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S-Triazine: a Privileged Structure for Drug Discovery and Bioconjugation

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S-Triazine: a Privileged Structure for Drug Discovery and Bioconjugation molecules Review s-Triazine: A Privileged Structure for Drug Discovery and Bioconjugation Anamika Sharma 1,2 , Rotimi Sheyi 1, Beatriz G. de la Torre 1,2 , Ayman El-Faham 3,4,* and Fernando Albericio 1,3,5,6,* 1 Peptide Science Laboratory, School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa; [email protected] (A.S.); [email protected] (R.S.); [email protected] (B.G.d.l.T.) 2 KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa 3 Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia 4 Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 12321, Egypt 5 Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain 6 CIBER-BBN (Networking Centre on Bioengineering, Biomaterials and Nanomedicine) and Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain * Correspondence: [email protected] (A.E.-F.); [email protected] (F.A.) Abstract: This review provides an overview of the broad applicability of s-triazine. Our many years working with this intriguing moiety allow us to discuss its wide activity spectrum (inhibition against MAO-A and -B, anticancer/antiproliferative and antimicrobial activity, antibacterial activity against MDR clinical isolates, antileishmanial agent, and use as drug nano delivery system). Most Citation: Sharma, A.; Sheyi, R.; of the compounds addressed in our studies and those performed by other groups contain only de la Torre, B.G.; El-Faham, A.; N-substitution. Exploiting the concept of orthogonal chemoselectivity, first described by our group, Albericio, F. s-Triazine: A Privileged we have successfully incorporated different nucleophiles in different orders into s-triazine core for Structure for Drug Discovery and Bioconjugation. Molecules 2021, 26, application in peptides/proteins at a temperature compatible with biological systems. 864. https://doi.org/10.3390/ molecules26040864 Keywords: s-triazine; nucleophiles; azide; orthogonal chemoselectivity Academic Editors: Julio A. Seijas Vázquez and María Ángeles Castro Received: 4 January 2021 1. Introduction Accepted: 4 February 2021 1,3,5-Triazine as s-triazine is an extensively studied privileged structure in medicinal Published: 6 February 2021 chemistry [1–5]. 2,4,6-Trichloro-1,3,5-triazine (TCT) is the starting core to afford several s-triazine derivatives, taking advantage of its low cost and easy manipulation of three Publisher’s Note: MDPI stays neutral independent, readily tunable ring positions, which facilitates the sequential nucleophilic with regard to jurisdictional claims in substitutions reactions with almost all types of nucleophiles (S, O and N) [6–12]. Figure1 published maps and institutional affil- shows the typical order of nucleophile incorporation onto TCT. The incorporation of the first iations. nucleophile can be performed at 0–5 ◦C, while the second one requires room temperature, and the third heating or reflux [13–15]. The reactivity of the s-triazine ring decreases upon substitution with different nucleophiles due to a gain of π-orbital electron density, thereby reducing the effectiveness of further nucleophilic substitution reactions under similar Copyright: © 2021 by the authors. conditions and thus requiring a higher temperature for further substitutions [8,16]. Licensee MDPI, Basel, Switzerland. s-Triazine is extensively studied because of its wide applications in biological systems This article is an open access article as an antibacterial, antiviral, anticancer, and antifungal agent, etc. [1,5,17,18]. Several distributed under the terms and commercial drugs contain the s-triazine core (Figure2)[ 3,5]. Apart from their applica- conditions of the Creative Commons tion as pharmacophores and in medicinal chemistry, s-triazine derivatives are useful as Attribution (CC BY) license (https:// organic reagents, energetics, and new materials (dendrimers, supra-molecular aggregates, creativecommons.org/licenses/by/ etc.) [4,12,19,20]. 4.0/). Molecules 2021, 26, 864. https://doi.org/10.3390/molecules26040864 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 864 2 of 19 Molecules 2021,, 26,, 864864 2 of 1719 Figure 1. 2,4,6-Trichloro-1,3,5-triazine (TCT) reactivity toward the nucleophilic substitution reaction. s-Triazine is extensively studied because of its wide applications in biological sys- tems as an antibacterial, antiviral, anticancer, and antifungal agent, etc. [1,5,17,18]. Several commercial drugs contain the s-triazine core (Figure 2) [3,5]. Apart from their application as pharmacophores and in medicinal chemistry, s-triazine derivatives are useful as or- ganic reagents, energetics, and new materials (dendrimers, supra-molecular aggregates, Figure 1. 