Synthesis of Cyclic Oligopeptide via Condensation of Aromatic Nitrile Derivatives with Aminothiols: Enhancing Peptide Permeability and Intracellular Retention

Synthesis of Cyclic Oligopeptide via Condensation of Aromatic Nitrile Derivatives with Aminothiols: Enhancing Peptide Permeability and Intracellular Retention | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 9 March 2026 V1 Latest version Share on Synthesis of Cyclic Oligopeptide via Condensation of Aromatic Nitrile Derivatives with Aminothiols: Enhancing Peptide Permeability and Intracellular Retention Authors : Anning Guo , Luo Chen , Zheng Xu , Bingyan Li , Haidi Song , Shuli Zhao , Guoqiang Shao , Feng Wang , and Ke Jiang [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.177303476.66085792/v1 137 views 36 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract While traditional cyclization often relies on catalysts or alkaline conditions with limited biocompatibility, the Nitrile-Aminothiol strategy provides a highly biocompatible alternative. By introducing short alkyl chains, we optimized the intramolecular cyclization efficiency and improved the peptide's drug-like properties. Remarkably, this method enhances both membrane permeability and intracellular retention in tumor cells, highlighting its significant promise for nuclear medicine applications. Cite this paper: Chin. J. Chem. 2025 , 43 , XXX—XXX. DOI: 10.1002/cjoc.70XXX Synthesis of Cyclic Oligopeptide via Condensation of Aromatic Nitrile Derivatives with Aminothiols: Enhancing Peptide Permeability and Intracellular Retention Anning Guo, a,b,1 Luo Chen a,b,1 , Zheng Xu d,1 , Bingyan Li a,b , Haidi Song a, b,c , Shuli Zhao d , Guoqiang Shao d *, Feng Wang d *, Ke Jiang a,b * a Nanjing Advanced Academy of Life and Health, Nanjing, China b Department of Life Sciences, Health, and Safety, University of Chinese Academy of Sciences, Nanjing，China c Nanjing Normal University, Nanjing, China d Nanjing First Hospital, Nanjing, China Aromatic nitriles | Aminothiols| Oligopeptides| Intramolecular condensation | Nuclear medicine | Comprehensive Summary While traditional cyclization often relies on catalysts or alkaline conditions with limited biocompatibility, the Nitrile-Aminothiol strategy provides a highly biocompatible alternative. By introducing short alkyl chains, we optimized the intramolecular cyclization efficiency and improved the peptide’s drug-like properties. Remarkably, this method enhances both membrane permeability and intracellular retention in tumor cells, highlighting its significant promise for nuclear medicine applications. Background and Originality Content Peptide-based therapeutics represent a rapidly growing class of pharmaceuticals, offering high target specificity and potency. However, linear peptides often suffer from inherent limitations, including poor metabolic stability, rapid clearance, and limited cell permeability，which collectively hinder their therapeutic efficacy and clinical translation. [1] Peptide cyclization has emerged as a powerful strategy. This approach confers enhanced conformational rigidity, leading to improved biological activity, proteolytic resistance, pharmacokinetic profiles, and target binding affinity. [2, 3] Despite their advantages, the development of efficient and broadly applicable cyclization methods for structural oligopeptides remains an active research frontier. Conventional cyclization techniques-including lactamization, disulfide bridge formation, palladium(II)-catalyzed late-stage C(sp2)–H amination of tryptophan-containing peptides (e.g., C4 diversification), palladium(II)-catalyzed tandem γ-C(sp2)–H arylation/cyclization of arylglyoxals with aryl iodides, and copper-catalyzed azide-alkyne cycloaddition (CuAAC, ”click chemistry”)- often suffer from inherent drawbacks such as susceptibility to enzymatic or reductive degradation and limited scalability. [4-8] Consequently, novel cyclization chemistries are highly desirable to advance the development of stable and effective peptide therapeutics. To address these limitations, we selected the aromatic nitrile–aminothiol condensation reaction as a macrocyclization strategy. [9] A critical design criterion required preferential intramolecular cyclization over intermolecular dimerization, necessitating kinetic discrimination between these pathways. The specific condensation reaction between aromatic