A Simple Synthesis of Tetraamino-[60]Fullerene Epoxides as Potential Antitumor Drug Candidates

Open AccessCCS ChemistryCOMMUNICATIONS10 Apr 2024A Simple Synthesis of Tetraamino-[60]Fullerene Epoxides as Potential Antitumor Drug Candidates Yicheng Lu†, Jie Li†, Xiaolong Liu†, Dan He, Libin Yang, Wei Zhou, Xie Wang, Shanshan Chen, Shiliang Chen, Yating Liu, Xin Wang, Jiao Li, Jiawei Huo, Yang Liu, Zehu Wang, Meihan Liu, Yijun Wang, Yamin Li, Fuwen Zhao, Shumu Li, Jinchao Wei, Jianan Liu, Wei Li and Chunru Wang Yicheng Lu† Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100190 , Jie Li† *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 , Xiaolong Liu† The National Center for Nanoscience and Technology, Beijing 100190 , Dan He Central South University, Changsha, 410082 Hunan , Libin Yang Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100190 , Wei Zhou Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310092 Zhejiang , Xie Wang Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310092 Zhejiang , Shanshan Chen Cancer Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100069 , Shiliang Chen Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100190 , Yating Liu Cancer Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100069 , Xin Wang Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100190 , Jiao Li Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 , Jiawei Huo Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100190 , Yang Liu Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100190 , Zehu Wang University of Chinese Academy of Sciences, Beijing 100190 Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190 , Meihan Liu Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100190 , Yijun Wang Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100190 , Yamin Li Beijing FULLCAN Biotechnology Co., Beijing 100085 , Fuwen Zhao Central South University, Changsha, 410082 Hunan , Shumu Li Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 , Jinchao Wei Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 , Jianan Liu Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 , Wei Li Cancer Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100069 and Chunru Wang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100190 https://doi.org/10.31635/ccschem.024.202303784 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Amphiphilic aminated fullerenes have a broad margin of safety and significant antitumor effects. Herein, we develop a simple and versatile synthesis strategy for tetraamino-[60]fullerene epoxide (C60(NR1R2)4O) using C60Cl6 as a precursor, which notably reduces the reaction time to less than 1 h while retaining a high yield of over 80% with both cyclic and linear secondary amine substrates even at the gram level. The molecular structure of C60(NR1R2)4O is first validated by single-crystal diffraction, and a two-step reaction mechanism comprising nucleophilic substitution of Cl and the oxidative elimination of Cl2 is proposed based on experimental verification and density functional theory simulation. A set of water-soluble aminated C60(NR1R2)4O was prepared in large quantities, and in vitro antitumor evaluation unveiled the critical role that terminal primary amino moieties of C60(NR1R2)4O play in their antineoplastic effects. This work provides an effective synthesis method for aminated C60(NR1R2)4O, facilitating the development of fullerene-derived tumor-targeted drugs. Download figure Download PowerPoint Introduction Cancer is a multifactorial disease, usually resulting from multiple genetic alterations,1 and it has become the second leading cause of death globally. Fullerene is a spherical molecule composed entirely of carbon with unique physical and chemical properties. Fullerene and its functional derivatives have excellent biocompatibility and noble antineoplastic effects that improve the tumor microenvironment (TME) or directly target the tumor cells. Oral administration of pristine [60]fullerene maintains intestinal inflammatory homeostasis to enhance systemic immunity for cancer therapy.2,3 Hydroxylated fullerenes inhibit tumor growth and metastasis as potent inhibitors of