Skip to main content
  • Research article
  • Open access
  • Published:

Synthesis of crocetin derivatives and their potent inhibition in multiple tumor cells proliferation and inflammatory property of macrophage



Crocetin is a major active component of saffron, which has a wide range of pharmacological effects. However, due to its low solubility, the pharmacological effects of crocetin cannot be better utilized.


In this study, we modified the chemical structure of crocetin by conjugating with ethylamine and 4-Fluorbenzylamine to enhance its solubility and biological activities. The solubility and the influence of synthesized derivatives on the proliferation of tumor cells and the inflammatory effect of macrophage were investigated.


It was shown that, compared with the crocetin, the synthesized derivatives have much higher solubility. Moreover, the inhibitory effect of the derivatives on varieties of tumor cells, including human ovarian carcinoma cell line, human lung cancer cell line, rat melanoma cell line was enhanced after the modification. Besides that, the derivatives were improved for the anti-inflammatory efficacy with the cytotoxicity decreased.


The synthesized derivatives were shown for their good solubility and the great potential in tumor and inflammation treatment.

Peer Review reports


Saffron, a spice and a food colorant derived from the flower of Crocus sativus, is widely cultivated in Iran, Greece, Italy, Spain, India, China, Japan and other countries as an herb [1]. After collection and dehydration, it can be used mainly as the medicinal parts [2]. The history of the Saffron application in clinic can be traced back to about 2300 Before Christ [3]. Saffron contains a variety of ingredients, including carotenoids, glycosides, flavonoids, amino acids, trace elements, etc. Among them, crocetin is one of the main effective components [2], with polyunsaturated conjugate oleic acid structure. Many studies have shown that crocetin has widely pharmacological effects, which contains anti-oxidation [4], anti-cancer [5], hepatoprotection [6, 7] However, consisting of a C-20 carbon chain with seven double bonds and a carboxylic acid group at each terminal parts of the molecule, crocetin is insoluble in water. Solving this problem is the key to promote the medicinal application of this natural product. Currently, it has been reported that the use of biomaterials such as poly (lactic-co-glycolic acid) and dendrimers can improve the bioavailability of the crocetin. However, the stability and production rates are still to be improved for these biomaterials and nanotechnology based strategies [8, 9]. In our previous study [10], it has been demonstrated that the conjugation of organic compounds can help derivatives to form stable hydrogen bond by lowing solvation energy [10, 11], which in turn increases the solubility of the compounds. In present study, by conjugating the crocetin with ethylamine and 4-Fluorobenzylamine, the solubility and bioactivity of crocetin were expected to be improved. We evaluated the solubility, anti-proliferation activity and anti-inflammatory property of the synthesized derivatives. Results of this strategy is expected to provide novel evidence for the property improvement and medicinal application of crocetin.



1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (EDCI); petroleum ether (PE); 4-fluorobenzylamine, ethylamine; 1-hydroxybenzotrizole (HOBt); Dulbecco’s modified Eagle’s medium (DMEM); Et3N, trimethylamine; the fetal bovine serum (FBS) and trypsin were purchased from the Gibco BRL (Gaithersberg, MD). BCA protein assay kit and Cell Counting Kit-8 were provided by Sangon Biotech (Shanghai) Co., Ltd. Nitric Oxide assay kit were purchased from Beyotime Institute of Biotechnology, (Jiangsu, China). The mouse macrophage cell line and the cancer cell lines were obtained from the Shanghai Institute for Biological Sciences, CAS (Shanghai). Other chemicals and reagents were of analytical grade.

Synthesis of crocetin derivatives

The synthesis route of crocetin derivatives was showed in Fig. 1. Briefly, HOBt (2 equiv) were added to EDCI (1.5 equiv) at 0 °C, and Et3N (1.5 equiv) and 4-fluorobenzylamine (1 equiv) were added subsequently. The mixture solution was proceed at 0 °C for about 6 h and then at 25 °C for 12 h. After that, the mixture solution was diluted with dichloromethane. And then the unreacted organic compound in mixture was washed with 2.5% HCl and 7.5% NaHCO3 (15 mL, three times). The product of synthesized crocetin derivatives were obtained by evaporated under reduced pressure. Then, crocetin derivatives were purified by column chromatography.

