Delineation of the human hematolymphoid system: potential applications of defined cell populations in cellular therapy.

Hematopoietic stem cells (HSC) have the capacity to reconstitute all the blood cells in the body. HSC are rare, representing on average 0.05% of the mononuclear cells present in healthy human bone marrow. Due to their capacity for self-renewal and their pluripotent, long-term reconstituting potential, HSC are considered ideal for transplantation to reconstitute the hematopoietic system after treatment for various hematologic disorders or as a target for the delivery of therapeutic genes. Human HSC also have potential applications in restoring the immune system in autoimmune diseases and in the induction of tolerance for allogeneic solid organ transplantation. With the increased interest in human HSC for clinical applications, technology for the isolation of candidate HSC and knowledge of human hematopoiesis have been growing rapidly. In this article, we discuss the functional characterization of a human CD34+Thy-1+ HSC population which is essentially free of residual disease, our efforts to generate alternate monoclonal antibodies for the isolation of clinically useful stem or progenitor cell populations, and the identification of a novel lymphoid progenitor as part of an exploration towards defining progenitors with potential application as adjuncts to HSC-based cellular therapy.

[Trypanocidal structure- activity relationship in 9-thioalkylacridines]. / Relations structure-activité trypanocide chez les 9-thioalkylacridines.

A set of 9-thioalkylacridinones, has been prepared and investigated "in vitro" against T. cruzi. Structure-antiparasitic activity relationships are detailed with a view to identify the major structural parameters for the activity under consideration.

Antimicrobial activity of 9-oxo and 9-thio acridines: correlation with interacalation into DNA and effects on macromolecular biosynthesis.

The antimicrobial activity of several new 9-acridinones and 9-thioalkylacridines towards Escherichia coli, Staphylococcus aureus, Mycobacterium smegmatis and Candida albicans was investigated. Minimal inhibitory, bactericidal and fungicidal concentrations were determined using a microplate assay which enabled inhibitory, bactericidal and fungicidal indices to be calculated. These indices facilitated structure/activity relationship studies. DNA-intercalating capability and DNA supercoiling inhibitory effects as well as inhibitory effects on macromolecular synthesis were determined. Results showed that intercalation into DNA, which is the mechanism of action usually postulated for acridines, cannot be correlated with the properties examined. However, inhibition of RNA synthesis may be involved in the antimicrobial activity of the drugs.

Immunomodulating effect of acridine tautomers on eukaryotic cells.

The immunomodulating effect of some new amino- and imino-acridine derivatives, were investigated on antibody dependent cellular cytotoxicity (ADCC) and induced-blast transformation of lymphocytes. In different concentrations (2.0 x 10(-6) M, 4.0 x 10(-8) M and 2.0 x 10(-5) M) the drugs produced a suppression of PHA and ConA induced cell proliferative response except in the case of 2b, 2d and 2g amino-acridines. The suppressive effects were dose dependent and exhibited a higher inhibitory level in the case of imino-acridines. Some drugs at low concentration exerted a little enhancing effect on ADCC reaction.

Synthesis and antiparasitic activity of new 1-nitro, 1-amino and 1-acetamido 9-acridinones.

The synthesis of 1-amino-10-alkyl-9-acridinones 4 and 5 and of homologous 9-thio-acridinones 7 and 8 are described. Similarly, the synthesis of 1-nitro-4-(2'-aminoethylamino)-9-acridinones 13 and 15, is described. Compound 4 was used as starting material for the preparation of 10-alkyl-9-acridinone dimers 6, bridged with an alpha,omega-diamido chain. Compound 15 was selected for biological investigations on pathogenic parasite strains, and a promising antiamoebic activity could be shown.

1,4-Dimethoxy-9(10H)-acridinone derivatives. Synthesis, DNA binding studies and trypanocidal activity.

New acridinonic derivatives, which are hydroxy- and methoxy-substituted in positions 1, 4, and 1,4 were prepared with a view to obtain antiparasitic drugs. These compounds were tested against Trypanosoma cruzi strains and their capability of interacalation into DNA was determined. Nucleus substitutions, DNA binding, and trypanocidal activities have been correlated.

New antiparasitic agents. III. Comparison between trypanocidal activities of some acridine derivatives against Trypanosoma cruzi in vitro.

Some acridine compounds referred to as 9-imino, 9-oxo and 9-thio derivatives were screened for activity against Trypanosoma cruzi in vitro. The results are discussed here with reference to the structure of the compounds tested. Attempts to elucidate the mode of action of active acridines are also included. The most active compounds that were tested were 9-thioacridanones and 9-thio-1,2,3,4-tetrahydroacridanones Added to this, the dialkylaminoalkylthio group seems to be the most convenient molecular moiety for trypanocidal activity in the 9-substituted acridine series.

Preparation of a series of 9-alkylaminoacridines and 9-imino-10-alkylacridines and their binding to desoxyribonucleic acid.

The preparation, separation and identification of a series of 9-alkylaminoacridines and 9-imino-10-alkylacridines is described. Their binding to desoxyribonucleic acid which has been investigated by a number of spectroscopic techniques is reported.

Antiamebic activity of new acridinic derivatives against Naegleria and Acanthamoeba species in vitro.

In vitro antiamebic activity of selected acridine derivatives has been investigated against Naegleria and Acanthamoeba species. The most active compounds belong to the 9-thioacridanone and the 1,2,3,4-tetrahydro-9-thioacridanone series. In addition, some structure-activity relationships are proposed.

New antiamebic acridines. II. Synthesis and DNA binding of a series of 9-acridanones and 9-iminoacridines.

A series of novel 9-acridanones and 9-iminoacridines has been prepared and investigated by a number of spectroscopic techniques in order to determine the nature and extent of the binding of these compounds to DNA. Results are discussed with reference to antiamebic activity in vitro.

Dipole moments and conformational equilibrium in some substituted 1-phenyl-1-fluoro-2-halogenoethanes.

Experimental dipole moments of substituted 1-phenyl-1-fluoro-2-halogenoethanes are compared with the vectorially and the theoretically calculated values using the CNDO/2 method. Results support the existence of a conformational mixture of these compounds as solutes; gauche structures are the prevailing conformations as in the related catecholamines.

[High resolution proton magnetic resonance study of a series of 9-substituted acridines: correlation with biological activities]. / Etude par résonance magnétique nucléaire protonique à haut champ d'une série d'acridines-9 substituées; essai de corrélation avec les activités biologiques.

250 MHz 1H N.M.R. spectra of a set of 9-substituted derivatives of acridine as solutes in DMSO-d6 were studied. Because of ABCD coupling figures, magnetic parameters were determined by means of simulated spectra. Semi-empirical correlations were proposed for chemical shifts. Moreover, pi distribution in the heterocycle was investigated. Results are discussed in relation to some weak biological properties of the acridine drugs.

Dipole moments and conformational structures of 2-substituted phenothiazines as solutes.

Experimental dipole moments measured in anhydrous benzene and dioxane are compared to the calculated values of some 2-substituted phenothiazine derivatives. The dipole moments and the solvent effects support the existence of a conformational mixture of these compounds as solutes.