CC BY 4.0 · Pharmaceutical Fronts 2024; 06(02): e136-e148
DOI: 10.1055/s-0044-1786032
Original Article

Design, Synthesis, and Evaluation of Novel Cryptotanshinone Derivatives for Activity against Triple-Negative Breast Cancer

Siyu Liu
1   National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
,
Panpan Zhang
1   National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
,
Qingyan Sun
1   National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
› Author Affiliations
Funding This work was supported by the National Key Laboratory of Lead Druggability Research (Grant No. NKLYT2023010) and the Three-year Action Plan for Shanghai TCM Development and Inheritance Program (Grant No. ZY [2021-2023]-0401).


Abstract

Triple-negative breast cancer (TNBC) can be difficult to treat because of resistance to existing therapeutic agents. Our prior studies revealed the inhibitory effect of the natural product cryptotanshinone (CTS) on the proliferation of TNBC cells; however, its clinical application was prevented due to its low water solubility and activity. This study aimed to synthesize derivatives of CTS with enhanced potency and water solubility. The structure of CTS was modified by adding amino acid side chains, which were derived into phosphonium salts. The derivatives were immersed in phosphate-buffered saline (PBS) to assess their water solubility. The antitumor effects of the derivatives against MDA-MB-231 breast cancer cells were assessed by evaluating their roles in regulating cell proliferation, cell apoptosis, and cell-cycle arrest using cell counting kit-8 (CCK-8), flow cytometry, and calcein-AM/propidium iodide assay, respectively. In this work, a total of 29 derivatives of CTS were synthesized, of which the tricyclohexylphosphine derivatives C4-2 and C5-2 were highly soluble in PBS, with 790- and 450-fold higher than that of CTS, respectively, and at the same time, the antitumor activities of C4-2 and C5-2 were also enhanced, with two- and fourfold higher than that of CTS, respectively. Further studies revealed that the compounds may inhibit the proliferation of MDA-MB-231 by inducing cellular arrest in the G2/M phase. These findings provided preliminary data for the mechanisms of CTS and its derivatives in blocking TNBC and suggested C4-2 and C5-2 as potential agents for the treatment of the disease in the future.

Supporting Information

Spectroscopic characterization processes (1H NMR and 13C NMR) for compounds A1 to A6-2, B1 to B5-1, and C1 to C6-2 are included in the Supporting Information ([Supplementary Figs. S1]–[S29] [available in the online version]).


Supplementary Material



Publication History

Received: 18 September 2023

Accepted: 23 March 2024

Article published online:
23 May 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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  • References

  • 1 Michaels E, Worthington RO, Rusiecki J. Breast cancer: risk assessment, screening, and primary prevention. Med Clin North Am 2023; 107 (02) 271-284
  • 2 Singh DD, Yadav DK. TNBC: potential targeting of multiple receptors for a therapeutic breakthrough, nanomedicine, and immunotherapy. Biomedicines 2021; 9 (08) 876
  • 3 Ferrari P, Scatena C, Ghilli M, Bargagna I, Lorenzini G, Nicolini A. Molecular mechanisms, biomarkers and emerging therapies for chemotherapy-resistant TNBC. Int J Mol Sci 2022; 23 (03) 1665
  • 4 Deng LJ, Qi M, Li N, Lei YH, Zhang DM, Chen JX. Natural products and their derivatives: promising modulators of tumor immunotherapy. J Leukoc Biol 2020; 108 (02) 493-508
  • 5 Li H, Gao C, Liu C. et al. A review of the biological activity and pharmacology of cryptotanshinone, an important active constituent in Danshen. Biomed Pharmacother 2021; 137: 111332
  • 6 Pan Y, Shi J, Ni W. et al. Cryptotanshinone inhibition of mammalian target of rapamycin pathway is dependent on oestrogen receptor alpha in breast cancer. J Cell Mol Med 2017; 21 (09) 2129-2139
  • 7 Zhou J, Xu XZ, Hu YR, Hu AR, Zhu CL, Gao GS. Cryptotanshinone induces inhibition of breast tumor growth by cytotoxic CD4+ T cells through the JAK2/STAT4/ perforin pathway. Asian Pac J Cancer Prev 2014; 15 (06) 2439-2445
  • 8 Park IJ, Kim MJ, Park OJ. et al. Cryptotanshinone induces ER stress-mediated apoptosis in HepG2 and MCF7 cells. Apoptosis 2012; 17 (03) 248-257
  • 9 Kobryń J, Dałek J, Musiał W. The influence of selected factors on the aqueouscryptotanshinone solubility. Pharmaceutics 2021; 13 (07) 992
  • 10 Zhang J, Huang M, Guan S. et al. A mechanistic study of the intestinal absorption of cryptotanshinone, the major active constituent of Salvia miltiorrhiza. J Pharmacol Exp Ther 2006; 317 (03) 1285-1294
  • 11 Xue M, Cui Y, Wang HQ, Hu ZH, Zhang B. Reversed-phase liquid chromatographic determination of cryptotanshinone and its active metabolite in pig plasma and urine. J Pharm Biomed Anal 1999; 21 (01) 207-213
  • 12 Li H. Design and Synthesis of Cryptotanshinone Derivatives and Their Effects on the Transcriptional Activity of STAT3 [In Chinese]. Fuzhou: Fujian University of Traditional Chinese Medicine; 2021
  • 13 Ding C, Li J, Jiao M, Zhang A. Catalyst-free sp3 C-H acyloxylation: regioselective synthesis of 1-acyloxy derivatives of the natural product tanshinone IIA. J Nat Prod 2016; 79 (10) 2514-2520
  • 14 Liang B, Yu SJ, Li J. et al. Site-selective Csp3-H aryloxylation of natural product tanshinone IIA and its analogues. Tetrahedron Lett 2017; 58 (19) 1822-1825
  • 15 Zhou JH. Synthesis and Vasodilative Activity of cryptotanshinone Derivatives [In Chinese]. Zhengzhou: Zhengzhou University; 2019
  • 16 Meng FF. Synthesis and Cardioprotective Activity Screening Research of Cryptotanshinone Derivatives [In Chinese]. Zhengzhou: Zhengzhou University; 2021
  • 17 Yan L. Cryptotanshinone Suppresses Triple Negative Breast Cancer via Ferroptosis [In Chinese]. Shanghai: Naval Medical University; 2021