nitrile derivatives and cysteine thiols has emerged as a powerful bio-orthogonal tool with significant implications across biomedicine and biomedical engineering. [10] Characterized by chemo-selectivity, rapid kinetics, and inherent biocompatibility, this reaction enables precise biomolecular construction and modification under physiological conditions. [11] These attributes facilitate diverse applications, including: 1) activatable probes for molecular imaging, diagnostics, and protein modification. For example, Jianghong Rao’s group utilized an N-terminal cysteine tag and small-molecule probes bearing a cyanobenzothiazole (CBT) unit to specifically label proteins. They developed a Caspase-3-activatable self-assembling probe, Ac-Asp-Glu-Val-Asp-Cys(StBu)-Lys(DOTA(Gd))-CBT (DEVDCS-Gd-CBT), for apoptosis imaging. [12, 13] Similarly, Gaoling Liang’s group designed a near-infrared (NIR) fluorescence probe, Cys(StBu)-Ile-Glu-Phe-Asp-Lys(Cy5.5)-CBT (Cy5.5-CBT), which employs a reduction-guided CBT-Cys click condensation for imaging granzyme B (GraB). The group also developed a photoacoustic (PA) probe, Cypate-CBT, that self-assembles into Cypate-containing nanoparticles in response to elevated intracellular glutathione (GSH) and cathepsin B (CTSB) in tumor cells, enabling sensitive and specific detection of CTSB activity. [14, 15] 2) Engineering of functional biomaterials, such as hydrogel crosslinking and surface functionalization with bioactive peptides or proteins (Scheme 1a). [16] These strategies are fundamental for fabricating tissue engineering scaffolds and stimuli-responsive drug delivery systems. The combined advantages of specificity, efficiency, and biocompatibility continue to drive the adoption of this chemistry for advanced biomedical innovations. [17] This report details the development of a rapid and efficient synthetic strategy for the cyclization of oligopeptides, employing an intramolecular condensation reaction between aromatic nitrile derivatives with alkyl moieties and cysteine residues to form stable covalent linkages, thereby generating structurally defined cyclic peptides (Scheme. 1b). [18] While previous studies have utilized analogous reactions for peptide cyclization, the modifications were primarily focused on achieving cyclization itself. In this work, we introduced alkyl moieties into the nitrile–aminothiol strategy, thereby revealing remarkable advantages of this cysteine-directed crosslinking approach: it proceeds under remarkably mild and physiologically compatible conditions， [19] exhibits good functional group tolerance, and yields cyclic constructs with enhanced metabolic stability, improved cellular internalization efficiency, and increased tumor-targeted uptake and retention properties. [20-22] These features are critical for therapeutic and diagnostic applications, particularly in nuclear medicine. [23] We investigate the key synthetic challenges associated with this intramolecular cyclization process, including optimization and considerations for scale-up. The report also highlights the method’s potential for advancing next-generation peptide radiopharmaceuticals, positioning it as a versatile tool for translational drug discovery. Scheme 1 Application of condensation reaction between aromatic nitrile derivatives and aminothiols. (Reproduced with permission from ref. [12-15] ) Results and Discussion Existing kinetic studies have established a second-order rate constant of 2.9 ± 0.3 M⁻¹s⁻¹ for intermolecular dimerization between CBT (2-cyanobenzothiazole) and cysteine. [24] Since aromatic nitrile reactivity is modulated by electronic effects, steric hindrance, and heteroatom composition, we performed kinetic profiling of commercially available derivatives 1-3 to establish structure-activity relationships. HPLC-based determination of second-order rate constants with L-cysteine (Table 1) revealed that: compound 1 showed undetectable reactivity; compound 2 exhibited a rate constant of 0.15 ± 0.04 M⁻¹s⁻¹; compound 3 demonstrated significantly lower reactivity (0.08 ± 0.02 M⁻¹s⁻¹), consistent with the enhanced electron-donating capacity of its methoxy group versus the methyl substituent in 2. Collectively, the superior reactivity of CBT relative to compounds 2-3 establishes that dual nitrogen atoms in the heteroaromatic system substantially enhance nitrile electrophilicity. Building on these