Clickable Selenylation – a Paradigm for Seleno‐Medicinal Chemistry

Abstract

Selenium (Se) is an emerging versatile player in medicinal chemistry. The incorporation of Se into small molecules and natural products could have multiple benefits. However, the lack of efficient methods for the synthesis of Se-containing chemical library has greatly hindered the development of seleno-medicinal chemistry. With the aim to address this issue, we proposed the development of "clickable selenylation" reactions, which can be used in the synthesis of Se-containing in situ library and DNA-encoded library (SeDEL), thereby quickly producing ultra-large collections of Se-containing compounds and boosting the development of seleno-medicinal chemistry. This research paradigm can be concluded as "clickable selenylation chemistry development!in situ library construction/SeDEL synthesis!phenotype-or target-based screening! seleno-hit compound".

Bioinspired Selenium‐Nitrogen Exchange (SeNEx) Click Chemistry Suitable for Nanomole‐Scale Medicinal Chemistry and Bioconjugation

“…The structure of 15 was unambiguously determined by X-ray crystal analysis. [43] Impressively, functional groups and pharmacophores including terminal alkenyl (3), adamantyl ( 6), primary alcohol (1-18, 69-70), benzyl alcohol (50), primary amine (22,28), tertiary amine (7, 55), nitro (13, 31, 42, 73), ester (14, 23-24, 54), aryl halo (9, 26, 49), alkyl halo (propargyl chloride, 75; 4-bromo-1-butyne, 76), cyano (35,36), aldehyde (41), amide (all cases), sulfonamide (34), silyl (21), phenol (33,62), quinoline (14), pyridine (15, 51, 63-65, 71-72), free and N-substituted pyrazole (16, 66-67), free indazole (17), pyrimidine (52), thiophene (53), carboxyl (43,54) and potential interfering bipyridine group ( 74) are all satisfactorily compatible in this transformation, demonstrating the excellent functional group tolerance of this chemistry. However, benzo[d]isothiazol-3(2H)-one did not work under the standard condition while afforded the desired product 56-S in 82 % yield by elevating the temperature to 70 °C and employing DMF as the solvent, highlighting the superior reactivity of SeÀ N over SÀ N bond (56-S, Supporting Information, Figure S8).…”

“…[40,51] However, most of the synthetic "toolbox" cannot be readily miniaturized. Encouraged by the robust performance, high yields of this SeNEx click chemistry, and our previous effort, [22,37] we subsequently performed a nanomole-scale parallel synthesis (using 200 nmol of natural products per reaction on 96 well-microplates) with a combination of 10 alkynyl-modified complex NPs and 30 BSEAs (Figure 4Ci and Supporting Information, Figure S14 and S15) upon simple agitation. The resulting Se-NP library was analyzed by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS).…”

“…[20] Notably, complement to selenoproteins, Se-containing small molecules can also modulate the oxidative stress status of cells mainly through their antioxidation and pro-oxidation effects. [21,22] As a result, the design and synthesis of organo-Se (Org-Se) compounds to prevent and/or treat diseases has attracted considerable interest in recent years. [23][24][25] However, the research on Org-Se therapeutic agents is still in its infancy as the synthetic toolbox lags severely behind compared to their sulfur counterparts.…”

Mask and Release Strategy‐Enabled Diversity‐Oriented Synthesis for DNA‐Encoded Library

“…[25][26][27][28][29][30][31] The success of DEL in identifying binders is due to its exceptional number and diverse chemotypes, introduced via DNA-compatible chemistry. Rapid advancements in DEL chemistry, [32][33][34] mainly including the building block (BB) connection reactions such as diazo-transfer, [35] amide formation, [36] diarylether synthesis, [37] various cross-coupling reaction, [38][39][40][41][42][43][44][45] C-H activation and functionalization, [46][47][48][49] photopromoted reaction, [50][51][52] sulfur-fluoride exchange (SuFEx) click chemistry, [53] bioinspired click selenylation, [54][55][56] and the progresses of on-DNA privileged heterocycles synthesis have further driven its rapid evolution and applications in basic research and drug discovery. [47,48,65,[57][58][59][60][61][62][63][64] However, at present, it is well recognized that the diversity of DEL is more dependent on the availability of the core skeletons than the commercially available common BBs.…”

Enolate–Azide [3 + 2]-Cycloaddition Reaction Suitable for DNA-Encoded Library Synthesis

“…Actually, the idiosyncratic properties of DNA and the properties of combinatorial synthesis have excluded many conventional organic reactions that have been widely used in modern synthetic medicinal chemistry from the DEL chemistry toolbox. Fortunately, researchers worldwide have dedicated themselves to developing a set of DNA-compatible chemical reactions, for instance, diazo-transfer, diarylether synthesis, amide formation, hydrogenation, cross-coupling reaction, − ring-closing metathesis, C–H activation and functionalization, − photopromoted reaction, sulfur-fluoride exchange (SuFEx) click chemistry, bioinspired click selenylation, , cycloaddition reaction, and the on-DNA synthesis of privileged heterocycles such as isocoumarin, azoles, benzimidazole, pyrazoline, pyrrole, and others. ,− Even so, continuously expanding the toolbox of DNA-compatible chemical reactions that can fulfill the stringent criteria of high fidelity, good conversions, chemoselectivity, predictability, and broad substrate scope is still the pillar to promote the future development of DEL technology.…”