Pascal Carato

Docking study of ligands into the colchicine binding site of tubulin.

Cancer is a major cause of mortality in developed countries, following only cardiovascular diseases. Death of cancerous cells can be achieved by stopping mitosis and the antimitotic class of drugs formed by the spindle poisons can be used for this purpose. Their role is to disorganize the mitotic spindle by targeting its main constituent, the microtubules, themselves made of heterodimers of α and β-tubulin. They disrupt the dynamics of the microtubules either by stabilizing them, as do paclitaxel or epothilones, or destabilizing them, as do colchicine. The binding site of colchicine seems to lie between the two units of the tubulin dimer. Here, we report on the characterization of this site by the docking of a series of reference compounds, and the subsequent docking of ligands prepared in our laboratory.

Benzopyridooxathiazepine derivatives as novel potent antimitotic agents

Herein, we describe the structure-activity relationship study of a new 1-(arylalkyl)-11H-benzo[f]-1,2-dihydropyrido[3,2,c][1,2,5]oxathiazepine 5,5-dioxide series of antimitotic agents. The pharmacological results obtained from previous works allowed us to identify compound 1 as a new cytotoxic agent inhibiting tubulin polymerization. We have undertaken the synthesis of its non-methylated analogue 7 and have extended our investigations to a novel, structurally related benzopyridooxathiazepine dioxide series. Among all analogues synthesized in this study, compound 10b was the most promising, being 12-fold more potent than compound 1. Its activity over a panel of five tumoral cell lines was in the nanomolar range for all of the histological types tested and flow cytometric studies performed on L1210 cells showed an accumulation of the cells in the G2/M phases of the cell cycle with a significant percentage of tetraploid cells (8N DNA content). This interesting pharmacological profile, resulting from inhibition of tubulin polymerization, encouraged us to perform preliminary in vivo studies.

A new mild and rapid deprotecting method for aryl cyclohex-2-en-1-yl ethers to phenols

Cyclohex-2-en-1-yl ether can be used as a new protecting group of mono and disubstituted phenols. The cleavage of the cyclohex-2-en-1-yl ether is mild, rapid with excellent yields.

Synthesis, biological evaluation and docking studies of 4-amino-tetrahydroquinazolino[3,2-e]purine derivatives.

The synthesis of new 4-amino-tetrahydroquinazolino[3,2-e]purine derivatives along with their activity in cell-free enzymatic assays on Src is reported. Some compounds emerged as moderately active inhibitors of the enzyme and showed antiproliferative effects on the murine leukemia L1210 cell line. Docking studies have been also performed to analyze the binding mode of compounds under study and to identify the structural determinants of their interaction. Therefore, this study provides a new promising scaffold with moderate enzymatic inhibitory activities for further development of new anticancer drugs targeting Src tyrosine kinase.

A Simple and Effective Method for the Thionation of Amides to Thioamides Using Al2O3-Supported P4S10

A simple and effective method for the thionation of amides to thioamides using Al2O3-supported F4S10 was developed and applied to a series of amides including some heterocyclic examples, The reaction was best performed in anhydrous dioxane at reflux temperature. Yields ranging from 62 - 93% are comparable to, or superior to those obtained with Lawessons reagent. The method uses inexpensive reagents and has the advantage that reagent-derived byproducts may be removed by a simple hydrolytic workup rather than by chromatography, as required for Lawessons reagent.

Synthesis and pharmacological evaluation of novel 4-(4-fluorobenzoyl)piperidine derivatives as mixed 5-HT1A/5-HT2A/D2 receptor ligands

Abstract A series of novel 4-(4-fluorobenzoyl)piperidine derivatives with benzothiazolin-2-one as a pivotal template was designed, synthesised and evaluated on a battery of receptors, including serotonin 5-HT 1A , 5-HT 2A and 5-HT 2C , dopamine D 2 and adrenergic α 1 receptors. The 4-(4-fluorobenzoyl)piperidine moiety is known as one of the most potent pharmacophores for the 5-HT 2A receptor. All compounds displayed high affinities for the central 5-HT 2A receptors (1 to 10 nM) combined with high to moderate 5-HT 1A (1 to 800 nM) and D 2 (5 to 1000 nM) affinities. Such a pharmacological profile could lead to new atypical antipsychotics.