2,4,6-Trichloro-1,3,5-triazine2,4,6-Trichloro-1,3,5-triazineetc.) [4,12,19,20]. (TCT) reactivity toward the nucleophilicnucleophilic substitutionsubstitution reaction.reaction. s-Triazine is extensively studied because of its wide applications in biological sys- tems as an antibacterial, antiviral, anticancer, and antifungal agent, etc. [1,5,17,18]. Several commercial drugs contain the s-triazine core (Figure 2) [3,5]. Apart from their application as pharmacophores and in medicinal chemistry, s-triazine derivatives are useful as or- ganic reagents, energetics, and new materials (dendrimers, supra-molecular aggregates, etc.) [4,12,19,20]. Figure 2. Some commercial drugs bearing the s-triazine ring. TakingTaking advantage ofof thethe uniqueunique reactivity reactivity shown shown by by TCT, TCT, we we have have synthesized synthesized several sev- erals-triazine s-triazine derivatives derivatives and and evaluated evaluated their their activity activity for several for several biological biological targets, targets, which which will willbe discussed be discussed in subsequent in subsequent sections sections [13,14 ,[1213,14,21–28].–28]. TCT has TCT been has further been further explored explored as a linker as athat linker encompasses that encompasses two key two chemical key chemical concepts, concepts, namely namely orthogonality orthogonality and chemoselectiv- and chemose- lectivityity [8,16, 29[8,16,29].]. This review This review compiles compiles all these all results these onresults TCT andon TCT broadly and covers broadly the covers following the followingthreeFigure sections: 2. three Some synthetic sections:commercial strategy;synthetic drugs bearing biological strategy; the s-triazine activity;biological andring. activity; orthogonal and orthogonal chemoselectivity. chemose- lectivity. 2. SynthesisTaking advantage of s-Triazine of the Derivatives unique reactivity shown by TCT, we have synthesized sev- 2.eral Synthesis s-triazineSeveral of derivatives derivatives s-Triazine were and Derivatives synthesizedevaluated their via activity different for routes, several resulting biological in eighttargets, series, which as willshown be discussed in Scheme in1. subsequent The replacement sections of the[13,14,21–28]. first and second TCT has Cl been atoms further was achieved explored inas Several derivatives were◦ synthesized via different routes, resulting in eight series, as shownathe linker presence in that Scheme encompasses of a 1. base The at replacement two 0 C key and chemical room of the temperature firstconcepts, and second namely (rt), respectively.Cl orthogonality atoms was Differentachieved and chemose- nucle-in the ophiles like piperidine, morpholine, benzylamine, and methanol (MeOH) were used for presencelectivity [8,16,29].of a base Thisat 0 °C review and room compiles temperat all theseure (rt), results respectively. on TCT and Different broadly nucleophiles covers the the replacement of the first and second Cl atoms in the presence of bases such as triethy- likefollowing piperidine, three morpholine,sections: synthetic benzylamine, strategy; and biological methanol activity; (MeOH) and wereorthogonal used for chemose- the re- lamine (TEA), diisopropylethylamine (DIEA), Na CO , etc. Series 1 was synthesized using placementlectivity. of the first and second Cl atoms in the2 presence3 of bases such as triethylamine dimethoxy-substituted s-triazine [21]. In this series, a solution of dimethoxy-substituted (TEA), diisopropylethylamine (DIEA), Na2CO3, etc. Series 1 was synthesized using di- 2.s-triazine Synthesis and of TEA s-Tr iniazine dioxane Derivatives was reacted until a white suspension formed. A solution of methoxy-substituted s-triazine [21]. In this series, a solution of dimethoxy-substituted s- amino acid and TEA in dioxane-H O (1:1) was added to form a clear solution. The reaction triazineSeveral and TEAderivatives in dioxane were was synthesized 2reacted until via diff a whiteerent routes,suspension resulting formed. in eight A solution series, ofas was stirred overnight at rt followed by neutralization with 1N HCl to yield a white solid, aminoshown acid in Scheme and TEA 1. Thein dioxane-H replacement2O (1:1) of the was first added and secondto form Cla clear atoms solution. was achieved The reaction in the which afforded the desired products (seven derivatives) upon filtration and drying. In waspresence stirred of overnighta base at 0 at °C rt and followed room bytemperat neutralizationure (rt), respectively.with 1N HCl Different to yield a nucleophiles white solid, likeSeries piperidine,
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