Laurent Désaubry

Design, synthesis and structure-activity relationships of a series of 9-substituted adenine derivatives as selective phosphodiesterase type-4 inhibitors.

Adenine derivatives substituted in position 9 have been demonstrated to have potent cyclic nucleotide phosphodiesterase (PDE) inhibition properties with high selectivity toward PDE-4. Starting from our initial lead compound 9-(2-fluorobenzyl)-N(6)-methyl-2-trifluoromethyladenine (4, NCS613), we designed and synthesized a new series of 9-substituted derivatives for developing structure-activity relationship studies. This new series of derivatives showed increased potencies and better selectivity profiles. Structural modifications were achieved in parallel on three different positions of the adenine ring, and led to the following observations: (i) introduction of a lipophilic substituent such as trifluoromethyl, n-propyl group or iodine in the C-2 position is favourable for both the PDE-4 inhibitory activity and the selectivity towards other isoenzymes; (ii) functionalization of the N9 benzyl group with a 2-methoxy substituent led to remarkably more active compounds; (iii) replacement of the N(6)-methylamino moiety by other amino groups is detrimental to the activity. Among all derivatives prepared, the 9-(2-methoxybenzyl)-N(6)-methyl-2-trifluoromethyladenine (9r), 9-(2-methoxybenzyl)-N(6)-methyl-2-n-propyladenine (9s), and the 2-iodo-9-(2-methoxybenzyl)-N(6)-methyladenine (13b) were found to be the most potent inhibitors within this series (PDE-4-IC(50)=1.4, 7.0, and 0.096 nM, respectively). Compared to our reference compound 4, which showed an IC(50) of 42 nM, the derivative 13b was found 450-fold more potent. Moreover, 2-iodo-9-(2-methoxybenzyl)-N(6)-methyladenine (13b) and 9-(2-methoxybenzyl)-N(6)-methyl-2-trifluoromethyladenine (9r), were at least 50000-150000 times more selective for the PDE-4 than for the other PDE families. Additionally, these new derivatives showed improved efficiency in inhibiting the TNFalpha release from mononuclear cells from healthy subjects (e.g. adenines 7l, 9s and 13b). Thus, compounds 7l, 9r, 9s and 13b are among the most potent and selective PDE-4 inhibitors reported so far and represent very promising pharmacological tools for a better understanding of the signal transduction involving cyclic AMP within the cell: this pathway is implicated in the physiology and the pathophysiology of inflammation, asthma and autoimmune disorders.

Synthesis of a conformationally constrained analogue of BW A78U, an anticonvulsant adenine derivative

Abstract The synthesis of a conformationally constrained analogue of the anticonvulsant BW A78U, a 9-benzyl-adenine derivative, has been devised, using silicon tetrachloride in a new cyclodehydration.

Toward higher polyprenols under ‘prebiotic’ conditions

Abstract Geraniol and isomers (C 10 ) can be obtained by the condensation of C 5 monoprenols at room temperature in the presence of montmorillonite K-10. It is also possible to obtain farnesol (C 15 ) and isomers by condensation of geraniol with isopentenol. Despite the low yields achieved, these findings support the hypothesis that polyprenyl phosphates may have been formed in prebiotic conditions, and served as constituents of primitive membranes.

Regio-controlled radical substitution of 9-substituted purines

Abstract 9-benzylpurine undergoes facile radical alkylation and acylation under standard Minisci s conditions affording regioselectively 6-substituted derivatives.

Anxiolytic and sedative properties of BW A78U, a novel anticonvulsant adenine derivative

The anticonvulsant BW A78U, tested in a free mouse exploratory situation, reduced in a dose-dependent fashion the locomotion and the number of rearings, this sedative effect being significant up to a dose of 15 mg/kg (IP, 20 min before testing). In an unconditioned conflict test, the light/dark box choice situation, specific for anxiolytics, low doses of BW A78U increased the time spent by mice in the lit box as well as the number of transitions between the two boxes. Finally, we demonstrated that this drug was able to protect mice against pentylenetetrazole-induced convulsions. Our data show that BW A78U possesses some of the characteristic properties of the minor tranquilizers. However, since this compound binds to the benzodiazepine receptor with a very low affinity (IC50 = 13.6 microM), it can be assumed that this drug does not exert its behavioral effects through these receptors. It may interfere with other targets involving adenosine, another potent physiological regulator of neuronal excitability.

Looking forward : a glance into the future of organic chemistry

What will organic chemistry do in the next forty years? This Perspective lists six tasks that have emerged during the first edition of ESYOP, a symposium devoted to the future of organic chemistry. The collective answer presented has been elaborated following a 4-step process: stimulating plenary lectures given by outstanding chemists and philosophers, short presentations given by each participant (average age: 34 years old), think-tank sessions and writing of the final report after the symposium.

