Diphenyl urea-benzylidene acetohydrazide hybrids as fibroblast growth factor receptor 1 inhibitors and anticancer agents.

Molecular hybridization between diphenyl urea and benzylidene acetohydrazide was adopted for the design of a new series of FGFR-1 targeting cancer. The designed series was synthesized and submitted to NCI-USA to be screened for their growth inhibitory activity on NCI cancer cell lines. Some of the synthesized hybrids displayed promising growth inhibitory activity on NCI cancer cell lines with a mean GI% between 70.39% and a lethal effect. Compounds 9a, 9i, 9j, and 9n-p were further selected for a five-dose assay and all the tested candidates showed promising antiproliferative activity with GI50 reaching the submicromolar range. Encouraged by the potent activity of 9a on colon cancer on the one hand and the well-known overexpression of FGFR-1 in it on the other hand, it was further selected as a representative example to be evaluated for its mechanism on the cell cycle and apoptosis of HCT116 cell line. Interestingly, 9a was found to pause the cell cycle of the HCT116 cell line at the G1 phase and induced late apoptosis. In parallel, all the synthesized hybrids 9a-p were examined for their potential to inhibit FGFR-1 at 10 µM. Compounds 9a, 9g, 9h, and 9p were found to have potent inhibitory activity with % inhibition = 63.04%, 58.31%, 60.87% and 79.84%, respectively. Molecular docking simulation of 9a in the binding pocket of FGFR-1 confirms its capability to achieve the characteristic interactions of the type II FGFR-1 inhibitors. Exploration of the ADME properties of 9a-p by SwissADME web tool proved their satisfactory physicochemical properties for the discovery of new anticancer hits.

Selective Peptide Cysteine Manipulation on Demand and Difficult Protein Chemical Synthesis Enabled by Controllable Acidolysis of N,S-Benzylidene Thioacetals.

Although solid-phase peptide synthesis combining with chemical ligation provides a way to build up customized polypeptides in general, many targets are still presenting challenges for the conventional synthetic process, such as hydrophobic proteins. New methods and strategies are still required to overcome these obstacles. In this study, kinetic studies of Cys/Pen ligation and its acidolysis were performed, from which the fast acidolysis of substituted N,S-benzylidene thioacetals (NBTs) was discovered. The study demonstrates the potential of NBTs as a promising Cys switchable protection, facilitating the chemical synthesis of peptides and proteins by efficiently disrupting peptide aggregation. The compatibility of NBTs with other commonly adopted Cys protecting groups and their applications in sequential disulfide bond formation were also investigated. The first chemical synthesis of the native human programmed death ligand 1 immunoglobulin V-like (PD-L1 IgV) domain was achieved using the NBT strategy, showcasing its potential in difficult protein synthesis.

Positional scanning of natural product hispidol's ring-B: discovery of highly selective human monoamine oxidase-B inhibitor analogues downregulating neuroinflammation for management of neurodegenerative diseases.

Multifunctional molecules might offer better treatment of complex multifactorial neurological diseases. Monoaminergic pathways dysregulation and neuroinflammation are common convergence points in diverse neurodegenerative and neuropsychiatric disorders. Aiming to target these diseases, polypharmacological agents modulating both monoaminergic pathways and neuroinflammatory were addressed. A library of analogues of the natural product hispidol was prepared and evaluated for inhibition of monoamine oxidases (MAOs) isoforms. Several molecules emerged as selective potential MAO B inhibitors. The most promising compounds were further evaluated in vitro for their impact on microglia viability, induced production of proinflammatory mediators and MAO-B inhibition mechanism. Amongst tested compounds, 1p was a safe potent competitive reversible MAO-B inhibitor and inhibitor of microglial production of neuroinflammatory mediators; NO and PGE2. In-silico study provided insights into molecular basis of the observed selective MAO B inhibition. This study presents compound 1p as a promising lead compound for management of neurodegenerative disease.

Design, synthesis, and evaluation of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides as antitumor agents.

