Samir Messaoudi

Isocombretastatins A versus Combretastatins A: The Forgotten isoCA-4 Isomer as a Highly Promising Cytotoxic and Antitubulin Agent

Herein is reported a convergent synthesis of isocombretastatins A, a novel class of potent antitubulin agents. These compounds having a 1,1-diarylethylene scaffold constitute the simplest isomers of natural Z-combretastatins A that are easy to synthesize without need to control the Z-olefin geometry. The discovery of isoCA-4 with biological activities comparable to that of CA-4 represents a major progress in this field.

Discovery of isoerianin analogues as promising anticancer agents.

The cytotoxic activity of a series of 23 new isoerianin derivatives with modifications on both the A and B rings was studied. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. The most cytotoxic compound, isoerianin (3), strongly inhibits tubulin polymerization in the micromolar range. Moreover, isoerianin leads to G2/M phase cell‐cycle arrest in H1299 and K562 cancer cells, and strongly induces apoptosis. Isoerianin also disrupts the vessel‐like structures formed by human umbilical vein endothelial cells (HUVECs) in vitro, suggesting that this compound may act as a vascular disrupting agent. It clearly appears that in this compound series, the 1,1‐ethane bridge encountered in isoerianin derivatives can replace the 1,2‐ethane bridge of natural erianin with no loss of activity. This reinforces the bioisosteric replacement approach in the combretastatin series previously reported by our research group.

Synthesis and biological activity of simplified denoviose-coumarins related to novobiocin as potent inhibitors of heat-shock protein 90 (hsp90)

A new series of coumarin inhibitors of hsp90 lacking the noviose moiety as well as substituents on C-7 and C-8 positions of the aromatic ring was synthesised and their hsp90 inhibitory activity has been delineated: for example, their capacity to induce the degradation of client proteins and to inhibit estradiol-induced transcription in human breast cancer cells. In cell proliferation assay, the most active compound 5g was approximately 8 times more potent than the parent novobiocin natural compound.

Synthesis, Biological Evaluation of 1,1‐Diarylethylenes as a Novel Class of Antimitotic Agents

The cytotoxic activities of 23 new isocombretastatin A derivatives with modifications on the B‐ring were investigated. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. Compounds isoFCA‐4 (2 e), isoCA‐4 (2 k) and isoNH2CA‐4 (2 s) were the most cytotoxic, and strongly inhibited tubulin polymerization with IC50 values of 4, 2 and 1.5 μM, respectively. These derivatives were found to be 10‐fold more active than phenstatin and colchicine with respect to growth inhibition but displayed similar activities as tubulin polymerization inhibitors. In addition, cell cycle arrest in the G2/M phase and subsequent apoptosis was observed in three cancer cell lines when treated with these compounds. The disruptive effect of 2 e, 2 k and 2 s on the vessel‐like structures formed by human umbilical vein endothelial cells (HUVEC) suggest that these compounds may act as vascular disrupting agents. Both compounds 2 k and 2 s have the potential for further prodrug modification and development as vascular disrupting agents for treatment of solid tumors.

Palladium-catalyzed decarboxylative coupling of quinolinone-3-carboxylic acids and related heterocyclic carboxylic acids with (hetero)aryl halides.

An efficient and practical decarboxylative cross-coupling reaction of quinolin-4(1H)-one 3-carboxylic acids with (hetero)aryl halides has been established. Under a bimetallic system of PdBr(2) and silver carbonate, the protocol proved to be general, and a variety of 3-(hetero)aryl 4-quinolinones and related heterocycles, such as 3-aryl-1,8-naphthyridin-4(1H)-ones, 3-arylcoumarins, 3-arylquinolin-2(1H)-ones, and 2-arylchromones, can be prepared in good to excellent yields.

Antiproliferative and apoptotic activities of tosylcyclonovobiocic acids as potent heat shock protein 90 inhibitors in human cancer cells.