findings, we next synthesized alkoxy derivatives 4 and 5 with different chain lengths to optimize reactivity (Table 1). The kinetic analysis showed that the rate constants decreased to 0.05 ± 0.002 M⁻¹s⁻¹ for 4 and 0.02 ± 0.003 M⁻¹s⁻¹ for 5 , confirming that reaction kinetics are modulated by alkyl chain length. It is known that cyclization increases molecular lipophilicity, and the introduction of aliphatic chains can exacerbate this effect, potentially compromising drug-like properties. Therefore, by applying our expertise in in-situ nanoprecipitation technology, we selected derivative 5 as the optimal cyclization motif. To validate the feasibility of this cyclization strategy for synthesizing cyclic oligopeptides, we designed oligopeptides with varied molecular properties. Reaction conditions including substrate concentration, reaction time, and pH were systematically optimized to maximize intramolecular cyclization yield (Table 2). Notably, model compound M1 (Scheme. 1a, R₂ = not applicable) showed undetectable cyclization below 500 μM. At elevated concentrations (1-20 mM), however, both rate and yield of intermolecular condensation products increased in a concentration-dependent manner (Fig. S18). This behavior is consistent with the rigid structural framework of M1 limiting conformational flexibility, thereby reducing productive molecular collisions. Consequently, efficient intermolecular condensation requires high concentrations to overcome the kinetic barriers. To test this hypothesis, glycine (which lacks a side chain) was incorporated into the M1 scaffold, resulting in M2 (Scheme. 2a). Similar to M1 , no reaction was observed below 500 μM. However, at 10-20 mM, M2 achieved a 95% yield of intermolecular condensation products (Fig. S18), confirming that reduced conformational rigidity facilitates intermolecular reactivity. Based on these findings, we hypothesized that increasing the distance between the aromatic nitrile derivative and the aminothiol moiety would enhance molecular flexibility and promote intramolecular cyclization. To investigate this, lysine or cysteine residues were introduced into the M2 framework, generating M3 and M4 , respectively (Scheme. 2a). HPLC analysis revealed that inserting two amino acid spacers between the aromatic nitrile and the aminothiol enabled selective intramolecular cyclization (Fig. S18). Crucially, this selectivity was unaffected by side-chain steric hindrance or the presence of additional amine/ thiol groups. To further explore the scope of the intramolecular cyclization, the peptide chain length was expanded by incorporating residues with diverse hydrophilic and hydrophobic properties ( M5 , M6 ; Scheme. 2a). Intramolecular cyclization proceeded efficiently with both hydrophilic and hydrophobic spacers. To evaluate the effects of charge, we introduced arginine (positively charged) or glutamate (negatively charged) adjacent to the cysteine residue, yielding M7 and M8 (Scheme. 2a). Neither positive nor negative charge inhibited the intramolecular cyclization. Table 1 Condensation reaction rate constants between the aromatic nitriles and aminothiols. 1 No 2 0.15 ± 0.04 3 0.08 ± 0.02 4 0.05 ± 0.002 5 0.02 ± 0.003 a 2nd Order rate constants were measured in PBS buffer at room temperature with HPLC assay. The rate constants were reported in reference. [24] Finally, to demonstrate the applicability of this method for oligopeptide modification, a decapeptide ( M9 , Scheme. 2a) was synthesized as the longest sequence investigated. Using this optimized protocol, intramolecular cyclization proceeded efficiently (> 95% yield, Fig. S18), and gram-scale synthesis of the cyclic peptide was successfully achieved (Scheme. 2b). Given the established efficiency of the condensation reaction between aromatic nitriles and aminothiols in forming cyclic products, the impact of peptide sequence on cyclization kinetics was investigated by determining first-order rate constants via HPLC (Fig. 1a). Initial studies employing oligopeptides M3, M5 , M7 , and M9 revealed that all exhibited 1st Order rate constants within the same order of magnitude, as summarized in Table 3. This finding indicates that the length of the oligopeptide spacer does not fundamentally influence the intramolecular cyclization rate under these conditions. However, significant variations correlated with charge and spatial factors