In our continuing search for novel small-molecule anticancer agents, we designed and synthesized a series of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides (5), focusing on the modification of substitution in the quinazolin-4(3H)-one moiety. The biological evaluation showed that all 13 designed and synthesized compounds displayed significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5l displayed cytotoxicity up to 213-fold more potent than 5-fluorouracil and 87-fold more potent than PAC-1, the first procaspase-activating compound. Structure-activity relationship analysis revealed that substitution of either electron-withdrawing or electron-releasing groups at positions 6 or 7 on the quinazolin-4(3H)-4-one moiety increased the cytotoxicity of the compounds, but substitution at position 6 seemed to be more favorable. In the caspase activation assay, compound 5l was found to activate the caspase activity by 291% in comparison to PAC-1, which was used as a control. Further docking simulation also revealed that this compound may be a potent allosteric inhibitor of procaspase-3 through chelation of the inhibitory zinc ion. Physicochemical and ADMET calculations for 5l provided useful information of its suitable absorption profile and some toxicological effects that need further optimization to be developed as a promising anticancer agent.

Mur ligases inhibitors with azastilbene scaffold: Expanding the structure-activity relationship.

Antibiotic resistance represents one of the biggest public health challenges in the last few years. Mur ligases (MurC-MurF) are involved in the synthesis of UDP-N-acetylmuramyl-pentapeptide, the main building block of bacterial peptidoglycan polymer. They are essential for the survival of bacteria and therefore important antibacterial targets. We report herein the synthesis and structure-activity relationships of Mur ligases inhibitors with an azastilbene scaffold. Several compounds showed promising inhibitory potencies against multiple ligases and one compound also possessed moderate antibacterial activity. These results represent a solid ground for further development and optimization of structurally novel antimicrobial agents to combat the rising bacterial resistance.

Novel 3-benzylidene/benzylphthalide Mannich base derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.

To discover novel multifunctional agents for the treatment of Alzheimer's disease, a series of 3-benzylidene/benzylphthalide Mannich base derivatives were designed, synthesized and evaluated. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound (Z)-13c raised particular interest because of its excellent multifunctional bioactivities. It displayed excellent EeAChE and HuAChE inhibition (IC50 = 9.18 × 10-5 and 6.16 × 10-4 µM, respectively), good MAO-B inhibitory activity (IC50 = 5.88 µM) and high antioxidant activity (ORAC = 2.05 Trolox equivalents). Additionally, it also exhibited good antiplatelet aggregation activity, moderate self- and Cu2+-induced Aß1-42 aggregation inhibitory potency, disaggregation ability on Aß1-42 fibrils, biometal chelating ability, appropriate BBB permeability and significant neuroprotective effect. Furthermore, (Z)-13c can also ameliorate the learning and memory impairment induced by scopolamine in mice. These multifunctional properties highlight compound (Z)-13c as a promising candidate for further development of multifunctional drug against AD.

Synthesis, Crystal Structure, Biological Evaluation and in Silico Studies on Novel (E)-1-(Substituted Benzylidene)-4-(3-isopropylphenyl)thiosemicarbazone Derivatives.

A series of (E)-1-(substituted benzylidene)-4-(3-isopropylphenyl)thiosemicarbazone derivatives were synthesized and characterized by FT-IR spectrum, elemental analysis, NMR spectrum, HR-MS spectrum, and X-ray single crystal diffraction technology. The crystal structures and packing of (E)-1-(4-fluorobenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone and (E)-1-(3-fluorobenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone were maintained through the intramolecular hydrogen bond (N3-H6⋅⋅⋅N1) and intermolecular hydrogen bonds (N2-H4⋅⋅⋅S1, C14-H14⋅⋅⋅F1 and C7-H7⋅⋅⋅S1). The results obtained by employing the DPPH free radicals scavenging assay indicated that (E)-1-(4-methoxylbenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone had a more significant antioxidant activity compared with other compounds. The results measured by adopting the disc diffusion method elucidated that (E)-1-(4-trifluoromethylbenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone possessed a more prominent antifungal activity than other compounds. Molecular docking showed that (E)-1-(4-chlorobenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone had the highest affinity with receptor protein (1NMT). Moreover, the drug-likeness characteristic, physicochemical properties, pharmacokinetic profiles, and bioactivity scores of all the compounds were predicted through in silico studies. The results illustrated that (E)-1-(4-fluorobenzylidene)-4-(3-isopropylphenyl)thiosemicarbazone had the drug-likeness characteristic and all the compounds were considered as moderately biological active molecules.

