Jean-Pierre Hénichart

Synthesis and biological activity of N-aroyl-tetrahydro-γ-carbolines

Research on dual inhibitors of both 5-LOX and COXs gained interest due to the overexpressions of these enzymes during the malignant state of the evolution of prostate cancer. In order to take part in this research, new N-aroyl-tetrahydro-gamma-carbolines issued from the modification of Indomethacin have been synthesised. As for the NSAIDs, the compounds have been tested for their activity against COX(1), COX(2) plus against 5-LOX and against the proliferation of malignant prostate cancer. Interesting cytotoxic activities and selectivities of some tetrahydro-gamma-carboline derivatives have been obtained.

Discovery of ferrocene-containing farnesyltransferase inhibitors. Investigation of bulky lipophilic groups for the A2 binding site of farnesyltransferase

A new family of protein farnesyltransferase inhibitors, based on a ferrocene scaffold, was designed and synthesized. The biological evaluation of these compounds showed that ferrocenyl(2,3,4-trimethoxyphenyl)methanone (4c) and (ferrocen-1-yl)(2,3,4-trimethoxyphenyl)hydroxyimine (16) were two of the most active compounds, with protein farnesyltransferase inhibition potencies in the low micromolar range. The investigation of the influence of different bulky substituents (paracyclophane, noradamantane and adamantane) on the biological activity showed that these structural modifications abolished farnesyltransferase affinity. Molecular modeling studies revealed that the ferrocene unit of newly synthesized compounds was a well tolerated bulky group, for the A2 binding site of farnesyltransferase. Compounds were also evaluated for their antiproliferative activity on a NCI-60 cancer cell line panel. Paracyclophane derivative 13 exhibited the most potent in vitro cytostatic activity inhibiting the growth of MCF7, MDA-MB-468, T-47D and HT-29 cell lines.

SYNTHESIS OF UNSYMMETRICAL DIALKOXY QUINAZOLINES

Quinazoline-derived compounds are gaining greater importance and wider use, mainly as the result of their applications in medicinal chemistry. For example, several quinazolines derivatives have been examined as inhibitors of a variety of transmembrane growth factor receptors,lJ or as inhibitors of famesyl protein transfera~e,~ in order to find some new method for the treatment of human cancer. They have also been developed as inhibitors of W-KB activation4 as a potential method for treating inflammatory diseases. Although this class of compounds is widely exploited, only few derivatives bear different ether side-chains at the 6and 7-positions of the quinazoline ring. Furthermore, to our knowledge, different ethers of the phenolic groups of catechols5 and more specifically of dihydroxyquinazolines derivatives are not well documented. Herein, we present an efficient route to quinazolines bearing different substituents, such as nbutoxyand diethylaminoethoxygroups at the 6and 7-positions of the quinazoline ring (Scheme I).

Eaton’s Reagent‐Mediated Domino π‐Cationic Arylations of Aromatic Carboxylic Acids to Iasi‐Red Polymethoxylated Polycyclic Aromatic Hydrocarbons: Products with Unprecedented Biological Activities as Tubulin Polymerization Inhibitors

A rapid domino π-cationic arylation of aromatic carboxylic acids, mediated by Eatons reagent, has been developed for the synthesis of Iasi-red polymethoxylated polycyclic aromatic hydrocarbons (PAHs). This route is currently the easiest method to obtain such popular PAH compounds, which bear in addition numerous methoxy groups. The domino process was generalized, the structure of the obtained red products and the mechanism of their formations were elucidated, and some of their photophysical properties were determined. Newly synthesized polymethoxylated-PAHs were tested for their interaction with tubulin polymerization as well as for their cytotoxicity on a panel of NCI-60 human cancer cell lines. Interestingly, one of these rubicene derivatives exhibited remarkable cytotoxicity in vitro, including inhibition of leukemia, colon, melanoma, CNS, and ovarian cancer cell lines with GI50 values in the low nanomolar range (GI50 < 10 nM).

5-Lipoxygenase inhibitors – patent and literature activity during 2001 – 2004

This article analyses the publications and patents on the therapeutic potential of 5-lipoxygenase (5-LOX) inhibitors appearing during the period 2001 – 2004. There have been long-standing attempts to introduce 5-LOX inhibitors for the treatment of asthma and allergic disorders but new evidence suggests that inhibition of 5-LOX may also prove useful against certain cardiovascular diseases and human tumours. This review summarises current knowledge on the regulation of 5-LOX and the commonly adopted approaches for enzyme inhibition, before going on to discuss new strategies for anti-LOX therapy and the development of inhibitors for the treatment of disease in these new therapeutic areas.

A convenient new synthesis of 1,2-diarylpyrroles from 3-ethoxycarbonyl-4-oxo-4-phenylbutyraldehyde

An efficient four-step synthesis of ethyl 1,2-diaryl-3-pyrrole carboxylates (4), an isomeric scaffold of pharmacologically active natural products, is reported. The key synthon 3-ethoxycarbonyl-4-oxo-4-phenylbutyraldehyde(3), whose new synthesis is detailed here, reacts conveniently with anilines to create the pyrrole ring.

Synthesis and configurational study of 2-arylmorpholines

The synthesis of various 2-(2,3-dihydro-3-methyl-2-oxobenz[d]oxazol-6-yl) morpholines is reported. It has been demonstrated that 2-hydroxymorpholines or β-hydroxyethylaminomethyl ketones are formed as intermediates as assessed by ir, uv, 1 H and 13 C nmr analyses. The configuration of the title compounds was also established and corresponds to an equatorial orientation of the aromatic substituent which is considered as essential for an adrenergic activity