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Peptidomimetics are a privileged class of pharmacophores that exhibit improved physicochemical and biological properties. Solid-phase synthesis is a powerful tool for gaining rapid access to libraries of molecules from small molecules to biopolymers and also is widely used for the synthesis of peptidomimetics. Small molecules including heterocycles serve as a core for hundreds of drugs, including peptidomimetic molecules. This review covers solid-phase synthesis strategies for peptidomimetics molecules based on heterocycles.

Microwave-assisted solid-phase synthesis method was simple, convenient, and fast, and herein adopted to produce nitrogen-doping carbon dots (N-CDs) in only 3 min. The N-CDs possessed high fluorescence quantum yield up to 15.9% with satisfactory stability to the environmental pH, ionic strength, and ultraviolet radiation. Particularly, the N-CDs had excellent dispersibility in both water and water-compatible organic solvents with similar fluorescence properties. Sunitinib, a small-molecule tyrosine inhibitor effective for some solid tumors, was found to quench the fluorescence of N-CDs in these media via the inner-filter effect. Hence, it was convenient to combine the proper sample pretreatment with the N-CD probe for sensing sunitinib avoiding the medium incompatibility problem. For rat plasma sample, salting-out liquid-liquid extraction was employed to minimize the sample matrix and concentrate the target sunitinib from aqueous to acetonitrile. The fluorescence detection of sunitinib was then achieved in acetonitrile by the addition of the proper amount of N-CDs. The method provided a good linearity of 0.1 μg/mL to 7 μg/mL with a limit of detection of 30 ng/mL, which met the requirement of the therapeutic drug monitoring of sunitinib. The developed method was potential for on-site detection of sunitinib.

Optimizing linker design is important for ensuring efficient degradation activity of proteolysis‐targeting chimeras (PROTACs). Therefore, developing a straightforward synthetic approach that combines the protein‐of‐interest ligand (POI ligand) and the ligand for E3 ubiquitin ligase (E3 ligand) in various binding styles through a linker is essential for rapid PROTAC syntheses. Herein, a solid‐phase approach for convenient PROTAC synthesis is presented. We designed azide intermediates with different linker lengths to which the E3 ligand, pomalidomide, is attached and performed facile PROTACs synthesis by forming triazole, amide, and urea bonds from the intermediates. A convenient solid‐phase PROTAC synthesis method that allows the conjugation of a POI ligand and an E3 ligand with linkers of various binding styles, was developed. Specifically, PROTACs with triazole, amide, and urea bonds were rapidly synthesized from azide intermediates on the resin.

Organoboron compounds have a wide range of applications in numerous research fields, and methods to incorporate them in biomolecules are much sought after. Here, on‐resin chemical syntheses of aliphatic and vinylogous peptide boronic acids are presented by transition metal‐catalyzed late‐stage hydroboration of alkene and alkyne groups in peptides and peptoids, for example on allyl‐ and propargylglycine residues, using readily available chemicals. These methods yield peptide boronic acids with much shorter linkers than previously reported on‐resin methods. Furthermore, the methods are regio‐ and stereoselective, compatible with all canonical amino acid residues and can be applied to short, long, and in part even “difficult” peptide sequences. In a feasibility study, the protected peptide vinylboronic acids are further derivatized by the Petasis reaction using salicylaldehyde derivatives. The ability of the obtained peptide boronic acids to reversibly bind to carbohydrates is demonstrated in a catch‐release model experiment using a fluorescently labeled peptide boronic acid on cross‐linked dextran beads. In summary, this highlights the potential of the target compounds for drug discovery, glycan‐specific target recognition, controlled release, and diagnostics. Transition metal‐catalyzed hydroboration of peptide alkenes and alkynes with readily available reactants selectively yields aliphatic‐ and vinylboronic acids in a straightforward, on‐resin, late‐stage functionalization approach. Reversible binding of the obtained peptide boronic acids to carbohydrates and further functionalization by Petasis reaction is also demonstrated.

All known methods for solid-phase synthesis of molecular arrays exploit positioning techniques to deposit monomers on a substrate preferably high densely. In this paper, stochastic patterning of molecule spots (250 000 spots monomers/cm 2 ) via random allocation of the microbeads on a microstructured glass is presented. The size and shape of the microbeads and the microcavities are selected in such a way so that only one microbead can fit into the respective microcavity. Each microbead can be loaded with a certain type of molecule e.g. amino acids and is brought in the microcavities stochastically. Applying solvent vapor and heating the substrate, the molecules are released from the microbeads and coupled to the functionalized substrate. To differentiate between the microbeads carrying different molecules, quantum dot labels are preliminary introduced into the microbeads. Fluorescence imaging and subsequent data analysis enable decoding of the molecule deposition patterns. After the coupling step is completed, the microbeads are mechanically removed from the microwells. The composition of the monomer microbeads, their deposition and the conditions of the monomer extraction are studied. The stochastic monomer patterning may be used to design novel molecular arrays.

Many methods have been developed for attaching an alcohol functionality to a solid support. However, not all of these methods are used to obtain peptide alcohols. In this Minireview, we will discuss several of the most important methods and approaches for the synthesis of peptide alcohols and the attachment of hydroxy groups to a solid support for the synthesis of cyclic peptides. Some of the methods include the use of functionalized Wang resin and the attachment of an alcohol to an enol ether resin. We also discuss the use of the chlorotrityl resin, one of the most common linkers used to obtain peptide alcohols. In addition, we outline the recently developed resins with the Rink, Ramage and Sieber handles. The majority of these methods have been used to synthesize many important drugs, such as octreotide and the antibiotic peptaibols. Several of the most important methods and approaches developed for the synthesis of peptide alcohols and the attachment of hydroxy groups to a solid support for the synthesis of cyclic peptides (head‐to‐tail) are reviewed. These methods include those involving the use of Wang trichloroacetamide, chlorotrityl chloride (CTC), dihydropyran, and many other resins. Several of the methods discussed here have been used to synthesize important drugs such as octreotide and the antibiotic alamethicin.