were observed. Specifically, M7 , which features a positively charged arginine adjacent to cysteine and an additional lysine residue (giving it the highest net positive charge), exhibited the highest rate constant ((0.84 ± 0.04) × 10⁻³) and did not yield detectable intermediate species (Fig. 1b). In contrast, M3 —the shortest sequence with a positively charged lysine adjacent to cysteine—showed a lower rate ((0.73 ± 0.02) × 10⁻³), and its reaction mixture contained transient intermediates, the proportion of which decreased between 20 and 60 min (Fig. 1b). Table 2 Reaction optimization with varying substrates and concentrations. M1 / 0.05 0 0 1 25 0 10 50 0 20 60 0 M2 G 0.05 0 0 1 60 0 10 95 0 20 95 0 M3 KG 0.05 0 > 95 1 0 > 95 5 0 > 95 10 0 > 95 M4 CG 0.05 0 > 95 1 0 > 95 5 0 > 95 10 0 > 95 M5 GLY 0.05 0 > 95 1 0 > 95 5 0 > 95 10 0 > 95 M6 FRFR 0.05 0 > 95 1 0 > 95 5 0 > 95 10 0 > 95 M7 RKDVY 0.05 0 > 95 1 0 > 95 5 0 > 95 10 0 > 95 M8 EFRFKS 0.05 0 > 95 1 0 > 95 5 0 > 95 10 0 > 95 M9 GHGLYGHGLY 0.05 0 > 95 1 0 > 95 5 0 > 95 10 0 > 95 Scheme 2 Structures of linear (1a) and cyclic (2a and 2b) peptides. Notably, M8 , which has a negatively charged glutamate adjacent to cysteine, showed a further reduced rate ((0.66 ± 0.02) × 10⁻³) and a higher proportion of intermediates compared to M3 (Fig. 1b). Similarly, M9 showed a rate (0.65 ± 0.02 × 10⁻³) comparable to that of M8 , suggesting that the distance between reactive groups may also influence the kinetics. While the precise structures of these putative intermediate species remain uncharacterized, their time-dependent decrease suggests they represent unstable conformational states that progress toward the stable cyclized product. Based on these collective observations, it is proposed that the presence of positively charged amino acids proximal to the reaction site enhances the cyclization rate, potentially in a charge-dependent manner, whereas negatively charged residues appear less favorable. Importantly, oligopeptide length itself showed no significant correlation with cyclization kinetics within the studied series. To investigate the influence of the relative positioning of aromatic nitrile and aminothiol groups within a peptide chain on cyclization efficiency, compound 7 (Fig. S3) was synthesized by coupling of 5 with Fmoc-Asp-OH. This modification allows for the insertion of the cyanide-functionalized derivative at any desired position within the peptide sequence. Through rational design, the following cyclic peptides were synthesized on solid phase: M5 (head-to-tail cyclized), M10 (side chain-to-tail cyclized), and M11 (side chain-to-side chain cyclized) (Scheme. 3). Table 3 Analysis of 1st Order rate constants. Cyc-M3 0.73 ± 0.02×10 -3 Cyc-M7 0.84 ± 0.04×10 -3 Cyc-M8 0.66 ± 0.02×10 -3 Cyc-M9 0.65 ± 0.02×10 -3 Figure 1 Kinetics and Time-Course Analysis of Intramolecular Condensation. (a) 1st Order rate constants for the cyclization of M3, M7, M8, and M9. (b) HPLC analysis of the cyclization reactions for M3, M7, M8, and M9 at 20, 40, and 60 minutes. Notably, all synthesized compounds underwent highly selective intramolecular condensation, affording the cyclic products in yields exceeding 95%. This demonstrates that the specific location of the aromatic nitrile and aminothiol groups do not significantly hinder the cyclization reaction. Furthermore, it confirms the versatility of this cyclization methodology for constructing cyclic peptides with diverse architectures. Gram-scale synthesis of Cyc-M3 to Cyc-M11 was subsequently performed in solution. HPLC analysis confirmed efficient cyclization for all targets, with yeils ranging from 85–95%, demonstrating the feasibility of scale-up. Although cyclization is theoretically feasible on solid support, this approach was not pursued at this stage. Future work will prioritize assessing the viability of on-resin synthesis for kilogram-scale production of these cyclic peptides. Building on the developed cyclization strategy utilizing aromatic nitrile and cysteine condensation, we applied this methodology to optimize the biological activity of peptide-based therapeutics. This approach is particularly promising for radiopharmaceuticals, which require rapid target accumulation and efficient clearance from non-target tissues. To this end, we modified PSMA-617—an FDA-approved therapeutic for metastatic castration-resistant prostate