Highlights on Steroidal Arylidene Derivatives as a Source of Pharmacologically Active Compounds: A Review.

Steroids constitute a unique class of chemical compounds, playing an important role in physiopathological processes, and have high pharmacological interest. Additionally, steroids have been associated with a relatively low toxicity and high bioavailability. Nowadays, multiple steroidal derivatives are clinically available for the treatment of numerous diseases. Moreover, different structural modifications on their skeleton have been explored, aiming to develop compounds with new and improved pharmacological properties. Thus, steroidal arylidene derivatives emerged as a relevant example of these modifications. This family of compounds has been mainly described as 17ß-hydroxysteroid dehydrogenase type 1 and aromatase inhibitors, as well as neuroprotective and anticancer agents. Besides, due to their straightforward preparation and intrinsic chemical reactivity, steroidal arylidene derivatives are important synthetic intermediates for the preparation of other compounds, particularly bearing heterocyclic systems. In fact, starting from arylidenesteroids, it was possible to develop bioactive steroidal pyrazolines, pyrazoles, pyrimidines, pyridines, spiro-pyrrolidines, amongst others. Most of these products have also been studied as anti-inflammatory and anticancer agents, as well as 5α-reductase and aromatase inhibitors. This work aims to provide a comprehensive overview of steroidal arylidene derivatives described in the literature, highlighting their bioactivities and importance as synthetic intermediates for other pharmacologically active compounds.

Design, Synthesis, and Anticancer Screening for Repurposed Pyrazolo[3,4-d]pyrimidine Derivatives on Four Mammalian Cancer Cell Lines.

The present study reports the synthesis of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to mono-, di-, and trimethoxy benzylidene moieties through hydrazine linkages. First, in silico docking experiments of the synthesized compounds against Bax, Bcl-2, Caspase-3, Ki67, p21, and p53 were performed in a trial to rationalize the observed cytotoxic activity for the tested compounds. The anticancer activity of these compounds was evaluated in vitro against Caco-2, A549, HT1080, and Hela cell lines. Results revealed that two (5 and 7) of the three synthesized compounds (5, 6, and 7) showed high cytotoxic activity against all tested cell lines with IC50 values in the micro molar concentration. Our in vitro results show that there is no significant apoptotic effect for the treatment with the experimental compounds on the viability of cells against A549 cells. Ki67 expression was found to decrease significantly following the treatment of cells with the most promising candidate: drug 7. The overall results indicate that these pyrazolopyrimidine derivatives possess anticancer activity at varying doses. The suggested mechanism of action involves the inhibition of the proliferation of cancer cells.

Biodegradable Polymersomes with Structure Inherent Fluorescence and Targeting Capacity for Enhanced Photo-Dynamic Therapy.

Biodegradable nanostructures displaying aggregation-induced emission (AIE) are desirable from a biomedical point of view, due to the advantageous features of loading capacity, emission brightness, and fluorescence stability. Herein, biodegradable polymers comprising poly (ethylene glycol)-block-poly(caprolactone-gradient-trimethylene carbonate) (PEG-P(CLgTMC)), with tetraphenylethylene pyridinium-TMC (PAIE) side chains have been developed, which self-assembled into well-defined polymersomes. The resultant AIEgenic polymersomes are intrinsically fluorescent delivery vehicles. The presence of the pyridinium moiety endows the polymersomes with mitochondrial targeting ability, which improves the efficiency of co-encapsulated photosensitizers and improves therapeutic index against cancer cells both in vitro and in vivo. This contribution showcases the ability to engineer AIEgenic polymersomes with structure inherent fluorescence and targeting capacity for enhanced photodynamic therapy.

Mechanistic Interrogation of Alkyne Hydroarylations Catalyzed by Highly Reduced, Single-Component Cobalt Complexes.