oncoproteins like matrix metalloproteinase 9 (MMP-9), histone deacetylase 1 (HDAC1), hypoxia inducible factor-1α (HIF-1α), and transforming growth factor-β (TGF-β).4–6 β-alanine modified fullerenes rebuild the immunosuppressive TME via diverse mechanisms, including polarization of the tumor-associated macrophages to M1 subtypes7,8 and angiogenesis suppression.9 Aminated [70]fullerene can directly inhibit the proliferation and metastasis of tumor cells.10,11 However, the ambiguous molecular structure of previous water-soluble fullerene derivatives makes it challenging to explore the structure–activity relationship for further drug development. Recently, we initially revealed that tetra[4-(amino)piperidin-1-yl]C60 epoxide (TAPC) with a clarified molecular structure can induce the G0/G1 cell cycle arrest and abolish the high mobility and the epithelial–mesenchymal transition of tumor cells. TAPC shows an in vivo inhibition index of more than 75% in tumor growth and metastasis and a broad safety margin.12 The amphiphilic structure and the terminal amino moieties play the dominant role in the antineoplastic effects of TAPC. This suggests the potential emergence of tetraamino-[60]fullerene epoxides (C60(NR1R2)4O) as novel candidates for antitumor drugs. Further, C60(NR1R2)4O can enable gene delivery to inhibit metastatic lung cancer.13 To prepare a variety of derivatives for structure–activity relationship studies and produce the best candidate compounds in bulk for drug development, an effective and adaptable synthetic route for C60(NR1R2)4O must be developed. C60(NR1R2)4O is commonly synthesized by the reaction of C60 with secondary amine substrates for longer than ten hours in the presence of oxidants.14 The optimal reaction yields have been questioned and inflated for poor reproducibility.15 The reaction has been optimized by adding dimethyl sulfoxide to promote the single electron transfer from amines to C60 and replacing O2 with peroxides as better oxidants. However, the reaction rate and yield have not been significantly increased.16,17 This reaction tends to produce a range of by-products with different addition numbers, making product purification challenging. Given its facile mass production and high reaction selectivity, chlorofullerene (C60Cl6) is used as a precursor to prepare penta-adducts of fullerene derivative with a fixed structure.18 C60Cl6 is susceptible to nucleophilic substances in which its chlorine atoms are replaced with various functional groups such as amino,19 thiol,20 and alkoxyl21 to form pentasubstituted products. The reaction of C60Cl6 with primary amines produces mainly pentaamino fullerenes (C60(NHR)5Cl or C60(NHR)5H) with moderate yield.19 A series of water-soluble C60(NHR)5Cl bearing amino acids can inhibit the nonsmall cell lung cancer by inducing G0/G1 cell cycle arrest, but none exhibit inhibition in tumor cells comparable to TAPC.22,23 Direct reaction of C60Cl6 with secondary amines produces primarily complex polyadducts, as shown in reactions with several piperazine substances.24 Herein, we enable high-efficiency and rapid synthesis of C60(NR1R2)4O via a reaction of C60Cl6 with secondary amine substrates in the presence of peroxides, and the reaction yields of above 80% were achieved within 1 h on various substrates, enabling the mass controlled production of various C60(NR1R2)4O for drug development. Several C60(NR1R2)4O with terminal primary amino groups comparably inhibit the proliferation, migration, and invasion of various tumor cells. Replacing the primary amine groups with a secondary amine moiety significantly alleviates the antineoplastic effect, which highlights the importance of the terminal amino type. Results and Discussion Following the reported procedure,18 C60Cl6 was synthesized and characterized with a purity of over 97% ( Supporting Information Figure S1). C60Cl6 was directly reacted with excess 4-(tert-butoxycarbonylamino)piperidine in toluene at room temperature, but the primary product was so unstable that it deteriorated during silica gel column chromatography or recrystallization. Tetra[4-(tert-butoxycarbonylamino)piperidin-1-yl]C60 epoxide (TAPC-Boc) was not