrolo annulated benzothiadiazepine acetic acids and some related derivatives are reported. The new compounds share chemical features with pyrrolo[1,2-d][1,4]benzodiazepin-6-one 1 and Ro 5-3335 pyrrylbenzodiazepinone 4, two inhibitors of HIV-replication at the level of reverse transcriptase (RT) and transcriptional transactivation by Tat, respectively. Two derivatives, namely methyl 10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine-11-acetic-5,5 -dioxide (5a) and 1,12b-dihydro-2H-azeto[2,1-d]pyrrolo[1,2-b][1,2,5]benzoth iadiazepin-2-one 8,8-dioxide (7a), were found to exhibit a significant, although not very potent, activity against human immunodeficiency virus Type 1 (HIV-1).

Antiviral Agents↗
PubMed1995

Antifungal agents. 9. 3-Aryl-4-[alpha-(1H-imidazol-1-yl)arylmethyl]pyrroles: a new class of potent anti-Candida agents.

A new class of potent antifungal agents, namely, 3-aryl-4-[alpha-(1H-imidazol-1-yl)arylmethyl]-pyrroles, is described. These compounds are related to bifonazole and pyrrolnitrin, two compounds belonging to the class of antimycotic drugs. The synthesis of the title pyrroles has been performed starting from 1,3-diaryl-2-propen-1-ones, which were reacted with tosylmethyl isocyanide to give 3-aroyl-4-arylpyrroles. Reduction of the resulting compounds by lithium aluminum hydride furnished the related alcohols, which were treated with 1,1'-carbonyldimidazole to afford the required imidazole derivatives. Forty-four new pyrroles which incorporate an (arylmethyl)imidazole moiety in the 3-arylpyrrole structure were prepared by the above procedure and tested in vitro against Candida albicans and Candida spp. Among test compounds, 10 were found to be highly active against C. albicans. The most active derivative (27) was twice as potent (MIC90) as bifonazole, and its activity was 4 times greater than those of miconazole and ketoconazole. The other nine compounds showed antifungal activity of the same order of that of bifonazole and were ca. 2 times as active as miconazole and ketoconazole. Derivatives 21 and 27 tested in vivo against C. albicans A170 were shown to be highly effective in rabbit skin candidosis. Pharmacological studies on compounds 27 and other related pyrroles (19, 35, 36, 38, 39, and 49) are in progress to select one of them as a potential candidate for clinical experiments.

Adult↗
PubMed1995

Synthesis and anti-HIV-1 activity of thio analogues of dihydroalkoxybenzyloxopyrimidines.

Various thio analogues of dihydroalkoxybenzyloxopyrimidines (DABOs), a new class of non-nucleoside reverse transcriptase inhibitors, were found to selectively inhibit the HIV-1 multiplication in vitro. Among the C-5 H-substituted 6-benzyl-3,4-dihydro-4-oxopyrimidines, the introduction of alkylthio or cycloalkylthio substituents at C-2 of the pyrimidine ring led to derivatives (S-DABOs) which were up to 10-fold more potent than the alkyloxy or cycloalkyloxy counterparts. The further introduction of a methyl group at the 3'-position of the benzyl portion of 2-(alkylthio)-6-benzyluracils reduced the cytotoxicity leading to more selective compounds. Among C-5 methyl-substituted S-DABOs, numerous derivatives showed EC50 values as low as 0.6 microM and lacked cytotoxicity at doses as high as 300 microM. In the C-5 double methyl-substituted series, a more pronounced cytotoxicity was observed and the further introduction of a methyl at the 3'-position in the benzylidene group resulted in total loss of antiviral activity. S-DABOs, namely 2-(alkylthio)-6-benzyl-3,4-dihydro-4-oxopyrimidines, were synthesized by reacting proper methyl (phenylacetyl)acetates or their 2-methyl compounds with thiourea to afford 6-benzyl-4-oxo-1,2,3,4-tetrahydro-2-thiaoxopyrimidines or the related 5-methyl derivatives. Treatment of the latter derivatives with alkyl or cycloalkyl halides in alkaline medium gave the required title compounds.