cancer—by inserting an aromatic nitrile derivative and a cysteine between the PSMA-targeting moiety and the radiometal chelator. Subsequent cyclization yielded the novel probe, Cyc-P1 (Fig. 2a). In vitro, 68 Ga-Cyc-P1 exhibited faster kinetics and a 3-fold higher peak uptake within 15 minutes, while maintaining a 50% higher retention (23.4 ± 0.09 %ID/g) at 60 minutes compared to 68 Ga-PSMA-617 (Fig. 2b, left). Scheme 3 Schematics of head-to-tail, side chain-to-tail, and side chain-to-side chain cyclization mediated by aromatic nitriles and cysteine residues. Efflux assays demonstrated slower externalization and prolonged intracellular retention for Cyc-P1, likely due to its increased hydrophobicity from cyclization, which favors interactions with the intracellular milieu (Fig. 2b, right). These findings were corroborated by small-animal PET/CT imaging (Fig. 2c). In LNCaP tumors, the uptake of 68 Ga-Cyc-P1 at 4 h remained approximately 2-fold higher than that of 68 Ga-PSMA-617 (16.5 % ± 0.07 ID/g) and was virtually identical to its own 1-h level (Fig. 2d, left). However, while cyclization improved tumor targeting and retention, the concomitant increase in hydrophobicity led to elevated and prolonged renal uptake (Fig. 2d, right). Consequently, future optimization will focus on refining this strategy to maintain enhanced tumor accumulation while improving the pharmacokinetic profile, particularly renal clearance—a critical determinant for successful radiopharmaceutical development. Figure 2 Comparative Evaluation of ⁶⁸Ga-Cyc-P1 and ⁶⁸Ga-PSMA-617 in LNCaP Tumor-Bearing Mice. (a) Chemical structure of Cyc-P1. (b) Cellular uptake and internalization kinetics of ⁶⁸Ga-Cyc-P1 compared to ⁶⁸Ga-PSMA-617 (mean ± SD, n = 3). (c) Representative small-animal PET/CT images at 1, 2, and 4 hours post-injection (top: ⁶⁸Ga-PSMA-617; bottom: ⁶⁸Ga-Cyc-P1; n = 3). The red circle indicates the tumor site (d) Column chart for tumor and kidney uptake at 1, 2, and 4 hours. Statistical significance: * P < 0.05, ** P < 0.01, *** P < 0.001. Conclusions In conclusion, we have successfully developed and applied a novel aromatic nitrile–aminothiol condensation strategy for oligopeptide modification. Our initial screening identified compounds with the slowest intermolecular condensation kinetics, which enabled a systematic investigation of the minimal peptide length required for selective intramolecular cyclization and the impact of peptide sequence on reaction efficiency. Subsequent quantification of the intramolecular condensation rates for derivatives M3, M7, M8, and M9 revealed that the presence of positively charged amino acids near the reaction site accelerates cyclization, providing critical structure–activity insights for optimization. Gram-scale synthesis of cyclic peptides Cyc-M3 to Cyc-M11 proceeded efficiently, affording isolated yields of 85%–95%, thereby demonstrating the robustness and scalability of this methodology. Finally, application to radiopharmaceutical design yielded Cyc-P1, a cyclized analogue of PSMA-617. In vivo evaluation confirmed its significantly enhanced tumor uptake compared to the parent compound. A key finding, however, was the concomitant elevation in kidney uptake, which necessitates future optimization to improve the tumor-to-kidney ratio and further advance the therapeutic utility of this cyclization platform for nuclear medicine. Experimental Synthesis of cyclic peptides. TCEP·HCl (5.0 equiv) was added to phosphate-buffered saline (1×PBS, pH 7.5) solution containing M1-M11, and the pH was adjusted to 7.5 by saturated NaHCO 3 (3 equiv) solution, affording a final substrate concentration of 50 μM to 10mM. The mixture was kept at room temperature and monitored by HPLC at 2h. The cyclized product was purified by Preparation of High-Performance Liquid Chromatography. General Methods for Measuring Intramolecular Cyclization Kinetics. The first-order rate constants for the cyclization of M3-M9 to generate CP3-CP6 were determined by HPLC assays adapted from the previously reported assay. [24] TCEP·HCl (5.0 equiv) was added to phosphate-buffered saline (1×PBS, pH 7.4) solution containing M3-M9, and the pH was adjusted to 7.5 by saturated NaHCO 3 (3 equiv) solution, affording a final substrate concentration of 100 μM. The mixture was kept at room temperature and monitored by HPLC at different time points. The remaining concentration