Guillaume Laconde

Designing Focused Chemical Libraries Enriched in Protein-Protein Interaction Inhibitors using Machine-Learning Methods

Protein-protein interactions (PPIs) may represent one of the next major classes of therapeutic targets. So far, only a minute fraction of the estimated 650,000 PPIs that comprise the human interactome are known with a tiny number of complexes being drugged. Such intricate biological systems cannot be cost-efficiently tackled using conventional high-throughput screening methods. Rather, time has come for designing new strategies that will maximize the chance for hit identification through a rationalization of the PPI inhibitor chemical space and the design of PPI-focused compound libraries (global or target-specific). Here, we train machine-learning-based models, mainly decision trees, using a dataset of known PPI inhibitors and of regular drugs in order to determine a global physico-chemical profile for putative PPI inhibitors. This statistical analysis unravels two important molecular descriptors for PPI inhibitors characterizing specific molecular shapes and the presence of a privileged number of aromatic bonds. The best model has been transposed into a computer program, PPI-HitProfiler, that can output from any drug-like compound collection a focused chemical library enriched in putative PPI inhibitors. Our PPI inhibitor profiler is challenged on the experimental screening results of 11 different PPIs among which the p53/MDM2 interaction screened within our own CDithem platform, that in addition to the validation of our concept led to the identification of 4 novel p53/MDM2 inhibitors. Collectively, our tool shows a robust behavior on the 11 experimental datasets by correctly profiling 70% of the experimentally identified hits while removing 52% of the inactive compounds from the initial compound collections. We strongly believe that this new tool can be used as a global PPI inhibitor profiler prior to screening assays to reduce the size of the compound collections to be experimentally screened while keeping most of the true PPI inhibitors. PPI-HitProfiler is freely available on request from our CDithem platform website, www.CDithem.com.

Solvent-free microwave-assisted Meyers' lactamization

Microwave solvent-free conditions developed for Meyers’ lactamization, a typical bielectrophile-binucleophile reaction that produces quaternary centers in a stereoselective manner, give access to Meyers’ chiral lactams in good yield and high diastereoselectivity in short times.

Racemic and diastereoselective construction of indole alkaloids under solvent- and catalyst-free microwave-assisted Pictet–Spengler condensation

An environment-friendly high-yielding method for the racemic and asymmetric diastereoselective preparation of indole alkaloids via Pictet–Spengler reaction is reported. The reaction proceeds with short reaction times under solvent-free and microwave-irradiation conditions.

Derivatives of Iressa, a Specific Epidermal Growth Factor Receptor Inhibitor, are Powerful Apoptosis Inducers in PC3 Prostatic Cancer Cells

The tyrosine kinase activity of the epidermal growth factor receptor (EGFR) is widely involved in signaling pathways and often deregulated in cancer. Its role in the development of prostate cancer is well established, and therapeutic strategies such as blockade of the intracellular tyrosine kinase domain with small‐molecule tyrosine kinase inhibitors have been proposed. Herein we describe the synthesis and in vitro pharmacological properties of C6‐ and C7‐substituted 4‐anilinoquinazolines, analogues of Iressa and powerful proapoptotic inducers in hormone‐independent prostate cancer PC3 cell lines.

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 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).