Exploring 6-(substituted sulfonyl)imidazopyridines as a potential scaffold for the design of 5-HT 6 ligands

Cognitive dysfunction is a characteristic of various forms of dementia such as Alzheimer’s disease. We have focused on the 5-HT6 receptor in order to identify potent ligands. Herein we report the design of a novel series of 6-sulfonylimidazole derivatives substituted with an alkylamino chain at the 2- or 3-position, their synthesis, and their ability to interact with 5-HT6 receptors as evaluated in radioligand binding assays.Graphical abstract

New phenylaniline derivatives as modulators of amyloid protein precursor metabolism

The chloroquinoline scaffold is characteristic of anti-malarial drugs such as chloroquine (CQ) or amodiaquine (AQ). These drugs are also described for their potential effectiveness against prion disease, HCV, EBV, Ebola virus, cancer, Parkinson or Alzheimer diseases. Amyloid precursor protein (APP) metabolism is deregulated in Alzheimers disease. Indeed, CQ modifies amyloid precursor protein (APP) metabolism by precluding the release of amyloid-beta peptides (Aβ), which accumulate in the brain of Alzheimer patients to form the so-called amyloid plaques. We showed that AQ and analogs have similar effects although having a higher cytotoxicity. Herein, two new series of compounds were synthesized by replacing 7-chloroquinolin-4-amine moiety of AQ by 2-aminomethylaniline and 2-aminomethylphenyle moieties. Their structure activity relationship was based on their ability to modulate APP metabolism, Aβ release, and their cytotoxicity similarly to CQ. Two compounds 15a, 16a showed interesting and potent effect on the redirection of APP metabolism toward a decrease of Aβ peptide release (in the same range compared to AQ), and a 3-10-fold increased stability of APP carboxy terminal fragments (CTFα and AICD) without obvious cellular toxicity at 100 µM.

SYNTHESIS OF 6-(2,2-DIMETHYL-3,4-DIHYDRO-3-OXO-1,4(2H)-BENZOXAZIN-7-YL)PYRIDAZIN-3-ONES

3. (a) Y. Tamura, T. Kawasaki, M. Adachi, M. Tanio, and Y. Kita, Tetrahedron Lett. 4417 (1977). (b) K. Yoshida, J. Am. Chem. Soc., 101,2116 (1979). (c) Y. Tamura, M. Adachi, T. Kawasaki, H. Tasuda and Y. Kita, J. Chem. Soc., Perkin Trans. 1,1132 (1980). (d) T. Kurihara, M. Hanakawa, T. Wakita and S . Harusawa, Heterocycles, 23,2221 (1985). (e) G. W. Gribble, T. C. Barden and D. A. Johnson, Tetrahedron, 44,3195 (1988). (f) I. Nagasaki, Y. Suzuki, K. Iwamoto, T. Higashino and A. Miyashita, Heterocycles, 46,443 (1997). (g) A. A. Pletnev, Q. Tian and R. C. Larwk, J. Org. Chem., 67,9276 (2002).

Synthesis of 2(3H)-benzoxazolone derivatives as potential melatonin receptor ligands

This article reports the synthesis of new 2(3H)-benzoxazolone-based ligands for the melatonin receptors in which an acetamidopropyl side-chain was incorporated. Construction of the acetamidopropyl moiety was achieved via a Wadsworth-Emmons approach. Although these compounds can be seen as derivatives of N-[3-(3-methoxyphenyl)propyl]acetamide (MPPA), which is the exact analogue of melatonin in which the 1,2-indole nitrogen atoms are deleted, they exhibit lower affinities for the melatonin receptors probably due to an unfavourable steric bulk and hydrophilic interactions.