of the initial substrate was calculated using the peak integrals of the starting material at 254 nm. According to the first-order reaction law, ln([At]/[A0]) was plotted against time, and the slope obtained from the linear regression gives the first-order reaction rate constant. Radiolabeling of the novel PSMA ligands. The radiolabeling of the novel PSMA ligands (P1, Cyc-P1) with 68 Ga (no-carrier added 68 Ga in 0.05 M HCl; ITG Corporation, Germany) was performed at pH 4.5 in a 1:4 (v/v) mixture of sodium acetate (0.25 M, pH ~4) and HCl (0.05 M, pH °C, followed by a quality control using carbon column to purify the mixture for obtaining the 68 Ga-labeled ligands. Supporting Information The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.70XXX. Acknowledgement We gratefully acknowledge the financial support from the Jiangsu Provincial Innovation and Entrepreneurship Talent Program, the Nanjing Zijinshan Talents Program, and the Nanjing Medical Science and Technology Development Foundation for Key Medical Research Program (ZKX23029). We also extend our thanks to the Department of Nuclear Medicine at Nanjing First Hospital for providing essential imaging platform support. 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Mol Pharm. 2025, 22, 3961-3975.[23] Weber, W.A.; Czernin, J.; Anderson, C.J.; Badawi, R.D.; Barthel, H.; Bengel, F.; Bodei, L.; Buvat, I.; DiCarli, M.; Graham, M.M.; Grimm, J.; Herrmann, K.; Kostakoglu, L.; Lewis, J.S.; Mankoff, D.A.; Peterson, T.E.; Schelbert, H.; Schöder, H.; Siegel, B.A.; Strauss, H.W. The Future of Nuclear Medicine, Molecular Imaging, and Theranostic. J Nucl Med. 2020, 61, 263s-272s.[24] Chen, Z.; Chen, M.; Cheng, Y.; Kowada, T.; Xie, J.; Zheng, X.; Rao, J. Exploring the Condensation Reaction between Aromatic Nitriles and Amino Thiols To Optimize In Situ Nanoparticle Formation for the Imaging of Proteases and Glycosidases in Cells. Angew Chem Int Ed Engl. 2020, 59, 3272-3279. Manuscript received: XXXX, 2024 Manuscript revised: XXXX, 2024 Manuscript accepted: XXXX, 2024 Version of record online: XXXX, 2024 Left to Right: Anning Guo, Luo Chen, Zheng Xu, Bingyan Li, Haidi Song, Shuli Zhao, Guoqiang Shao, Feng Wang, Ke Jiang. Entry for the Table of Contents Synthesis of Cyclic Oligopeptide via Condensation of Aromatic Nitrile Derivatives with Aminothiols: Enhancing Peptide Permeability and Intracellular Retention Anning Guo, a,b,1 Luo Chen a, b,1 , Zheng Xu d,1 , Bingyan Li a, b , Haidi Song a, b,c , Shuli Zhao d , Guoqiang Shao d* , Feng Wang d* , Ke Jiang a,b* Chin. J. Chem. 2025 , 43 , XXX—XXX. DOI: 10.1002/cjoc.70XXX A new cyclization method leverages the fast reaction of aromatic nitrile derivatives with cysteine to facilitate rapid generation of cyclic oligopeptides. Notable for its mild conditions and excellent biocompatibility, this approach markedly improves drug delivery and retention in tumors, holding great promise in the field of nuclear medicine. Information & Authors Information Version history V1 Version 1 09 March 2026 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords aminothiols aromatic nitriles intramolecular condensation nuclear medicine oligopeptides Authors Affiliations Anning Guo Chinese Academy of Sciences Nanjing Branch View all articles by this author Luo Chen Chinese Academy of Sciences Nanjing Branch View all articles by this author Zheng Xu Nanjing First Hospital View all articles by this author Bingyan Li Chinese Academy of Sciences Nanjing Branch View all articles by this author Haidi Song Chinese Academy of Sciences Nanjing Branch View all articles by this author Shuli Zhao Nanjing First Hospital View all articles by this author Guoqiang Shao Nanjing First Hospital View all articles by this author Feng Wang Nanjing First Hospital View all articles by this author Ke Jiang [email protected] Chinese Academy of Sciences Nanjing Branch View all articles by this author Metrics & Citations Metrics Article Usage 137 views 36 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Anning Guo, Luo Chen, Zheng Xu, et al. Synthesis of Cyclic Oligopeptide via Condensation of Aromatic Nitrile Derivatives with Aminothiols: Enhancing Peptide Permeability and Intracellular Retention. Authorea . 09 March 2026. DOI: https://doi.org/10.22541/au.177303476.66085792/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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