Antiviral Agents↗
PubMed1995

[[[(Thienylcarbonyl)alkyl]oxy]phenyl]- and [[[(pyrrylcarbonyl)alkyl]oxy]phenyl]oxazoline derivatives with potent and selective antihuman rhinovirus activity.

As an approach to more extensive structural modifications of [(oxazolylphenoxy)alkyl]isoxazoles, we synthesized new compounds characterized by the replacement of the isoxazole nucleus with furan, pyrrole, and thiophene rings and by the presence of a ketocarbonyl group in the aliphatic chain connecting these pentatomic heterocycles to the 4-(4,5-dihydro-2-oxazolyl)phenoxy, 4-(ethoxycarbonyl)phenoxy, and 4-carboxyphenoxy moieties. Some pentamethylene derivatives were also prepared, and their antirhinovirus activity was compared to that of the corresponding ketomethylene derivatives. Syntheses were carried out by Friedel-Crafts acylation of the above pentatomic heterocycles and subsequent reaction of chloroalkyl ketones with the proper 4-substituted phenol. Reduction of the ketone function afforded the related polymethylene derivatives. The new compounds were tested for antirhinovirus activity and cytotoxicity in comparison with WIN 51711, used as reference drug. Inspection of the structure-activity relationships revealed that the thiophene ring and the carbonyl group are the structural components which to a large extent contribute to the positive biological profile in terms of both wideness of spectrum and low cytotoxicity. Among the various derivatives, compounds 8e,d showed in vitro the same potency of WIN 51711 but a cytotoxicity at least 10 times lower.

Antiviral Agents↗
PubMed1995

Synthesis of pyrryl aryl sulfones targeted at the HIV-1 reverse transcriptase.

Various aryl 1-pyrryl sulfones were synthesized and tested as inhibitors of HIV-1. 2-Nitrophenyl-2-ethoxycarbonyl-1-pyrryl sulfone, the most active among test derivatives, was selected as lead compound of the aryl pyrryl sulfone series. The in vitro anti-HIV-1 activity and cytotoxicity of 41 compounds is reported. Some structure-activity relationships are discussed also in comparison with the known NPPS (2-nitrophenyl phenyl sulfone).

Cell Survival↗
PubMed1995

Drug resistant bacteria in non carbonated mineral waters.

The presence of antibiotic resistant bacteria was revealed among bacteria isolated from non carbonated mineral waters bottled in plastic (PVC) and in glass containers. Heterotrophic plate count values ranged between < 10 and 4.3 x 10(3) and between < 10 and 1.2 x 10(4) colony forming units/ml for the waters bottled in PVC and glass, respectively. The greatest resistance to a single antibiotic, 39.1% of 320 isolates from mineral waters, was found for nalidixic acid. Resistance to the other antibiotics was as follows: ampicillin (26.2%), bacitracin (19.7%), cotrimoxazole (18.7%), streptomycin (15.0%), tetracycline (14.4%), gentamycin (11.6%), chloramphenicol and rifampin (9.7%). The strains resistant to two or more antibiotics (multiple antibiotic resistant, MAR) provided 51% of the total isolates. Identification of 127 MAR strains showed that in the mineral waters gram-positive cocci dominated. The second, third and fourth group of identified MAR phenotypes were, in order to importance, gram-negative non-fermentative rods, gram-positive rods and gram-negative fermentative rods. The importance of the antibiotic resistant bacteria in mineral water is discussed.

Anti-Bacterial Agents↗
PubMed1995

Antifungal agents. 10. Synthesis and antifungal activities of aryl-(1H-imidazol-1-yl)-(isoquinolin-1-yl) methane derivatives.