obtained, and only a little hexasubstituted by-product could be collected ( Supporting Information Figure S2). It has been shown that atmospheric O2 participates in the direct amination of C60 and can be converted to hydrogen peroxide (H2O2). Base-catalyzed epoxidation reaction with H2O2 produced the final epoxy products.16 Using peroxide as an oxidant can facilitate the formation of C60(NR1R2)4O,16 and cumene hydroperoxide (CHP) is screened to be the best oxidant. Nevertheless, whether air is present, the reaction between C60Cl6 and 4-(tert-butoxycarbonylamino)piperidine does not produce TAPC-Boc. Therefore, three-fold CHP was added to this reaction system, and the main product was successfully separated by a silica gel column and characterized as TAPC-Boc. The reaction conditions have been optimized based on the reaction between C60Cl6 and 4-(tert-butoxycarbonylamino)piperidine. Toluene is a better solvent than chlorobenzene, and the optimal ratio of CHP and amine to C60Cl6 is 3-fold and 7.5-fold, respectively ( Supporting Information Table S1). Excessive amine improved the reaction rate but produced more hexasubstituted by-products. Hydrogen chloride molecules formed by the substitution of chlorine atoms by secondary amine substrates formed amine hydrochlorides, and the reaction rate was greatly improved by adding excessive anhydrous K2CO3 (100 equiv) to neutralize the produced HCl. The reaction is so fast that it ends within 1 h with all the cyclic or linear secondary amine substrates. In contrast to the direct amination of C60, whose reaction yields decrease when exposed to light,16 the new reaction proceeds regardless of whether it is exposed to light (entries 9 and 10 in Supporting Information Table S1), H2O, or O2. The product was washed with a saturated aqueous solution of NH4Cl and NaHCO3 to quench residual CHP and purified on a silica gel chromatography column with toluene–ethyl acetate as eluent. Under optimal conditions, a set of C60(NR1R2)4O generated from multiple secondary amines was synthesized (Figure 1a) and validated by nuclear magnetic resonance and electron spray ionization-high resolution mass spectrometry ( Supporting Information Figures S3–S13). C60(NR1R2)4O with purities of over 95% were achieved using a single silicone column separation ( Supporting Information Figures S3–S13). The entire synthesis from C60Cl6 is significantly faster than the ideal reaction between C60 and these amine substances, and it achieves high yields of over 80% in less than an hour. This is most likely due to the quick substitution of Cl by amine and the speedy removal of HCl. Compared to the optimal reaction with C60 as feedstock,16 the yield of TAPC-Boc (compound 3) increases from 88% in 12 h to 92% within 1 h, and that of compound 6 increased from 76% in 48 h to 92%, and compound 11 got the highest yield of 95% (Figure 1b). Furthermore, diethylamine (DEA), a substrate, does not produce any product in the reaction with C60;14 instead, it yields C60(NEt2)4O (compound 10) with a 93% yield after 0.5 h, suggesting a wider variety of substrates. A single-crystal diffraction investigation has confirmed the structure of compound 10, which first validates the molecular structure of C60(NR1R2)4O (Figure 1c and Supporting Information Table S2). The crystal data of compound 10 has been submitted to the Cambridge Crystallographic Data Centre (CCDC), and the CCDC number is 2312119. As predicted, two Cl next to each other are occupied by epoxy, and four DEA residues take up the locations of the original Cl encircling a pentadiene surface. Tetra[4-(tert-butoxycarbonylaminomethyl)piperidin-1-yl]C60 epoxide (TAMPC-Boc), tetra[4-(tert-butoxycarbonylaminoethyl)piperidin-1-yl]C60 epoxide (TAEPC-Boc), and tetra(4-tert-butoxycarbonylpiperazin-1-yl)C60 epoxide (TPPC-Boc) were the acronyms for compounds 4, 5, and 6, respectively. Water-soluble aminated [60]fullerenes like TAPC can be prepared by removing Boc groups in trifluoroacetic acid/dichloromethane ( Supporting Information Figures S14–S17). The gram-level preparation of TAPC (Figure 1d), TAMPC, TAEPC, and TPPC in 1 h (Figure 1c) produces the same high yields, demonstrating the