Fig. 1
figure 1

Synthesis and chemical structures of compounds A and B

Solubility assays

To determine the solubility of crocetin and the synthesized derivatives in methanol, we established the standard curve by measuring its maximum absorbance with ultraviolet spectrophotometer. First, dissolving the samples in water. And then the solution was ultrasounded until the supersaturated solution was generated. After that, supersaturated solution was centrifugated at 12,000 rpm for 15 min. The supernatant of the solution was collected and freeze-dried, followed by using methanol to re-dissolve for UV detection. The concentration of the solution could be figured out by the standard curve. Upon that, we could obtain the solubility of the crocetin and its synthesized derivatives.

Cell culture

The mouse macrophage cell line and the cancer cell lines were cultured in the DMEM medium containing 10% Fetal Bovine Serum (FBS) at 37 °C, in humidified atmosphere containing 5% CO2. The cell medium was replaced every two days. Once cells reached 70–80% confluence, they could be used in the next experiments.

Anti-proliferation assay

The anti-proliferation effects of compounds on tumor cells were calculated by CCK-8 assay using Cell Counting Kit-8 (Sangon Biotech, Shanghai) according to manufacturer’s protocol. Cancer cell lines (SKOV3, A549 and B16F10 cells) were seeded in 96-well plates. 5 × 103 cancer cells were added to each well and incubated overnight for proliferation. And then in test groups, they were treated with different concentrations of synthesized derivatives, which are dissolved in DMSO and diluted by cell medium. The group, whose cells were incubated without compounds, was regard as control group. After incubated for 24 h or 48 h, the cell medium was changed by fresh medium (90 μl) and 10 μl of CCK-8 assay reagent. The cells were incubated at 37 °C for 1 h. The OD values of each well were measured at 450 nm.

Evaluation of the anti-inflammatory effect in LPS-stimulated macrophages

The anti-inflammatory effect was evaluated by using Nitric Oxide Assay kit. The RAW 264.7 cells with cell concentration 4 × 105 cells/ml were seeded in a 48-well plate in DMEM containing 10% Fetal Bovine Serum and incubated overnight at 37 °C, 5% CO2 humidifier incubator. The cells were then treated and induced by 5 μL LPS (1 mg/mL) for 0.5 h. We used the Griess reagent to measure the NO accumulation in the supernatant. Compared with the absorbance of blank group, the NO concentration was calculated. The number of cells was calculated according to the total protein concentration analyzed by BCA assays. Thus, the anti-inflammatory effect could be calculated by the level of nitrite divide by the total protein of the corresponding well.

Statistical analysis

Statistical analysis was performed with Origin 8.0 software (Origin Lab Inc. Massachusetts, USA). All data were expressed as mean ± standard error (SD). Comparison between two groups was done with independent sample t-test and correlation analysis. The significance was indicated by the P value. P values less than 0.05 (P < 0.05) were considered statistically significant.


Solubility of the crocetin derivatives

The solubility of the synthesized derivatives was shown in Fig. 1. The results showed that the solubility in water of crocetin was 1.238 μg/mL, while the solubility in water of compound A and B were 19.55, 12.28 times more than that of crocetin, respectively (Table 1). The significant increase in the solubility of these synthesized derivatives indicated that the chemical modification of these groups, which enhanced hydrophilicity and increased hydrogen bond formation [12], is an effective strategy to increase solubility of crocetin.

Table 1 Water solubility of crocetin, synthesized derivatives A and B

Anti-tumor effects of the crocetin derivatives

The influence of these compounds in the viability of three kinds of cancer cell lines was investigated. With different solubility, the highest concentration of the tested compounds in the mixture of water with 1% DMSO was tested as 15.24 μg/mL, 60.98 μg/ml and 60.98 μg/mL. As shown in Fig. 2, we first investigated the effects of different concentrations of crocetin and synthesized derivatives on the proliferation of A549, a lung cancer cell [13]. After one day of incubation of the compound with the cells, it was found that the cells viability was significantly decreased in contrast to that of solvent treated group. The crocetin expressed the highest suppression percentage at the 15.24 μg/mL, and the cells viability was decreased to 56%. While the maximum inhibitory efficiency of the compound A and B was expressed as 48.52 and 38.41%, at the 15.24 and 60.98 μg/mL, respectively.

