Mol2Net-04 Utilization of click chemistry in drug discovery. - PDF document

Mol2Net-04 , 2018 , BIOCHEMPHYS-01 (pages 1- x, type of paper, doi: xxx-xxxx http://sciforum.net/conference/mol2net-4 SciForum Mol2Net-04 Utilization of click chemistry in drug discovery. Applications to the synthesis of new bioactive triarylmethanes Ameni Hadj Mohamed * 1, 2 , Mehdi El Arbi 3 , Moncef Msaddek 2 , Maité Sylla-Iyarreta Veitía * 1 1 Equipe de Chimie Moléculaire, Laboratoire Génomique, bioinformatique et chimie Moléculaire GBCM, EA 7528, Conservatoire national des arts et métiers, 2 rue Conté, 75003, Paris France; HESAM Université maite.sylla@lecnam.net 2 Laboratoire de Chimie Hétérocyclique, Produits Naturels et réactivité (LR11ES39). Faculté des Sciences de Monastir, Université de Monastir, Boulevard de l'Environnement, 5019, Monastir, Tunisie; moncefmsadek@gmail.com Laboratoire de Biotechnologie Microbienne et d’Ingénierie des Enzymes (LBMIE). Centre de 3 Biotechnologie de Sfax, Université de Sfax, Route de Sidi Mansour Km 6, BP 1177, 3018 Sfax, Tunisie; mehdi_arbi@yahoo.fr * Author to whom correspondence should be addressed; E-Mail: amenihajmohamed@gmail.com, maite.sylla@lecnam.net Tel.: +33-1-58 80 84 82 Received: / Accepted: / Published: Abstract: The process of drug discovery or lead optimization involves the efficient synthesis of molecules and the creation of chemical libraries. For this reason, the rapid generation of new molecules is essential. Originally defined by Professors Barry K. Sharpless and M. G. Finn in 2001, click chemistry is a very powerful tool to develop a set of original, selective, and modular building blocks such as azide and alkyne in small and large scales. It is a new type of chemistry that generates complex molecules in an efficient way. The applications of this modular approach concern several domains of drug discovery, extending from lead finding through combinatorial chemistry, bionanoparticles, target-template to proteomics and DNA research using bioconjugation reactions. This article summarizes some progress and applications of click chemistry in drug discovery. We also describe the synthesis and characterization of a new triarylmethane prepared in our laboratory using this chemical strategy. Keywords: click chemistry, drug discovery, cycloaddition reaction, 1,2,3 triazole. 1. Introduction Thus, click chemistry has recently emerged to In the recent years, there has been an ever- become one of the most powerful tools in drug increasing need for powerful, straightforward and discovery, chemical biology, and proteomic rapid strategies for drug discovery. Despite many applications. Using the most facile and selective successes, drug discovery approaches that are chemical transformations, click chemistry often hampered by slow and complex syntheses. simplifies compound synthesis, providing the