We evaluated whether inhibition of heat shock protein 90 (hsp90) function by novobiocin derivatives could induce the degradation of signal transducers that drive cancer cell growth and thereby promote apoptosis. Removal of the noviose moiety in novobiocin and introduction of a tosyl substituent at C-4 or C-7 coumarin nucleus provided derivatives 4TCNA and 7TCNA which compared favourably with novobiocin in MCF-7 breast cancer cells. Here we extend the antiproliferative and apoptotic properties of these analogues to a panel of cancer cell lines. Destabilization of hsp90 client proteins Raf-1, HER2, and cdk4 suggests inhibition of hsp90 chaperoning function. In HT29 colon and IGROV1 ovarian cancer cells, the growth inhibiting effect of 4TCNA and 7TCNA was consistent with the stimulation of cell death as assessed by the processing and activation of caspase 9, 8, 7 and 3 and the subsequent cleavage of poly(ADP-ribose) polymerase (PARP). In Ishikawa endometrial adenocarcinoma cells, 4TCNA also promoted apoptosis and the processing of PARP. These derivatives impacting multiple pathways involved in the neoplastic process may represent promising drugs for cancer therapy.

A site selective C–H arylation of free-(NH2) adenines with aryl chlorides: Application to the synthesis of 6,8-disubstituted adenines

An efficient site selective method for the direct arylation of free-(NH2) adenines 1 to provide a range of C-8 arylated adenines 3 in excellent yields is described. This process based on the use of Pd(OH)2/C as the catalyst and a stoichiometric amount of CuI under ligandless conditions is general. It allows the coupling to proceed with a variety of aryl halides, including for the first time cheaper and less reactive aryl chlorides. The extension of this process for the sequential preparation of non-symmetrical C8/N6-arylated adenines 4 is also reported.

A General Copper Powder-Catalyzed Ullmann-Type Reaction of 3-Halo-4(1H)-quinolones With Various Nitrogen-Containing Nucleophiles

3-(N-Substituted) 4(1H)-quinolinones were synthesized using the copper-catalyzed Ullmann C-N bond forming strategy in moderate to quantitative yields. Starting from 3-halo-4(1H)-quinolones, various nucleophiles including amides, lactams, sulfonamides and NH-containing azoles have been used successfully. In all cases, the reactions take place rapidly in toluene and proceed by using copper powder as a catalyst, DMEDA as a ligand and K(2)CO(3) as a base. In addition, other related heterocycles such as 3-bromoquinolin-2(1H)-ones, 3-bromocoumarin, and 3,5-dibromo-2-pyridone show good to very high reactivity with various nucleophiles under our Cu/DMEDA catalyst system.

Palladium(II)-catalyzed oxidative arylation of quinoxalin-2(1H)-ones with arylboronic acids.

A straightforward palladium-catalyzed oxidative C-3 arylation of quinoxalin-2(1H)-ones with arylboronic acids is reported. This protocol is compatible with a wide range of functional groups and allows construction of various biologically important quinoxalin-2(1H)-one backbones.

Discovery and biological activity of 6BrCaQ as an inhibitor of the Hsp90 protein folding machinery.

Heat shock protein 90 (Hsp90) is a significant target in the development of rational cancer therapy, due to its role at the crossroads of multiple signaling pathways associated with cell proliferation and viability. Here, a novel series of Hsp90 inhibitors containing a quinolein‐2‐one scaffold was synthesized and evaluated in cell proliferation assays. Results from these structure–activity relationships studies enabled identification of the simplified 3‐aminoquinolein‐2‐one analogue 2 b (6BrCaQ), which manifests micromolar activity against a panel of cancer cell lines. The molecular signature of Hsp90 inhibition was assessed by depletion of standard known Hsp90 client proteins. Finally, processing and activation of caspases 7, 8, and 9, and the subsequent cleavage of PARP by 6BrCaQ, suggest stimulation of apoptosis through both extrinsic and intrinsic pathways.