Design, synthesis, and biological activity of TLR7-based compounds for chemotherapy-induced alopecia

  • Jincheng YangEmail author
  • Kun Chen
  • Bin Wang
  • Liudi Wang
  • Shuya Qi
  • Weihua Wang


Hair loss is a common dermatosis symptom and side-effect in cancer chemotherapeutics. Imiquimod application at mid and late telogen activated the hair follicle stem cells leading to premature hair cycle entry. Based on quinoline structure, a newly synthesized compound 6b displayed proliferation activity in vitro and in vivo through branch chain replacement and triazole ring cyclization. Toll-like receptors (TLRs) are also critical mediators of the immune system, and their activation is linked to various diseases. The present study aimed to expand new agonists within co-crystallization of TLR7 (PDB code: 5GMH); however, biological assays of NF-κB activity and NO-inhibition indicated that five selected compounds were TLR7 antagonists. Molecular docking indicated the binding mode differences: antagonists binding TLR7 in a different direction and interacting with adjacent TLR7 with difficulty in forming dimers.


TLR7 Hair follicle stem cell Chemotherapy-induced alopecia Antagonist Synthesis 



The key structures have applied Chinese patent. (CN201711279295, CN108003153A).

We thank Zhejiang Ruyao Biotech Co.,LTD for technologic support.


The work was supported by National Natural Science Foundation of China (No. 81603218).

Compliance with ethical standards

Conflict of interest

Author Jincheng Yang declares that he has no conflict of interest. Author Kun Chen declares that she has no conflict of interest. Author Bin Wang declares that he has no conflict of interest. Author Liudi Wang declares that she has no conflict of interest. Author Shuya Qi declares that she has no conflict of interest. Author Weihua Wang declares that she has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors. Animal experiments were approved by the Institutional Animal Care and Use Committee at National Cancer Center, Chinese Academy of Medical Sciences. (NCC2016A050, 9 March 2016) All applicable international, national, and institutional guidelines for the care and use of animals were followed.