viability of mass production of well-defined water-soluble fullerene derivatives using this synthesis approach. The hydrodynamic diameters of TAPC, TAMPC, TAEPC, and TPPC are primarily distributed below 10 nm, and their zeta potentials range from 30 to 40 mV, showing that their physical and chemical properties are similar ( Supporting Information Figure S18). Figure 1 | (a) Synthesis of C60(NR1R2)4O using C60Cl6 as a precursor and preparation of TAPC by removing Boc groups. (b) Table showing the yields and reaction times for synthesizing C60(NR1R2)4O using various substrates. (c) Molecular structure of compound 10 according to the X-ray single-crystal diffraction (C, gray; H, white; N, blue; O, red). (d) Gram-level preparation of TAPC. Download figure Download PowerPoint The study of the total chlorine content using quantitative combustion ion chromatography (CIC) following the reaction indicates that just four times as many chlorine species are residual following the consumption of each C60Cl6 molecule ( Supporting Information Figure S19). CIC does not detect the remaining two Cl of C60Cl6 in the final product, which ought to be transformed into volatile compounds like Cl2. The four chlorine species from C60Cl6 were extracted and identified as chloride ions (Cl−) by ion chromatography ( Supporting Information Figure S20). This confirms that four Cl− are substituted by four secondary amino substances to form four HCl, which is then neutralized by excessive K2CO3, indicating the probable formation of a carbon cage carrying four amine residues and two Cl (C60Cl2(NR1R2)4) as intermediate products during this process. Based on previous research and experimental findings, a mechanism involving Cl substitution and elimination was proposed (Figure 2a). Notably, when less than 4 equiv of secondary amine—insufficient even for a single substitution step—was supplied, no mono-, bi-, or tri-adducts were observed or collected ( Supporting Information Figure S21). This implies that the entire procedure works as a chain reaction that, once initiated, will not stop until the final product (C60(NR1R2)4O) is generated. We wondered if the reaction could be too fast to follow, making it difficult to collect any intermediate products. Anticipating that the structure of C60Cl2(NR1R2)4 is crucial to understanding the complete process and using C60Cl2(Et2N)4 as an example, the optimum energy of all nine probable isomers was evaluated using density functional theory (DFT) computation to find the most likely intermediate structure. The optimum energy of isomer 9, which has two Cl atoms left at the neighboring sites, is the lowest (Figure 2b). In functionalization reactions of C60Cl6,25–27 substitution/elimination is a common step. Nevertheless, the elimination process is carried out by rearranging double bonds26,27 or in the presence of Fe3+ catalysis.25 It has also been observed that triphosphite esters, N,N-diisopropylethylamine,28 or tetrathiapentalene type29 can directly start the dehalogenation of halogenated fullerenes. In reactions of C60Cl6 with primary amines, nucleophilic reagents commonly replace the five Cl surrounding cyclopentadiene to form pentaadducts, leaving the last site owing to steric hindrance. In this reaction, the secondary amine appears to undergo nucleophilic substitution and facilitate the removal of chlorine with high regioselectivity. The unexpected synergistic effect of amine and peroxide to initiate the Cl elimination process is probably due to the unique structure of fullerene. Figure 2 | (a) Proposed mechanism for synthesizing C60(NR1R2)4O. (b) DFT calculations of optimized relative energies of all nine potential isomers of C60Cl2(Et2N)4 as an intermediate compared to isomer 1. (c) DFT calculations of the thermodynamic energy change of the epoxy structure formation and the Cl2 departure, with or without secondary amines. Download figure Download PowerPoint Using C60Cl2(Et2N)4 as the reactant of the epoxidation step, the theoretical energy of epoxidation and the subsequent reactions were calculated (Figure 2c). The oxidative reaction initiated by the peroxide is substantially exothermal (−0.90 eV) and should not