Highly reactive catalysts for ortho-hydroarylations of alkynes have previously been reported to result from activation of CoBr2 by Grignard reagents, but the operative mechanism and identity of the active cobalt species have been undefined. A mechanistic analysis of a related system, involving hydroarylations of a (N-aryl)aryl ethanimine with diphenylacetylene, was performed using isolable reduced Co complexes. Studies of the stoichiometric reaction of Co(I) or Co(II) precursors with CyMgCl implicated catalyst initiation via a ß-H elimination/deprotonation pathway. The resulting single-component Co(-I) complex is proposed as the direct pre-catalyst. Michaelis-Menten enzyme kinetic studies provide mechanistic details regarding the catalytic dependence on substrate. The (N-aryl)aryl ethanimine substrate exhibited saturation-like behavior, whereas alkyne demonstrated a complex dependency; rate inhibition and promotion depend on the relative concentration of alkyne to imine. Activation of the aryl C-H bond occurred only in the presence of coordinated alkyne, which suggests operation of a concerted metalation-deprotonation (CMD) mechanism. Small primary isotope effects are consistent with a rate-determining C-H cleavage. Off-cycle olefin isomerization catalyzed by the same Co(-I) active species appears to be responsible for the observed Z-selectivity.

Homobenzylic Oxygenation Enabled by Dual Organic Photoredox and Cobalt Catalysis.

Activation of aliphatic C(sp3)-H bonds in the presence of more activated benzylic C(sp3)-H bonds is often a nontrivial, if not impossible task. Herein we show that leveraging the reactivity of benzylic C(sp3)-H bonds to achieve reactivity at the homobenzylic position can be accomplished using dual organic photoredox/cobalt catalysis. Through a two-part catalytic system, alkyl arenes undergo dehydrogenation followed by an anti-Markovnikov Wacker-type oxidation to grant benzyl ketone products. This formal homobenzylic oxidation is accomplished with high atom economy without the use of directing groups, achieving valuable reactivity that traditionally would require multiple chemical transformations.

Benzylidene thiazolidinediones: Synthesis, in vitro investigations of antiproliferative mechanisms and in vivo efficacy determination in combination with Imatinib.

Thiazolidinedione (TZD) has been an interesting scaffold due to its proven antidiabetic activity and encouraging findings in anticancer drug discovery. We synthesised benzylidene thiazolidinedione derivatives which exhibited excellent antiproliferative effects in chronic myeloid leukemic cells K562 and the most active compounds 3t and 3x had GI50 value of 0.9 and 0.23 µM respectively. Both the compound was found to arrest the growth of K562 cells in G0/G1 phase in a time and dose dependent manner. Further, western blot analysis revealed that 3t and 3x could also inhibit the expression of cell proliferation markers, PCNA and Cyclin D1 and compound 3x up-regulated apoptosis markers, cleaved PARP1 and activated caspase 3, which could be a possible mechanism for the excellent antiproliferative effects exhibited by these compounds. In vitro combination studies of 3t and 3x with Imatinib found to potentiate the antitumor effects of Imatinib. Further in vivo efficacy in K562 xenografts, of 3t and 3x alone and in combination with Imatinib was found to be promising and far better than control group and combination treatment was found to be more effective as compared to only Imatinib treated or test compound treated animals. Thus, our findings suggest that these compounds are promising antitumor agents and could help to enhance the anticancer effects of Imatinib and other tyrosine kinase inhibitors, when used in combination.

Discovery of benzo[cd]indol-2-one and benzylidene-thiazolidine-2,4-dione as new classes of NLRP3 inflammasome inhibitors via ER-ß structure based virtual screening.

The structure-guided virtual screening (VS) has proved to be successful strategy in identification of new scaffolds for biological targets. The overactivity of NLRP3 inflammasome has been implicated in variety of inflammatory diseases including Alzheimer's disease. The up-regulation of estrogen-receptor ß (ER-ß) activity has been directly linked with inhibition of NLRP3 inflammasome activity. In the present study, we report discovery of new NLRP3 inflammasome inhibitors via ER-ß crystal structure (PDB: 5TOA) guided virtual screening of 20,000 compound library. For experimental validation, top 10 ligands were selected based on structure novelty, docking score, prime MMGB/SA binding affinity and interaction pattern analysis. Amongst the tested compounds, three thiazolidin-4-ones IIIM-1268, IIIM-1269 and IIIM-1270 and benzo[cd]indol-2-one IIIM-1266 have shown 73, 69, 75 and 77% suppression of IL-1ß release in mouse macrophages (J774A.1 cells) at 10 µM. Benzylidene-thiazolidine-2,4-diones IIIM-1268 and IIIM-1270 inhibited IL-1ß release with IC50 of 2.3 and 3.5 µM and also significantly decreased the protein expression level of mature form of IL-1ß in western-blot analysis. IIIM-1266 and IIIM-1270 displayed bidentate H-bonding with Arg 346 and Glu 305 residues in the active site of ER-ß; and they also strongly occupied the ADP-binding site of NLRP3 protein. The results presented herein, indicate that ER-ß guided VS can be successfully used to identify new NLRP3 inflammasome inhibitors, which may have potential in the development of novel anti-Alzheimer agents.