Various aryl-(1H-imidazol-1-yl)-(isoquinolin-1-yl)methane derivatives have been synthesized and tested as antifungal agents. The new imidazoles have been obtained by the action of 1,1'-sulfinyldiimidazole on aryl-(isoquinolin-1-yl)carbinols, which have been prepared by standard procedures starting from isoquinoline. Among 44 test derivatives only a few have exhibited some antifungal activity, the most active compound (4e) being twofold less potent than miconazole, ketoconazole and bifonazole, used as standard drugs.

Antifungal Agents↗
PubMed1994

The effect of some antibiotics on Enterococcus faecium SF 68 inoculated in germ-free mice.

A strain of Enterococcus faecium SF 68 (sensitive to penicillin, tetracycline, virginiamicin and tylosin, but resistant to streptomycin) was administered to five groups of germ-free mice. Each group was subsequently given 40 micrograms/ml and then 80 micrograms/ml of a single antibiotic. The following determinations were made: a) colonization of the bacterial strain before and after administration of the antibiotic and b) the MICs in the original strain and after administration of the antibiotic (80 micrograms Iml). The results show that in the mice treated with streptomycin, colonization is not influenced by the antibiotic treatment; in mice treated with antibiotics to which the strain is sensitive, the colonization increases in proportion to the level of the antibiotic resistance (tylosin and tetracycline).

Animals↗
PubMed1994

Characterization of the anti-HIV-1 activity of 3,4-dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs), new non-nucleoside reverse transcriptase inhibitors.

Novel 3,4-dihydro-6-benzyl-4-oxopyrimidines (DABOs), variously substituted at both the C-2 and C-5 positions of the pyrimidine ring, proved to be specific inhibitors of the human immunodeficiency virus type 1 (HIV-1) in vitro. Some compounds showed potency at micromolar doses, no cytotoxicity at the maximum testable doses and selectivity indexes comparable to that of 2'-3'-dideoxyinosine (ddI). Mode of action studies suggested that DABOs interfered with a step of the virus multiplication cycle following adsorption and preceding integration. Enzyme assays indicated that DABOs targeted HIV-1 reverse transcriptase: they inhibited the RNA-dependent DNA polymerase activity in a template-dependent manner and, to a lesser extent, the DNA-dependent DNA polymerase activity. No inhibition of the RNase-H associated activity was observed. When DABOs were assayed in combination with 3'-azido-3'-dideoxythymidine (AZT) or ddI against HIV-1 in cell cultures, a slightly synergistic inhibitory effect was observed. The combination of DABO 546 and AZTTP in enzyme assays showed that the two compounds were kinetically mutually exclusive.

Antiviral Agents↗
PubMed1994

Antifungal agents. VIII. Synthesis and antifungal activities of bipyrryl analogues of bifonazole.

Various bipyrryl analogues of bifonazole were synthesized starting from aryl-3-pyrryl-1-imidazolylmethanes. The introduction of a second pyrryl portion was performed by linking an acrylate moiety at 1-position of the pyrrole ring and then by treatment with TosMIC. The bipyrryl esters were hydrolyzed and decarboxylated to afford the required imidazoles. All new imidazole derivatives were tested against Candida albicans and Candida spp using as standard controls miconazole, bifonazole and ketoconazole.

Antifungal Agents↗
PubMed1993

Antifungal agents, II: Synthesis and antifungal activities of aryl-1H-pyrrol-2-yl-1H-imidazol-1-yl-methane derivatives with unsaturated chains.

The synthesis and antifungal activities of aryl-1H-pyrrol-2-yl-1H-imidazol-1-yl-methanes having allyl, crotyl, and acrylate chains linked to the N-pyrrole atom and substituted at phenyl ring by Cl, F, CH3, and NO2 groups are reported. In vitro tests against Candida albicans and Candida spp. showed 2,4-dichlorophenyl-1-allyl-1H-pyrrol-2-yl-1H-imidazol-1-yl-methane to be the most potent derivative with activities comparable to those of ketoconazole and slightly inferior to those of bifonazole and miconazole. Some structure-activity relationships are discussed.

Antifungal Agents↗