Fig. 2
figure 2

Crocetin and its synthesized derivatives A、B inhibits cell proliferation in A549 cells. A549 cells were treated with different concentrations of crocetin and its synthesized derivatives A、B inhibits. After 24 h’ co-incubation at 37 °C, the cell survival rate was determined by MTT assays. Data represent mean ± SD. The results shown were reproduced at least 6 independent experiments. *** Indicates p < 0.001, ** indicates p < 0.01, and * indicates p < 0.05, for each treatment group versus solvent control group

Then we investigated the influence of the compound on B16F10 cell proliferation. As shown in Fig. 3, for group treated by crocetin, the highest suppression was shown as the 21.13% at the 15.24 μg/ml. Although compound A promoted cell proliferation at concentrations of 0.91 and 3.84 μg/mL, it inhibited the proliferation with 47.14% at concentrations of 60.98 μg/mL. In the case of compound B, it showed a strong inhibitory effect on B16F10. At the concentration of 60.98 μg/mL, the inhibition rate was 65.54%.

Fig. 3
figure 3

Crocetin and its synthesized derivatives A、B inhibits cell proliferation in B16F10 cells. B16F10 cells were treated with different concentrations of crocetin and its synthesized derivatives A、B inhibits. After 24 h’ co-incubation at 37 °C, the cell survival rate was determined by MTT assays. Data represent mean ± SD. The results shown were reproduced at least 6 independent experiments. *** Indicates p < 0.001, ** indicates p < 0.01, and * indicates p < 0.05, for each treatment group versus solvent control group

As shown in Fig. 4, we also investigated the effect of the compound on SKOV3 cells. Compared with the crocetin, the compound A, B showed the enhanced cancer inhibition efficacy of 28.53, 41.85% at 60.98, 15.24 μg/mL.

Fig. 4
figure 4

Crocetin and its synthesized derivatives A、B inhibits cell proliferation in SKOV3 cells. SKOV3 cells were treated with different concentrations of crocetin and its synthesized derivatives A、B inhibits. After 24 h’ co-incubation at 37 °C, the cell survival rate was determined by MTT assays. Data represent mean ± SD. The results shown were reproduced at least 6 independent experiments. *** Indicates p < 0.001, ** indicates p < 0.01, and * indicates p < 0.05, for each treatment group versus solvent control group

These results indicated that crocetin and its derivatives have a good inhibitory effect on the proliferation of the tested tumor cells. With the increased solubility of the derivatives, the anti-tumor activity of the crocetin was obviously improved. The inhibitory effect of compound on A549 and B16F10 cells was significantly higher than that of crocetin. For SKOV3 cells, there was no dose-dependent effect. But the overall inhibition efficacy was strong. As shown in Table 2, compound B had the lowest IC50 value, which indicated that it had the strongest anti-proliferation effect in the tested tumor cells. Results of this study proved the scientific evidence for that the modification of N atoms with hydrophilic groups is a promising strategy, which enhances the solubility and the biological effects of crocetin and has potential application for the anti-tumor and anti-inflammation.

Table 2 IC50 values of the synthesized compounds in different tumor cell lines

Anti-inflammatory effect of the crocetin derivatives

Oxidative stress is one of the critical steps that induce a lot of disease, including inflammation. Despite that various studies have reported the anti-oxidative effect of saffron, there are few study on the anti-inflammatory effects of crocetin to be reported [14]. In our study, the anti-inflammatory potential of crocetin and its derivatives were investigated. Large amounts of nitric oxide (NO) are positively correlated with the degree of inflammatory response [15]. Therefore, we determined the effect of compound at 2、4、10、20 and 40 μg/mL on the NO concentration in LPS activated macrophage cells to indicate their anti-inflammatory potential. As shown in Fig. 5, the level of NO in the macrophage was significantly reduced by the crocetin or derivatives treatments. When the compound A treatment at the 20 μg/mL, the NO concentration was under the detection limit. NO could not be detected in the compound B at the 40 μg/mL treated cells. The anti-inflammatory effect of compound A was dose-dependent. These results indicated that crocetin compounds have great significance in research and application.

