Mouâd Alami

A convenient route to unsymmetrical conjugated diynes

Various unsymmetrical conjugated diynes can be prepared in good to excellent isolated yields by copper catalyzed coupling reaction of terminal alkynes with 1-iodo alkynes in pyrrolidine. In the case of 1-bromo alkynes, the presence of a catalytic amount of PdCl2(PPh3)2 improved the yield of coupling products.

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.

Weakly ligated palladium complexes PdCl2(RCN)2 in piperidine: versatile catalysts for Sonogashira reaction of vinyl chlorides at room temperature

Abstract Copper iodide and weakly ligated palladium complexes PdCl2(RCN)2 (R=Ph, Me) catalyzed efficiently the coupling reaction of vinyl chlorides with 1-alkynes in the presence of piperidine to give the corresponding conjugated enynes in good to excellent yields. The reaction takes place rapidly and cleanly at room temperature. Application to the synthesis of terbinafine which exhibits strong antimycotic activity has been realized.

Synthesis and antitumor activity of benzils related to combretastatin A-4.

A series of benzil derivatives related to combretastatin A-4 (CA-4) have been synthesized by oxidation of diarylalkynes promoted by PdI(2) in DMSO. Using this new protocol, 14 benzils were prepared in good to excellent yields and their biological activity has been delineated. Several benzils exhibited excellent antiproliferative activity: for example, 4j and 4k bearing the greatest resemblance to CA-4 and AVE-8062, respectively, were found to inhibit cell growth at the nanomolar level (20-50nM) on four human tumor cell lines. Flow cytometric analysis indicates that these compounds act as antimitotics and arrest the cell cycle in G(2)/M phase. A cell-based assay indicated that compounds 4j and 4k displayed a similar inhibition of tubulin assembly with an IC(50) value similar to CA-4. These results clearly demonstrated that the Z-double bond of CA-4 can be replaced by a 1,2-diketone unit without significant loss of cytotoxicity and inhibition of tubulin assembly potency.

Copper-catalyzed reductive coupling of tosylhydrazones with amines: A convenient route to α-branched amines

A general procedure for the reductive coupling of N-tosylhydrazones with amines in the presence of Cu(acac)(2) and Cs(2)CO(3) has been developed. The protocol is very effective and chemoselective with various primary and secondary aliphatic amines, aminoalcohols as well as azole derivatives to give α-branched amines in good 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.

Convenient one-pot synthesis of functionalized unsymmetrical (Z) or (E)-enediynes from (Z) or (E)-1,2-dichloroethylene. An efficient route to (Z,Z,Z) and (Z,E,Z)-trienes

Abstract A variety of functionalized unsymmetrical (Z) or (E)-enediynes 1 and 2 are stereospecifically prepared in good overall yield by a simple straightforward one-pot procedure from (Z) or (E)-1,2-dichloroethylene and 1-alkynes. Zinc reduction of 1 and 2 leads efficiently to pure (Z,Z,Z) and (Z,E,Z) conjugated trienes.

A stereoselective route to 1-chloro-1-halo-enynes, versatile precursors for the synthesis of chloroenediynes and enetriynes

Abstract 1-Chloro-1-halo-enynes, readily available by metallation of (E)-chloroenynes, undergo sequential coupling with terminal alkynes under Pd-catalysis to produce stereoselectively chloroenediynes and enetriynes in good yields.

A two-step synthesis of terbinafine

Abstract An efficient and high yielding synthesis of terbinafine 1a and amino enyne derivatives 1b-f is described from amino vinyl chlorides 2a-b and 1-alkynes in the presence of a weak ligated palladium complex: PdCl2(PhCN)2 in piperidine.