Synthesis and biological evaluation of novel (E)-N'-benzylidene hydrazides as novel c-Met inhibitors through fragment based virtual screening.

C-Met plays a crucial role in the development and progression of neoplastic disease. Type II c-Met inhibitors recognise the inactive DFG-out conformation of the kinase, result in better anti-tumour effects due to synergistic effect against the other kinases. According to our previous works, an (E)-N'-benzylidene group was selected as the initial fragment. Two series of (E)-N'-benzylidene hydrazides were designed by fragment growth method. The inhibitory activities were in vitro investigated against c-Met and VEGFR-2. Compound 10b exhibited the most potent inhibitory activity against the c-Met inhibitor (IC50 = 0.37 nM). Compound 11b exhibited multi-target c-Met kinase inhibitory activity as a potential type II c-Met inhibitor (IC50 = 3.41 nM against c-Met; 25.34 nM against VEGFR-2). The two compounds also demonstrate the feasibility of fragment-based virtual screening method for drug discovery.

Specific Targeting, Imaging, and Ablation of Tumor-Associated Macrophages by Theranostic Mannose-AIEgen Conjugates.

Tumor-associated macrophages (TAMs) that exist in tumor microenvironment promote tumor progression and have been suggested as a promising therapeutic target for cancer therapy in preclinical studies. Development of theranostic systems capable of specific targeting, imaging, and ablation of TAMs will offer clinical benefits. Here we constructed a theranostic probe, namely, TPE-Man, by attaching mannose moieties to a red-emissive and AIE (aggregation-induced emission)-active photosensitizer. TPE-Man can specifically recognize a mannose receptor that is overexpressed on TAMs by the sugar-receptor interaction and enables fluorescent visualization of the mannose-receptor-positive TAMs in high contrast. The histologic study of mouse tumor sections further verifies TPE-Man's excellent targeting specificity being comparable with the commercial mannose-receptor antibody. TAMs can be effectively eradicated upon exposure to white light irradiation via a photodynamic therapy effect. To our knowledge, this is the first small molecular theranostic probe for TAMs that revealed combined advantages of low cost, high targeting specificity, fluorescent light-up imaging, and efficient photodynamic ablation.

A novel colorimetric and ratiometric fluorescent probe for sensing SO2 derivatives and their bio-imaging in living cells.

We report a novel fluorescent probe HBN-TCF for the detection of SO2 derivatives. This probe exhibited near-infrared fluorescence emission with an excitation wavelength of 620 nm. After reacting with SO32-, the emission channel at 664 nm decreased, while the new strong emission channel at 482 nm increased (λex = 400 nm), with a large emission distance (Δλ = 182 nm) observed. This probe exhibited the rapid and selective detection of SO2 derivatives compared with other sulfur-containing species and featured a low detection limit (82 nM). This colorimetric and ratiometric fluorescent probe showed high selectivity and sensitivity for detecting SO2 derivatives. The probe was also successfully exploited for the fluorescence imaging of intracellular and exogenous SO2 derivatives in BEL-7402 cells.

Total synthesis of dryocrassin ABBA and its analogues with potential inhibitory activity against drug-resistant neuraminidases.

