Emmanuel Moreau

Design, synthesis, biological evaluation, and structure-activity relationships of substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates as new tubulin inhibitors mimicking combretastatin A-4.

Sixty-one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and 13 of their tetrahydro-2-oxopyrimidin-1(2H)-yl analogues (PPB-SOs) were prepared and biologically evaluated. The antiproliferative activities of PIB-SOs on 16 cancer cell lines are in the nanomolar range and unaffected in cancer cells resistant to colchicine, paclitaxel, and vinblastine or overexpressing the P-glycoprotein. None of the PPB-SOs exhibit significant antiproliferative activity. PIB-SOs block the cell cycle progression in the G2/M phase and bind to the colchicine-binding site on β-tubulin leading to cytoskeleton disruption and cell death. Chick chorioallantoic membrane tumor assays show that compounds 36, 44, and 45 efficiently block angiogenesis and tumor growth at least at similar levels as combretastatin A-4 (CA-4) and exhibit low to very low toxicity on the chick embryos. PIB-SOs were subjected to CoMFA and CoMSIA analyses to establish quantitative structure–activity relationships.

Synthesis and antiviral activity of an imidazo[1,2-a]pyrrolo[2,3-c]pyridine series against the bovine viral diarrhea virus.

A series of imidazo[1,2-a]pyrrolo[2,3-c]pyridines has been prepared and evaluated for their anti-BVDV activities in MDBK cells. From the synthesized analogues bearing modifications of the substituents at positions 2, 3, 7 and 8, compounds 10a, b, 16, 24, 25 and 26 exhibited significant anti-BVDV activities.

Novel imidazo[1,2-a]naphthyridinic systems (part 1) : Synthesis, antiproliferative and DNA-intercalating activities

Novel imidazo[1,2-a]naphthyridinic systems 6a-15a and 6b-15b were obtained from Friedländers reaction in imidazo[1,2-a]pyridine series. Most of the compounds were evaluated for their antitumor activity in the NCIs in vitro human tumor cell line screening panel. Among them, pentacyclic derivatives 13b and 14a exhibited in vitro activity comparable to anticancer agent such as amsacrine. Their mechanism of cytotoxicity action was unrelated to poisoning or inhibiting abilities against topo1. On the contrary, we highlighted a direct intercalation of the drugs into DNA by electrophoresis on agarose gel.

New Opportunities with the Duff Reaction

The Duff reaction (HMTA, AcOH or TFA) was studied on substituted [6 + 5] heterocyclic compounds. This reaction provides a useful route to aldehydes for compounds bearing sensitive amide functions. It gives also access to tricyclic lactams of potential biological interest. The formation of an aminomethyl intermediate in the Duff reaction mechanism is unequivocally demonstrated.

Efficient synthesis of novel dipyridoimidazoles and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives

Abstract Novel dipyrido[1,2- a ;3′,4′- d ]imidazoles 7a – d , dipyrido[1,2- a ;4′,3′- d ]imidazoles 8a , c and pyrido[1′,2′;1,2]imidazo[4,5- d ]pyridazine derivatives 9a – d were synthesized by two pathways: thermal electrocyclic reaction of 3-alkenylimidazopyridine-2-oximes 10 and direct condensation of ethyl glycinate (or hydrazine) with 2,3-dicarbonylimidazo[1,2- a ]pyridines 11 .

The binding affinity of double‐stranded RNA motifs to HIV‐1 Tat protein affects transactivation and the neutralizing capacity of anti‐Tat antibodies elicited after intranasal immunization

In this study we examined the hypothesis that the binding affinity of two double‐stranded (ds) RNA motifs to HIV‐1 Tat protein might affect transactivation and the type of anti‐Tat immune responses. Using surface plasmon resonance technology we demonstrated the capacity of the poly(A):poly(U) (pA:pU) motif to bind with high affinity to a totally synthetic Tat protein and to inhibit more efficiently the Tat/transactivation response element (TAR) RNA interaction as compared to the poly(I):poly(C) (pI:pC) motif. Furthermore, the pA:pU motif was tenfold more effective in inhibiting Tat‐driven transactivation than the pI:pC motif. Following intranasal immunization of mice, both dsRNA motifs enhanced the antibody (serum and mucosal) and cellular responses to Tat. However, only the serum samples of mice immunized with Tat + pI:pC inhibited Tat‐driven transactivation. The profile of serum antibody subclasses together with the secreted cytokines by Tat‐stimulated splenocyte cultures indicated that both dsRNA motifs favored the induction of a balanced Th1 and Th2 immune response. The demonstration in this study that two dsRNA motifs had a marked effect on Tat/TAR RNA interaction and on the neutralizing capacity of anti‐Tat specific antibody responses highlights their potential for biological applications and the importance of selecting the appropriate motif as an adjuvant for vaccine design.

Substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamides as antimitotics. Antiproliferative, antiangiogenic and antitumoral activity, and quantitative structure-activity relationships

The importance of the bridge linking the two phenyl moieties of substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) was assessed using a sulfonamide group, which is a bioisostere of sulfonate and ethenyl groups. Forty one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamide (PIB-SA) derivatives were prepared and biologically evaluated. PIB-SAs exhibit antiproliferative activities at the nanomolar level against sixteen cancer cell lines, block the cell cycle progression in G(2)/M phase, leading to cytoskeleton disruption and anoikis. These results were subjected to CoMFA and CoMSIA analyses to establish quantitative structure-activity relationships. These results evidence that the sulfonate and sulfonamide moieties are reciprocal bioisosteres and that phenylimidazolidin-2-one could mimic the trimethoxyphenyl moiety found in the structure of numerous potent antimicrotubule agents. Finally, compounds 16 and 17 exhibited potent antitumor and antiangiogenic activities on HT-1080 fibrosarcoma cells grafted onto chick chorioallantoic membrane similar to CA-4 without significant toxicity for the chick embryos, making this class of compounds a promising class of anticancer agents.

Generation and Characterization of Neutralizing Human Monoclonal Antibodies against Human Immunodeficiency Virus Type 1 Tat Antigen

ABSTRACT The human immunodeficiency virus Tat regulatory protein is essential for virus replication and pathogenesis. From human peripheral blood mononuclear cells of three Tat toxoid-immunized volunteers, we isolated five Tat-specific human monoclonal antibodies (HMAbs): two full-length immunoglobulin G (IgG) antibodies and three single-chain fragment-variable (scFv) antibodies. The two IgGs were mapped to distinct epitopes within the basic region of Tat, and the three scFvs were mapped to the N-terminal domain of Tat. The three scFvs were highly reactive with recombinant Tat in Western blotting or immunoprecipitation, but results were in contrast to those for the two IgGs, which are sensitive to a particular folding of the protein. In transactivation assays, scFvs were able to inhibit both active recombinant Tat and native Tat secreted by a transfected CEM cell line while IgGs neutralized only native Tat. These HMAbs were able to reduce viral p24 production in human immunodeficiency virus type 1 strain IIIB chronically infected cell lines in a dose-dependent manner.

Aminoimidazo[1,2-a]pyridines: regioselective synthesis of substituted imidazonaphthyridines, azacarbolines and cyclazines

Abstract In order to study the regioselectivity of thermal cyclocondensation, aminoimidazo[1,2-a]pyridines (AIP) 5a–e were prepared, further converted into iminophosphoranes 7a–e , and ultimately converted regioselectively in angular annulated imidazonaphthyridines (IN) 8a , 10a , 11a , 12a or linear annulated dipyridoimidazole (DPI) 17a . From 2-substituted derivative 23 , the peri annulated product 24a was obtained. The starting amines 5a–f reacted with aldehydes to yield regioselectively IN 8a–c , 10a–c , 11a–c , 12a,b , DPI 16a–e , 17a–d and TIBO like structures (±)-13 and 24a–c , as proved by X-ray analysis. The 1,2- or 1,4-addition between amines and α,β-unsaturated aldehydes concerning the pyridine and imidazole moieties is discussed in the light of these results.

Synthesis of polyfused heterocycle derivatives containing the dipyridoimidazole core by Friedländer's reaction : Access to analogs of ellipticine

Reaction of 3-amino-2-formylimidazo[l,2-a]pyridine with various aldehydes and ketones by Friedlanders methodology afforded an entry to dipyridoimidazole, tri(tetra)azacyclopenta[b]fluorene, tri(tetra)azabenzo[b]-fluorene and triazaindeno[2,1-b]phenanthrene derivatives. Intercalation with a synthetic oligodeoxynucleotide was examined.