Vectorial properties of small vesicles

Abstract 31 P-NMR spectra of suspensions of small phospholipidic vesicles (SUVs) often give two peaks, assigned to the outside and inside leaflets of the membranes. We now show that SUVs formed from polyprenyl phosphates, postulated as primitive membranes, can exhibit this phenomenon. At pH 7.35, stable SUVs could not be obtained from phytanyl phosphate, as vesicles spontaneously grew too much. Phytanyl phosphate + 5 mol% phytanol produced stable SUVs at the same pH, in which, however, 31 P-NMR showed a single symmetrical peak. At pH 8.9, where dianion phosphates are predominant (they may occupy principally the outer leaflet), 31 P-NMR showed two signals of the phosphate both in phytanyl phosphate and phytanyl phosphate/5 mol% phytanol SUVs. This asymmetry of the membrane implies a difference in the ionisation state of the phosphate groups on both sides of the membrane. The resulting gradient of electrochemical properties implies the presence of vectorial properties, a factor that may lead to the self-complexification of these vesicles towards proto-cells.

Biomimetic Synthesis and Properties of Polyprenoid

The polyprenoids, which represent the largest family of natural products in the living world, are biogenic compounds that derive from the assemblage and modification of fivecarbon isoprene units. Some polyprenoids, such as cholesterol in animals, phytosterols in plants or hopanoids and uf061uf02cuf077-dihydroxylated carotenoids in Bacteria (Fig. 1), are of paramount importance in biological membranes, where they act as reinforcers (Ourisson & Nakatani, 1994). Without these reinforcers, the self-organization of phospholipid molecules would not resist from shear stresses. Membranes of Bacteria and Eukarya are formed by the self-assembly of amphiphilic phospholipids whose polar head-groups are linked to two fatty acid chains by ester bonds. The molecular dimensions of cholesterol, phytosterols and hopanoids approach closely those of hydrophobic parts of phospholipid molecules in their stretched form, and their hydrophobic tails are localized in the middle of the membrane (Yamamoto et al., 1993). Thus, these terpenoids reinforce the lipid bilayer by cooperative attractive van der Waals forces and modulate membrane rigidity and fluidity (Milon, Lazrak et al., 1986). In some Bacteria, carotenoids reinforce membrane by crossing both halves of the bilayer (Milon, Wolff et al., 1986). Archaea, the third major kingdom of living organisms, possess structurally unique lipids: their polar head groups are linked to polyprenyl chains by ether bonds, in contrast to the ester bonds and n-acyl chains in Eucarya and Procarya. These ether linkages, which are chemically stable, enable these organisms containing membranes to survive under extreme conditions of pH, temperature, pressure and salt concentration (Chong, 2010; Koga et al., 1993). Another striking feature of some archaeal lipids is the presence of 72-membered rings (Eguchi et al., 2000). Apart from this maintenance of the membrane integrity, membrane terpenoids fulfill many other functions. Dolichol phosphates are widely present in membranes and are involved in the N-glycosylation of proteins. Ubiquinones, which are composed of a 1,4-benzoquinone

Abstract A23: eIF4F is a key and targetable convergence nexus of multiple mechanisms of resistance to anti-BRAF and anti-MEK cancer therapies

The V600E mutation in BRAF is the most frequent oncogenic mutation in human cancers, and can be targeted by specific anti-BRAF agents. However, several mechanisms of resistance have been identified, leading to reactivation of the initially blocked MAP-kinase pathway (known as ERK-dependent mechanisms) or reactivation of alternative ones, like the PI3K-AKT-mTOR pathway, or inhibition of the apoptotic cascade (ERK-independent). These pathways converge to regulate the formation of the eIF4F translation initiation complex that binds to the 7-methylguanosine cap at the 5′ end of mRNAs, thereby modulating mRNA translation of specific mRNAs. We addressed the potential role of the eIF4F eukaryotic translation initiation complex in resistance or sensitivity to anti-BRAF and anti-MEK agents in several BRAF mutant cells, xenografts and tumors. Our data demonstrate that the formation of the eIF4F complex is associated with most resistance mechanisms to these targeted therapies, independently of their capacity to reactivate or not the MAP-kinase pathway. Formation of this complex can be explored in tumor samples using a new in situ technology. Inhibitors of the eIF4F complex synergize with anti-BRAF agents and can thus reverse resistance. Citation Format: Lise Boussemart, Helene Malka-Mahieu, Isabelle Girault, Delphine Allard, Oskar Hemmingson, Nyam Kamsu-Kom, Sandrine Agoussi, Alexander Eggermont, Laurent Desaubry, Caroline Robert, Stephan Vagner. eIF4F is a key and targetable convergence nexus of multiple mechanisms of resistance to anti-BRAF and anti-MEK cancer therapies. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A23.

Synthesis and biological evaluation of PEG-tirofiban conjugates

We have conjugated tirofiban, an antagonist of the GPIIb/IIIa integrin receptor, to PEG, and shown that these polymers effectively inhibit platelet aggregation. This inhibition decreased with the size of the polymer. Our goal was to develop new cryoprotective agents to store frozen platelets. Surprisingly, tirofiban-conjugated PEG did not exhibit any protection.