Mol2Net , 2018 , 1(Section A, B, C, etc.), 1- x, type of paper, doi: xxx-xxxx 2 faster lead discovery and optimization. aromatic or heteroaromatic sulfonamides whose anion coordinates to the Zn 2+ ion in the active site. Furthermore, the ease of purification of product, the simplicity of this reaction has opened new Authors chosen the acetylenic benzenesulfon- pathways in generating new series of compounds amide (1) as a reactive scaffold for capturing complementary azide reagents to form “divalent” with a therapeutic interest. Click reaction promotes essential criteria of a good synthesis process CA inhibitors in situ . Compound 1 binds to bovine efficiency, versatility and selectivity. It includes carbonic anhydrase II with nanomolar affinity simple conditions without any insensitivity to (K d =37 nM±6) (Scheme 1). oxygen or water, readily available starting materials and reagents, no solvents or green and bovine carbonic anhydrase II O (1 mg/mL. approx. 30 µM) O N N ecofriendly solvents such as water, successful S N 3 R S N R 1 H 2 N O aq. buffer pH 7.4 H 2 N O 37°C, 40 h performance at room temperature and simple (400 µM) O K d =37 nM±6 (bCA II) R 2 purification without using chromatography. The 1 2 3 present article highlights some applications of R 1 R 2 click chemistry in medicinal chemistry with a particular insight into the Cu(I) catalyzed Huisgen cycloaddition, the most studied reaction between 3a i- Pr an azide and a terminal alkyne affording the 1,2,3- NH triazole moiety. This reaction allows the S 3b introduction of a wide range of substituents. Bn N H Moreover, triazoles are a privileged structures in medicinal chemistry present in numerous bioactive compounds such as anticancer[1-3] , antifungal, N 3c i- Pr N H antibacterial[4-6], antituberculosis [7-9] and antiviral compounds [10-12]. Triazoles have also Scheme 1: In situ screening protocol and reagents the interesting physicochemical properties. They used to develop carbonic anhydrase inhibitors by are stable to acid and basic hydrolysis and in situ click chemistry. reductive and oxidative conditions, indicative of a high aromatic stabilization. Its high dipole moment In situ click experiments were performed in a 96- allows to participate actively in hydrogen bond well microtiter plates with each well containing a formation as well as in dipole-dipole and  mixture of bovine CA II (bCA II), an acetylenic stacking interactions. In some cases, triazole benzenesulfonamide at a concentration enough to moiety improve pharmacokinetic properties. saturate the enzyme active site, and a We also present an example developed in our corresponding azide reagent in phosphate buffer laboratory concerning the functionalization by solution (pH 7.4). The formation of the product (3) click chemistry of a new bioactive triarylmethane. was monitored by HPLC analysis and mass spectrometry by electrospray ionization. Each 1.1 In situ Click Chemistry acetylene/azide combination was incubated with mixtures of enzyme and the known active-site Kolb and co-workers have successfully employed inhibitors ethoxazolamide and with bovine serum the in situ click-chemistry to identify a novel albumin in place of bCAII. carbonic anhydrase (CA) inhibitors. Analysis of the crude reaction mixture with Carbonic anhydrases are zinc-containing enzymes LCMS-SIM revealed that 12 out of the 24 reagent involved in respiration processes and the transport combinations acetylene/azide led to triazole of CO 2 /HCO 3- , acid secretion and pH control, formation in the presence of the enzyme. Most of calcification acetylene/azide and tumorigenicity. the in situ hits are derived from α -substituted azido Carbonic anhydrase inhibitors have long been used acid amides. The results obtained by the authors to control the elevated intraocular pressure related revealed that enzyme reaction was highly anti- with glaucoma. Furthermost inhibitors are selective compared with the thermal cycloaddition.

Mol2Net , 2018 , 1(Section A, B, C, etc.), 1- x, type of paper, doi: xxx-xxxx 3 This suggest that the formation of the product is In 2015, the same authors successfully applied enzyme controlled [13]. CuAAC click chemistry in order to develop a similar delivery system for analogues of AZT- 1.2 Click chemistry for functionalizing triphosphates (AZT*TP) based on SiO 2 nanoparticles to drug delivery application nanoparticles. The results obtained demonstrated a possibility of Vasilyeva and co-workers explored click the utilization of SiO 2 nanoparticles as vehicles for chemistry to develop a delivery system for 2’ - the delivery of nucleoside triphosphates analogues deoxyribonucleoside triphosphates. They designed into cells. It was shown that the proposed SiO 2 nanocomposites conta ining analogues of 2’ - dNTP nanocomposites (9,10) penetrated into deoxyribonucleoside triphosphate (dNTP) eukaryotic cells. Preliminary result also displayed immobilized into SiO 2 and to study their substrate that these nanocomposites at low concentrations properties in reactions catalyzed by DNA can inhibit the reproduction of Herpes viruses. All polymerases and their ability to penetrate into this justify the use of nanobiocomposites bearing eukaryotic cells. nucleoside triphosphate analogues as promising They suggested a simple and versatile method of therapeutic drugs [15]. their covalent attachment to nanoparticle: the click 1.3 Click chemistry for reengineering drugs reaction between premodified nanoparticles (6) bearing the azido groups and dNTP bearing the alkyne-modified gamma-phosphate group (7,8) . Click chemistry has been used for reengineering Scheme 2 illustrates the cooper(I)-catalyzed azide- drugs. Thus, Silverman and co-workers reported a alkyne cycloaddition (CuAAC) reaction that click chemistry approach towards reengineered resulted in the formation of the wanted vancomycin derivatives with high potency against nanocomposites (9,10) [14]. methicillin-resistant aureus Staphylococcus (MRSA) and vancomycin resistant Enterococci (VRE; VanB). They synthesized a series of click O SiO 2 NH 2 O vancomycin derivatives starting from vancomycin 5 H N SiO 2 N N 3 N 3 Et 3 N O itself (11) (Scheme 3). O 4 O 6 DMSO CuSO 4 /TBTA, O O O Na ascorbate B HN P O P O P O O O - O - O - H 2 O/DMSO O OH 7, 8 H SiO 2 N N N N O O O O B NH P O P O P O O O O - O - O - OH 9, 10 NH 2 7, 9 B= N OH O N O O 8, 10 B= O S O O N N H H HN OH O N Scheme 2: Functionalizing of SiO 2 Scheme 3: Synthesis of vancosamine modified nanoparticles by click chemistry triazole derivative