be a speed-limit step. In contrast, the desorption of Cl2 requires a significant amount of energy (1.21 eV) without any helping agents. The secondary amine (Et2NH) significantly improved the detachment of Cl2, which lowered the energy to as low as 0.51 eV. Excessive secondary amines facilitate the epoxidation process by promoting the Cl2 detachment. In the experiments, a slight excess of secondary amines accelerated the reaction correspondingly. It has been discovered that TAPC made from C60 can prevent tumor growth, metastasis, and epithelial-mesenchymal transition.12 Here, a set of water-soluble amphiphilic C60(NR1R2)4O prepared by the new method (Figure 3a) was tested for their antineoplastic potential against a range of tumor cell lines, including B16 mouse melanoma cells (B16), MCF7 human breast cancer cell (MCF7), U-87MG human glioblastoma cell (U87), and A549 human lung cancer cells (A549) (Figure 3b, Supporting Information Figures S22–S24). The half inhibitory concentrations (IC50) of TAPC created using the new approach are nearly identical to those of TAPC derived from C60 when it comes to U87 (12.0 vs 9.7 μM) and A549 (7.2 vs 7.7 μM) cells. TAPC, TAMPC, and TAEPC highly inhibit all tumor cells, and their IC50 values are comparable. This implies that the antitumor effects of C60(NR1R2)4O are only marginally impacted by including a short alkyl chain between the piperidine ring and the amino group. It is interesting to note that TPPC has IC50 values against every tumor cell that are more than three times greater than TAPC's. The uptake rate of both tumor cells should be similar because TPPC and TAPC have the same zeta potential and amphiphilic molecular structure. This suggests that the differences in their antitumor actions are unrelated to cell uptake. The type of segmental amine was the only difference between TPPC and TAPC. The antiproliferation effects of C60(NR1R2)4O is greatly diminished if a secondary amine was substituted for the terminal primary amine. Moreover, the Transwell test was used to measure the A549 cells' capacity for migration and invasion. In vitro, TAPC shows the most inhibitory effect on tumor metastasis. Comparatively, the inhibitory efficiency of TAMPC and TAEPC has only slightly decreased, while that of TPPC has been significantly diminished (Figure 3c,d). Therefore, the antineoplastic activity of water-soluble amphiphilic C60(NR1R2)4O is somewhat mediated by introducing an alkyl chain between the piperidine ring and the amino group. However, the antitumor effect is greatly diminished if a secondary amine is substituted for the terminal primary amine. This reveals that the terminal primary amino moieties of C60(NR1R2)4O play a dominant role in preventing tumor growth and metastasis. Figure 3 | (a) Molecular structures of TAPC, TAMPC, TAEPC, and TPPC. (b) List of IC50 values (left) in B16, MCF7, U87, and A549 cells and cell viability (right) of B16 cells after 48 h treatment. Images and quantification of (c) migrated and (d) invaded A549 cells treated with TAPC, TAMPC, TAEPC, and TPPC, respectively. (*p > 0.1, **p > 0.01, ***p > 0.001, and ****p > 0.0001). Download figure Download PowerPoint Conclusion We have created a new and adaptable synthetic method that uses C60Cl6 as a precursor to quickly and efficiently synthesize structurally well-defined C60(NR1R2)4O on the gram level. The probable reaction mechanism is the nucleophilic substitution of Cl by the secondary amine substrate and the oxidative elimination of Cl2, as shown by experimental data and DFT simulations. The molecular structure of C60(NR1R2)4O has been confirmed by X-ray single-crystal diffraction for the first time. The new method has prepared a set of water-soluble C60(NR1R2)4O with terminal amino groups (TAPC, TAMPC, TAEPC, and TPPC). 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Google Scholar Previous articleNext article FiguresReferencesRelatedDetails Issue AssignmentNot Yet AssignedSupporting Information Copyright & Permissions© 2024 Chinese Chemical SocietyKeywordstetraamino-[60]fullerene epoxidessimple synthesisC60Cl6water-soluble aminated fullereneantitumor Downloaded 0 times PDF downloadLoading ...