Fig. 5
figure 5

Influenced of crocetin and its synthesized derivatives A、B on NO production in RAW 264.7 cell. RAW 264.7 cells were treated with different concentrations of crocetin and its synthesized derivatives A、B inhibits. After 24 h’ co-incubation at 37 °C, the expression of NO was measured by Griess reagent and protein levels were calculated by the BCA assays. Data represent mean ± SD. The results shown were reproduced by at least 6 independent experiments. ⁠** Indicates p < 0.01 for each treatment group compared with 2 μg/ml group; * indicates p < 0.05 for each treatment group compared with 2 μg/ml group

Cytotoxicity of the crocetin derivatives

In order to investigate whether the inhibition in the level of NO can be induced by cytotoxic effect, we examined the viability of RAW 264.7 cells treated with the compound by CCK-8 assays. As shown in Fig. 6, the tested compounds expressed no significant toxicity to the macrophage cells at all the tested concentration.

Fig. 6
figure 6

Cytotoxicity of crocetin and its synthesized derivatives A、B in RAW 264.7 cells. Total protein concentration of the cells were determined by BCA assays. Data represent mean ± SD. The results shown were reproduced by at least 6 independent experiments. ⁠** Indicates p < 0.01 for each treatment group compared with 2 μg/ml group; * indicates p < 0.05 for each treatment group compared with 2 μg/ml group


The major pharmacological component of saffron, crocetin possesses many pharmacological activities. However, due to its low water solubility, the clinical applications of crocetin is scarce [16]. It was reported that a large number of solvents have to be added to dissolve the compound and/or loaded onto other drug delivery vehicles. But these methods have limitations, such as side effects or complicated procedures. At the same time, few studies have reported the strategies that modifying the chemical structure of crocetin to improve its solubility. In this study, we investigated the influence of the conjugation of crocetin with the ethylamine or 4-Fluorbenzylamine in the solubility and biological activities of the derivatives. The results showed that this strategy have significantly not only increased the solubility, but also improved the anti-tumor properties and anti-inflammatory potential of the derivatives. Particularly, on the basis of retaining the structure with polyenoid as the core, the synthesized derivatives exert its pharmacological activities without obvious cytotoxicity to normal cells induced, indicating that the synthesized derivatives have a selective anti-proliferation effect on tumor cells that has great potential for in vivo application.

In mammals, oxidative stress and inflammatory responses cause major defense networks that help cells adapt to changes in the environment [4, 17,18,19]. However, chronic oxidative stress or inflammation is one of the most significant risk factor for the development of various human diseases including cancer, diabetes, neurological diseases [20,21,22]. The relationship between inflammation and cancer has been a hot area to be investigated for decades. The results of our study showed that the crocetin derivatives can effectively decrease the level of nitric oxide (NO) secretion, one of the most important inflammatory cytokines. At the same time, the test result of cytotoxicity of the synthesized compounds in the mouse macrophage cell line showed that the crocetin derivatives do not cause any damage to the cells, indicating the specific inhibition of the crocetin derivatives in NO secretion. Bathaie et al. reported that crocetin might interact with DNA and cause certain conformational changes, making the DNA unstable. In addition, they found that the crocetin significantly inhibits the expression of matrix metalloprotein (MMPs) in tumor cells, which is related to tumor invasion and its metastasis [23,24,25]. The anti-proliferation effects of the crocetin derivatives identified in this study might be contributed to the inhibition of the tested compounds in the process of synthesizing DNA dependent RNA polymerase II enzyme, biomacromolecule [23,24,25]. The anti-inflammatory potential of the compounds might also contribute to the anti-tumor potential of the derivatives. The significantly increased solubility of the derivatives might also be a major contribution to the improved efficacy.


This study demonstrated that the conjugation of ethylamine or 4-Fluorbenzylamine with the crocetin is the novel and hopeful strategy to enhance the solubility, anti-tumor properties and anti-inflammatory potential of crocetin. The synthesized derivatives are shown as the hopeful therapeutic agents with good solubility and vigorous bioactivities in the tumor and inflammation treatment.

Availability of data and materials

All data generated or analysed during this study are included in this article.