  1. 1.
    Nalluri R, Harries M (2016) Alopecia in general medicine. Clin Med 16(1):74–78CrossRefGoogle Scholar
  2. 2.
    Chen C, Chang Y, Liu H, Chen Y (2018) Cancer risk in patients with alopecia areata: a nationwide population-based matched cohort study. Cancer Med 7:2153–2159CrossRefGoogle Scholar
  3. 3.
    Seo H, Han S, Kim J (2018) Cancer risks among patients with alopecia areata: a population-based case-control study in Korea. J Am Acad Dermatol 78:209–211CrossRefGoogle Scholar
  4. 4.
    Roe H (2011) Chemotherapy-induced alopecia: advice and support for hair loss. Br J Nurs 20:S4–S11Google Scholar
  5. 5.
    Jayde V, Boughton M, Blomfield P (2013) The experience of chemotherapy-induced alopecia for Australian women with ovarian cancer. Eur J Cancer Care (Engl) 22:503–512CrossRefGoogle Scholar
  6. 6.
    Wang J, Lu Z, Au LS (2006) Protection against chemotherapy-induced alopecia. Pharm Res (Dordrecht) 23(11):2505–2514CrossRefGoogle Scholar
  7. 7.
    Trüeb RM (2009) Chemotherapy-induced alopecia. Semin Cutan Med Surg 28(1):11–14CrossRefGoogle Scholar
  8. 8.
    Panteleyev A (2018) Functional anatomy of the hair follicle: the secondary hair germ. Exp Dermatol 27:701–720CrossRefGoogle Scholar
  9. 9.
    Chen R, Miao Y, Hu Z (2019) Dynamic nestin expression during hair follicle maturation and the normal hair cycle. Mol Med Rep 19(1):549–554Google Scholar
  10. 10.
    Ralf P, Haslam Iain S, Sharov Andrey A et al (2013) Pathobiology of chemotherapy-induced hair loss. Lancet Oncol 14:e50–e59CrossRefGoogle Scholar
  11. 11.
    Amberg N, Holcmann M, Stulnig G, Sibilia M (2016) Effects of Imiquimod on hair follicle stem cells and hair cycle progression. J Invest Dermatol 136(11):2140–2149CrossRefGoogle Scholar
  12. 12.
    Letada PR, Sparling JD, Norwood C (2007) Imiquimod in the treatment of alopecia universalis. Cutis 79(2):138–140Google Scholar
  13. 13.
    Paus R, Cotsarelis G (1999) The biology of hair follicles. N Engl J Med 341(7):491–497CrossRefGoogle Scholar
  14. 14.
    Kontogiorgis CA, Hadjipavloulitina DJ (2017) Synthesis and antiinflammatory activity of coumarin derivatives. J Med Chem 48(20):6400–6408CrossRefGoogle Scholar
  15. 15.
    Zheng Y, Hsieh J-C, Escandon J, Cotsarelis G (2016) Isolation of mouse hair follicle bulge stem cells and their functional analysis in a reconstitution assay. Methods Mol Biol Chapter 8. 1453:57-69Google Scholar
  16. 16.
    Ma DR, Yang EN, Lee ST (2004) A review: the location, molecular characterisation and multipotency of hair follicle epidermal stem cells. Ann. Acad. Med. Singap 33:784–788Google Scholar
  17. 17.
    Meihua G, Pan Z, Chunyang L et al (2018) Protective mechanism of adipose-derived stem cells in Remodelling of the skin stem cell niche during Photoaging. Cell Physiol Biochem 51:2456–2471CrossRefGoogle Scholar
  18. 18.
    Sasaki S, Baba T, Muranaka H, Tanabe Y, Takahashi C, Matsugo S, Mukaida N (2018) Involvement of prokineticin 2-expressing neutrophil infiltration in 5-fluorouracil-induced aggravation of breast cancer metastasis to lung. Mol Cancer Ther 17:1515–1525CrossRefGoogle Scholar
  19. 19.
    Wang D, Bhagat L, Yu D, Zhu FG, Tang JX, Kandimalla ER, Agrawal S (2009) Oligodeoxyribonucleotide-based antagonists for toll-like receptors 7 and 9. J Med Chem 52(2):551–558CrossRefGoogle Scholar
  20. 20.
    Drake M, Scott G, Proskocil B et al (2013) Toll-like receptor 7 rapidly relaxes human airways. Am J Respir Crit Care Med 188(6):664–672CrossRefGoogle Scholar
  21. 21.
    Young A, Arif A (2016) The use of scalp cooling for chemotherapy-induced hair loss. Br J Nurs 25:S22–S27CrossRefGoogle Scholar
  22. 22.
    Katikaneni R, Ponnapakkam T, Matsushita O, Sakon J, Gensure R (2014) Treatment and prevention of chemotherapy-induced alopecia with PTH-CBD, a collagen-targeted parathyroid hormone analog, in a non-depilated mouse model. Anti-Cancer Drugs 25(1):30–38CrossRefGoogle Scholar
  23. 23.
    Belen R-G, Margit J, Jamie F et al (2018) Pathogenesis and treatment options for chemotherapy-induced alopecia: a systematic review. Int J Dermatol 57:1417–1424CrossRefGoogle Scholar
  24. 24.
    Rubtsova K, Marrack P, Rubtsov AV (2015) TLR7, IFNγ, and T-bet: their roles in the development of ABCs in female-biased autoimmunity. Cell Immunol 294(2):80–83CrossRefGoogle Scholar
  25. 25.
    Swindell William R, Michaels Kellie A, Sutter Andrew J et al (2017) Imiquimod has strain-dependent effects in mice and does not uniquely model human psoriasis. Genome Med 9:24CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacy, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
  2. 2.State Key Laboratory of Molecular Oncology/Department of Immunology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
  3. 3.Clinical Stem Cell CenterThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina

Personalised recommendations