The stems of Dryopteris crassirhizoma, one of the main components of Lianhua-Qingwen Formula (LQF) was traditionally used for heat-clearing and detoxifying. Dryocrassin ABBA is a key antiviral component in the herbal medicine while the compound is hard to get in large amounts with the features of homologous compounds, polyphenol groups, and low contents. Therefore, the present work aims to seek influenza H7N9 virus inhibitors from natural source by synthesis of dryocrassin ABBA and its analogues. As a result, total synthesis of the compound was achieved in nine steps with an over-all yield of 4.6%. Neuraminidases (NAs) inhibitory activities of the synthesized product and its analogues were evaluated afterward. Comparing with the positive control, OSV (9.6 µM), it was very exciting that dryocrassin ABBA and its analogues (b5 and e2) showed better NAs inhibitory activity against Anhui H7N9 with IC50 values of 3.6 µM, 2.5 µM and 1.6 µM. For the highly resistant Shanghai N9, these compounds can also show medium inhibitory activities. Docking results indicated the direct interaction of synthesized 3 hits with the key K294 by hydrogen bonds, but no direct interaction of OSV with the key K294 was observed in Shanghai N9. This study suggested that dryocrassin ABBA and its analogues especially AB, which consisted of polyphenol groups may have beneficial effects on treating avian influenza H7N9 virus.

Syntheses of Molybdenum Oxo Benzylidene Complexes.

The reaction between Mo(O)(CHAro)(ORF6)2(PMe3) (Aro = ortho-methoxyphenyl, ORF6 = OCMe(CF3)2) and 2 equiv of LiOHMT (OHMT = O-2,6-(2,4,6-Me3C6H2)2C6H3) leads to Mo(O)(CHAro)(OHMT)2, an X-ray structure of which shows it to be a trigonal bipyramidal anti benzylidene complex in which the o-methoxy oxygen is coordinated to the metal trans to the apical oxo ligand. Addition of 1 equiv of water (in THF) to the benzylidyne complex, Mo(CArp)(OR)3(THF)2 (Arp = para-methoxyphenyl, OR = ORF6 or OC(CF3)3 (ORF9)) leads to formation of {Mo(CArp)(OR)2(µ-OH)(THF)}2(µ-THF) complexes. Addition of 1 equiv of a phosphine (L) to Mo(CArp)(ORF9)3(THF)2 in THF, followed by addition of 1 equiv of water, all at room temperature, yields Mo(O)(CHArp)(ORF9)2(L) complexes in good yields for several phosphines (e.g., PMe2Ph (69% by NMR), PMePh2 (59%), PEt3 (69%), or P( i-Pr)3 (65%)). The reaction between Mo(O)(CHArp)(ORF9)2(PEt3) and 2 equiv of LiOHMT proceeds smoothly at 90 °C in toluene to give Mo(O)(CHArp)(OHMT)2, a four-coordinate syn alkylidene complex. Mo(O)(CHArp)(OHMT)2 reacts with ethylene (1 atm in C6D6) to give (in solution) a mixture of Mo(O)(CHArp)(OHMT)2, Mo(O)(CH2)(OHMT)2, and an unsubstituted square pyramidal metallacyclobutane complex, Mo(O)(CH2CH2CH2)(OHMT)2, along with ethylene and ArpCH═CH2. Mo(O)(CHArp)(OHMT)2 also reacts with 2,3-dicarbomethoxynorbornadiene to yield syn and anti isomers of the "first-insertion" products that contain a cis C═C bond.

Fluorescent Metallacage-Core Supramolecular Polymer Gel Formed by Orthogonal Metal Coordination and Host-Guest Interactions.

Herein, we report the preparation of a multifunctional metallacage-core supramolecular gel by orthogonal metal coordination and host-guest interactions. A tetragonal prismatic cage with four appended 21-crown-7 (21C7) moieties in its pillar parts was first prepared via the metal-coordination-driven self-assembly of cis-Pt(PEt3)2(OTf)2, tetraphenylethene (TPE)-based sodium benzoate ligands and linear dipyridyl ligands. Further addition of a bisammonium linker to the cage delivered a supramolecular polymer network via the host-guest interactions between the 21C7 moieties and ammonium salts, which formed a supramolecular gel at relatively higher concentrations. Due to the incorporation of a TPE derivative as the fluorophore, the gel shows emission properties. Multiple stimuli responsiveness and good self-healing properties were also observed because of the dynamic metal coordination and host-guest interactions used to stabilize the whole network structure. Moreover, the storage and loss moduli of the gel are 10-fold those of the gel without the metallacage cores, indicating that the rigid metallacage plays a significant role in enhancing the stiffness of the gel. The studies described herein not only enrich the functionalization of fluorescent metallacages via elegant ligand design but also provide a way to prepare stimuli-responsive and self-healing supramolecular gels as robust and smart materials.