Amidine-substituted phenylbenzimidazoles are well-established DNA-binding structural motifs that have contributed to the development of diverse classes of DNA-targeted agents; this ring system not only assists in increasing the overall DNA affinity of an agent, but can also influence its site selectivity. Seeking a means to conveniently exploit these attributes, a protocol for the on-resin synthesis of amino acid- and peptide-phenylbenzimidazole-amidine conjugates was developed to facilitate installation of phenylbenzimidazole-amidines into peptide chains during the course of standard solid-phase syntheses. Building from a resin-bound amino acid or peptide on Rink amide resin, 4-formyl benzoic acid was coupled to the resin-bound free amine followed by introduction of 3,4-diamino-N′-hydroxybenzimidamide (in the presence of 1,4-benzoquinone) to construct the benzimidazole heterocycle. Finally, the resin-bound N′-hydroxybenzimidamide functionality was reduced to an amidine via 1 M SnCl₂·2H₂O in DMF prior to resin cleavage to release final product. This procedure permits the straightforward synthesis of amino acids or peptides that are N-terminally capped by a phenylbenzimidazole-amidine ring system. Employing this protocol, a series of amino acid–phenylbenzimidazole-amidine (Xaa-R) conjugates was synthesized as well as dipeptide conjugates of the general form Xaa-Gly-R (where R is the phenylbenzimidazole-amidine and Xaa is any amino acid).

Recent advances in end-to-end continuous-flow synthesis are rapidly expanding the capabilities of automated customized syntheses of small-molecule pharmacophores, resulting in considerable industrial and societal impacts; however, many hurdles persist that limit the number of sequential steps that can be achieved in such systems, including solvent and reagent incompatibility between individual steps, cumulated by-product formation, risk of clogging and mismatch of timescales between steps in a processing chain. To address these limitations, herein we report a strategy that merges solid-phase synthesis and continuous-flow operation, enabling push-button automated multistep syntheses of active pharmaceutical ingredients. We demonstrate our platform with a six-step synthesis of prexasertib in 65% isolated yield after 32 h of continuous execution. As there are no interactions between individual synthetic steps in the sequence, the established chemical recipe file was directly adopted or slightly modified for the synthesis of twenty-three prexasertib derivatives, enabling both automated early and late-stage diversification.Although strategies for the automated assembly of compounds of pharmaceutical relevance is a growing field of research, the synthesis of small-molecule pharmacophores remains a predominantly manual process. Now, an automated six-step synthesis of prexasertib is achieved by multistep solid-phase chemistry in a continuous-flow fashion using a chemical recipe file that enables automated scaffold modification through both early and late-stage diversification.

A series of N‐terminally Fmoc‐protected linkers of the general formula Fmoc‐X−CO−O−Y−COOH have been prepared, where X is −NH−CH2−CH2‐ or ‐p‐(aminomethyl)phenyl‐ and Y is −(CH2)n− (n is 1 or 4) or ‐p‐(methyl)phenyl‐. These linkers can easily be covalently attached via their C‐terminal carboxyl group to a resin bearing a free amino group. After cleavage of the N‐terminal Fmoc group, the linkers can be extended by standard solid‐phase peptide synthesis techniques. These ester linkers are acid‐stable and resistant to the base‐mediated diketopiperazine formation that often occurs during the synthesis of ester‐bound peptides; they are stable at neutral pH in aqueous buffers for days but can be effectively cleaved with 0.1 m NaOH or aq. ammonia within minutes or hours, respectively. These properties make these ester handles well suited for use as linkers for the solid‐phase peptide synthesis of immobilized peptides when the stable on‐resin immobilization of the peptides and the testing of their biological properties in aqueous buffers at neutral pH are necessary. The missing link: A series of Fmoc‐protected ester linkers for the solid‐phase synthesis of immobilized peptides was prepared, and the stability of linkers in buffers was studied. The linkers are fully compatible with Fmoc‐tBu peptide synthesis, resistant to diketopiperazine formation, and stable in aqueous buffers with neutral pH values, but cleavable with 0.1 M NaOH or aqueous ammonia. These ester handles are optimal for the synthesis of immobilized peptides and their biological applications.

The excellent optical properties and biocompatibility of red fluorescence carbon dots (R-CDs) provide a new approach for the effective analysis of hexavalent chromium Cr(VI) in environmental and biological samples. However, the application of R-CDs is still limited by low yield and unfriendly synthesis route. In this study, we developed a new type of R-CDs based on a simple and green solid-phase preparation strategy. The synthesized R-CDs can emit bright red fluorescence with an emission wavelength of 625 nm and also have an obvious visible light absorption capacity. Furthermore, the absorption and fluorescence signals of the R-CDs aqueous solution are sensitive to Cr(VI), which is reflected in color change and fluorescence quenching. Based on that, a scanometric and fluorescent dual-mode analysis system for the rapid and accurate detection of Cr(VI) was established well within the limit of detection at 80 nM and 9.1 nM, respectively. The proposed methods also possess high specificity and were applied for the detection of Cr(VI) in real water samples. More importantly, the synthesized R-CDs with good biocompatibility were further successfully applied for visualizing intracellular Cr(VI) in Hela cells.