Mickaël Jean

The Prins Reaction Using Ketones: Rationalization and Application toward the Synthesis of the Portentol Skeleton

We report a TMSI-promoted Prins cyclization reaction with ketones as carbonyl partners to prepare polysubstituted chiral spirotetrahydropyrans. In the presence of racemic 2-methylcyclohexanone a dynamic kinetic resolution occurred affording one stereoisomer. The observed enantiospecificity has been rationalized by DFT calculation.

Synthesis of stachybotrin C and all of its stereoisomers: structure revision.

We disclose the first total synthesis of stachybotrin C, a potent neuroprotective natural compound. All of the four stereoisomers have been prepared and fully characterized with the aim to attribute the absolute configuration of the two adjacent stereocenters of the stachybotrin C.

Review of PI3K/mTOR Inhibitors Entering Clinical Trials to Treat Triple Negative Breast Cancers

BACKGROUND Constitutive activation of the PI3K/mTOR signaling pathway is observed in most, if not all, breast cancers. Accordingly, many PI3K and/or mTOR inhibitors have entered clinical trials, and completed studies should soon reveal the efficacy of these new drug families in the treatment of cancer patients. OBJECTIVE We present the PI3K/Akt/mTOR signaling pathway and the structure and the anti-tumor efficiency of some mTOR inhibitors such as rapalogues and competitive inhibitors, which have entered clinical trials. We also discuss some of the clinical trial results associated with these molecules mainly focusing on studies performed on relapsing breast cancer patients - but not only. RESULTS Most of the clinical trials with PI3K/mTOR inhibitors alone or in combination with chemotherapies were performed in heavily pre-treated patients and revealed non-negligible amounts of partial responses and long-term stable disease for these patients. Therefore, these compounds seem to prevent tumor growth and survival of cancer cells in Human, representing a new range of anti-tumor drugs that can be utilized not only as first-line treatments but as second- and third-line agents for patients who relapse. CONCLUSION Drugs inhibiting the PI3K/mTOR signaling pathway may represent tailored anti-tumor agents, paving the way for their clinical application in different tumor types.

A Novel Covalent mTOR Inhibitor, DHM25, Shows in Vivo Antitumor Activity against Triple-Negative Breast Cancer Cells

Constitutive activation of the PI3K/mTOR signaling pathway contributes to carcinogenesis and metastasis in most, if not all, breast cancers. From a chromene backbone reported to inhibit class I PI3K catalytic subunits, several rounds of chemical syntheses led to the generation of a new collection of chromologues that showed enhanced ability to kill PI3K-addicted cancer cells and to inhibit Akt phosphorylation at serine 473, a hallmark of PI3K/mTOR activation. This initial screen uncovered a chromene designated DHM25 that exerted potent antitumor activity against breast tumor cell lines. Strikingly, DHM25 was shown to be a selective and covalent inhibitor of mTOR using biochemical and cellular analyses, modeling, and a large panel of kinase activity assays spanning the human kinome (243 kinases). Finally, in vivo, this novel drug was an efficient inhibitor of growth and metastasis of triple-negative breast cancer cells, paving the way for its clinical application in oncology.

Synthesis and evaluation of amides surrogates of dopamine D3 receptor ligands

Isosteric replacement of the amide function and modulation of the arylpiperazine moiety of known dopamine D3 receptor ligands led to potent and selective compounds. Enhanced bioavailability and preferential brain distribution make compound 6c a good candidate for pharmacological and clinical evaluation.

Strategy of total synthesis based on the use of Rh-catalyzed stereoselective 1,4-addition

In 1998, Hayashi and Miyaura reported the first asymmetric conjugate addition of aryl- and alkenyl-boronic acids to α,β-unsaturated ketones using chiral rhodium complexes as catalysts. During the last decade, this reaction has been developed quickly and the enantioselectivity was significantly improved with the emergence of new phosphine ligands. In addition to the methodological work, this reaction was applied as a key step in the total synthesis of natural compounds. The purpose of this paper focuses on examples of the use of this reaction to prepare elaborated chiral molecules with high diastereoselectivies and/or enantioselectivities.

Modular Synthesis of Arylacetic Acid Esters, Thioesters, and Amides from Aryl Ethers via Rh(II)-Catalyzed Diazo Arylation.

One-pot formation of arylacetic acid esters, thioesters, and amides via Rh(II)-catalyzed arylation of a Meldrums acid-derived diazo reagent with electron-rich arenes is described. The methodology was used to efficiently synthesize an anticancer compound.

A solid phase parallel synthesis of diverse amides as dopamine D3 receptor ligands

A solid phase parallel synthesis using SynPhase™ technology was used to couple a series of 21 carboxylic with three different 4-(4-arylpiperazinyl)butanamines. The resulting library was evaluated as dopamine D3 receptor ligands giving rise to several compounds with affinities in the low nanomolar concentration range (9e and 9n with binding affinities at D3 receptors of 0.10 and 0.35 nM respectively).

Synthesis of new simplified hemiasterlin derivatives with α,β-unsaturated carbonyl moiety.

In this Letter, we report a convenient and efficient method for the synthesis of new simplified derivatives of hemiasterlin in which the α,α-dimethylbenzylic moiety A is replaced by α,β-unsaturated aryl groups as Michael acceptor. Most of these derivatives have a strong cytotoxic activity on three human tumor cell lines (KB, Hep-G2 and MCF7). Analogs 17b and 17f showed a high cytotoxicity against KB and Hep-G2 cancer cell lines comparable to paclitaxel and ellipticine.

Synthesis of new bioisosteric hemiasterlin analogues with extremely high cytotoxicity

In this Letter, the synthesis and the evaluation of the cytotoxicity of new hemiasterlin analogues were reported. The indole moiety was replaced respectively by benzofurane, naphthalene and 4-bromobenzene groups. Most of these derivatives possess strong cytotoxic activity on two human tumour cell lines (KB and Hep-G2), and some analogues showed comparable cytotoxic activity to that observed for paclitaxel and ellipticine, against KB and Hep-G2 cancer cell lines.