Bicinchoninic acid


Cell counting kit-8








Dulbecco’s modified eagle’s medium


Dimethyl sulphoxide


1-(3-dimethylaminopropyl)-3-ethyl carbodiimide




Ethyl acetate


Fetal bovine serum


Hydrochloric acid




1-Hydroxy, benzotriazole, hydrate


Inducible nitric oxide synthase






Sodium bicarbonate


Nitric oxide


Petroleum ether


Standard deviation


  1. G. Gutheil W, Reed G, Ray A, Anant S, Dhar A. Crocetin: an Agent Derived from Saffron for Prevention and Therapy for Cancer. Curr Pharm Biotechnol. 2012;13:173–9.

    Article  Google Scholar 

  2. Kalalinia F, Ghasim H, Amel Farzad S, Pishavar E, Ramezani M, Hashemi M. Comparison of the effect of crocin and crocetin, two major compounds extracted from saffron, on osteogenic differentiation of mesenchymal stem cells. Life Sci. 2018;208:262–7.

    Article  CAS  PubMed  Google Scholar 

  3. Christodoulou E, Kadoglou NP, Kostomitsopoulos N, Valsami G. Saffron: a natural product with potential pharmaceutical applications. J Pharm Pharmacol. 2015;67:1634–49.

    Article  CAS  Google Scholar 

  4. Ohba T, Ishisaka M, Tsujii S, Tsuruma K, Shimazawa M, Kubo K, et al. Crocetin protects ultraviolet A-induced oxidative stress and cell death in skin in vitro and in vivo. Eur J Pharmacol. 2016;789:244–53.

    Article  CAS  PubMed  Google Scholar 

  5. Arzi L, Riazi G, Sadeghizadeh M, Hoshyar R, Jafarzadeh N. A Comparative Study on Anti-Invasion, Antimigration, and Antiadhesion Effects of the Bioactive Carotenoids of Saffron on 4T1 Breast Cancer Cells Through Their Effects on Wnt/β-Catenin Pathway Genes. DNA Cell Biol. 2018;37:dna.2018.4248.

    Article  CAS  Google Scholar 

  6. Chen P, Chen Y, Wang Y, Cai S, Deng L, Liu J, et al. Comparative evaluation of hepatoprotective activities of geniposide, crocins and crocetin by CCl4-induced liver injury in mice. Biomol Ther. 2016;24:156–62.

    Article  Google Scholar 

  7. Cai J, Yi FF, Bian ZY, Shen DF, Yang L, Yan L, et al. Crocetin protects against cardiac hypertrophy by blocking MEK-ERK1-2 signalling pathway. J Cell Mol Med. 2009;13:909–25.

    Article  CAS  Google Scholar 

  8. Garvin N, Doucette WJ, White JC. Investigating differences in the root to shoot transfer and xylem sap solubility of organic compounds between zucchini, squash and soybean using a pressure chamber method. Chemosphere. 2015;130:98–102.

    Article  CAS  PubMed  Google Scholar 

  9. Nidhi K, Indrajeet S, Khushboo M, Gauri K, Sen DJ. Hydrotropy: a promising tool for solubility enhancement: a review. Int J Drug Dev Res. 2011;3:26–33.

    Google Scholar 

  10. Chu Y, Gao J, Niu J, Huang YF, Chen M, Wang MZ, et al. Synthesis, characterization and inhibitory effects of crocetin derivative compounds in cancer and inflammation. Biomed Pharmacother. December 2017;2018(98):157–64.

    Google Scholar 

  11. Chen Y, Zhang H, Zhou W, Deng C, Liao J. The solvent effects on dimethyl phthalate investigated by FTIR characterization, solvent parameter correlation and DFT computation. Spectrochim Acta - Part A Mol Biomol Spectrosc. 2018;199:412–20.

    Article  CAS  Google Scholar 

  12. Soltani F, Ramezani M, Amel Farzad S, Mokhtarzadeh A, Hashemi M. Comparison study of the effect of alkyl-modified and unmodified PAMAM and PPI dendrimers on solubility and antitumor activity of crocetin. Artif Cells, Nanomedicine Biotechnol. 2017;45:1356–62.

    Article  CAS  Google Scholar 

  13. Zhang K, Wang L, Si S, Sun Y, Pei W, Ming Y, et al. Crocin improves the proliferation and cytotoxic function of T cells in children with acute lymphoblastic leukemia. Biomed Pharmacother. 2018;99:96–100.

    Article  CAS  PubMed  Google Scholar 

  14. Jakubowska MA, Ferdek PE, Gerasimenko OV, Gerasimenko JV, Petersen OH. Nitric oxide signals are interlinked with calcium signals in normal pancreatic stellate cells upon oxidative stress and inflammation. Open Biol. 2016;6:160149.

    Article  Google Scholar 

  15. Iantorno M, Campia U, Daniele N, Nistico S, Forleo G, Cardillo C, et al. Obesity, inflammation and endothelial dysfunction. Int J Immunopathol Pharmacol. 2014;28:169–76.

    Article  Google Scholar 

  16. Shahdadi H, Barati F, Bahador RS, Eteghadi A. Clinical applications of saffron (Crocus sativus) and its constituents: A literature review. 2016;8:205–9.

  17. Wang W, Liu P, Hao C, Wu L, Wan W, Mao X. Neoagaro-oligosaccharide monomers inhibit inflammation in LPS-stimulated macrophages through suppression of MAPK and NF-κB pathways. Sci Rep. 2017;7:1–11.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Cruz-Vega D, Verde-Star MJ, Salinas-Gonzalez NR, Rosales-Hernandez B, Estrada-Garcia I, Mendez-Aragon P, et al. Review of pharmacological effects of Glycyrrhiza radix and its bioactive compounds. Zhongguo Zhong Yao Za Zhi. 2008;2009(22):557–9.

    Google Scholar 

  19. Diao SL, Sun JW, Ma BX, Li XM, Wang D. Influence of crocetin on high-cholesterol diet induced atherosclerosis in rats via anti-oxidant activity together with inhibition of inflammatory response and p38 MAPK signaling pathway. Saudi J Biol Sci. 2018;25:493–9.

    Article  CAS  PubMed  Google Scholar 

  20. Reuter S, Gupta SC, Chaturvedi M, M, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked?. Free radical biology & medicine. 2010;49(11):1603–16.

    Article  CAS  Google Scholar 

  21. Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O. Oxidative stress and antioxidant defense. The World Allergy Organization journal. 2012;5(1);9–19.

    Article  CAS  Google Scholar 

  22. Yan LJ. Pathogenesis of chronic hyperglycemia: from reductive stress to oxidative stress. J Diabetes Res. 2014;2014:137919.

    Google Scholar 

  23. Ashrafi M, Bathaie SZ, Taghikhani M, Moosavi-Movahedi AA. The effect of carotenoids obtained from saffron on histone H1 structure and H1-DNA interaction. Int J Biol Macromol. 2005;36:246–52.

    Article  CAS  Google Scholar 

  24. Bukhari SI, Manzoor M, Dhar MK. A comprehensive review of the pharmacological potential of Crocus sativus and its bioactive apocarotenoids. Biomed Pharmacother. 2017;2018(98):733–45.

    Article  CAS  Google Scholar 

  25. Bathaie SZ, Bolhasani A, Hoshyar R, Ranjbar B, Sabouni F, Moosavi-Movahedi A-A. Interaction of saffron carotenoids as anticancer compounds with ctDNA, Oligo (dG.dC)15, and Oligo (dA.dT)15. DNA Cell Biol. 2007;26:533–40.

    Article  CAS  PubMed  Google Scholar 

Download references


Not applicable.


The study was supported by National Key Research and Development Program of China (2018YFC1105404), National Natural Science Foundation of China (81473145), and the open project of State Key Laboratory of Quality Research in Chinese Medicine (Macau University of Science and Technology) funded by the Macao Science and Technology Development Fund, Macau Special Administrative Region, China.

Author information

Authors and Affiliations



L.H.P. and Z.H.J designed the study. M.Z.W., J.G., Y.C., N.J., M.C. and Q.S. performed the experiments. M.Z.W and J.G. analyzed the experimental data. L.H.P. and Z.H.J wrote and revised the paper, respectively. All authors read and approved the manuscript.

Corresponding authors

Correspondence to Li-Hua Peng or Zhi-Hong Jiang.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, MZ., Gao, J., Chu, Y. et al. Synthesis of crocetin derivatives and their potent inhibition in multiple tumor cells proliferation and inflammatory property of macrophage. BMC Complement Med Ther 20, 29 (2020).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: