Chemistry:Lucanthone

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Lucanthone (Miracil D, Myracyl D) is a drug used to treat parasitic diseases such as schistosomiasis,[1][2][3] which was invented in 1938 by Hans Mauss and colleagues at Bayer AG.[4][5] It is a prodrug and is converted to the active metabolite hycanthone.[6][7] It is no longer commonly used in humans due to hepatotoxicity,[8] especially after the subsequent development of safer drugs with similar efficacy such as praziquantel.

Mechanism of action

Hycanthone binds to acetylcholine receptors in the worm[9] and results in increased sensitivity to stimulation by 5-HT causing increase in motility, paired worms are separated and reproduction is stopped. It causes damage of the integument and vitelline duct.

Research

Lucanthone also shows anti-cancer activity, and while it has never been approved for medical use as a chemotherapy drug due to its toxicity, it has been tested in human clinical trials as an adjuvant therapy to increase the effectiveness of other chemotherapy medications, and continues to be used in cancer research.[10][11][12][13][14][15][16][17][18][19][20]

Synthesis

The original synthesis route by Mauss and colleagues produces a mixture of isomers which then needs to be separated,[21] this was subsequently improved upon in the 1950s.[22]

Lucanthone synthesis
Lucanthone improved precursor

References

  1. ↑ "Lucanthone hydrochloride; a review". Bulletin of the World Health Organization 18 (5–6): 989–1010. 1958. PMID 13573122. 
  2. ↑ "Chemotherapy of Helminthic Infections". Experimental chemotherapy.. 1. New York, New York: Academic Press. 2013. pp. 770. ISBN 978-1-4832-7308-2. https://books.google.com/books?id=3C0SBQAAQBAJ&dq=Lucanthone&pg=PA770. 
  3. ↑ "Schistosomiasis chemotherapy". Angewandte Chemie 52 (31): 7936–7956. July 2013. doi:10.1002/anie.201208390. PMID 23813602. 
  4. ↑ Mauss H, "Verfahren zur Herstellung von Xanthenen oder Thioxanthenen.", DE patent 919107, issued 1954-10-14
  5. ↑ "Untersuchungen über die tumorhemmende Wirkung des Miracils" (in de). The Science of Nature 36 (1): 29–29. January 1949. doi:10.1007/BF00588669. 
  6. ↑ "Hycanthone, a new active metabolite of lucanthone". Journal of Medicinal Chemistry 10 (5): 867–876. September 1967. doi:10.1021/jm00317a025. PMID 4963368. 
  7. ↑ "Comparison of schistosomicidal activity of xanthenones and 4-methyl-3-chloroanilines and their hydroxymethyl analogs in Swiss mice and Syrian hamsters infected with Schistosoma mansoni". Journal of Medicinal Chemistry 12 (4): 607–610. July 1969. doi:10.1021/jm00304a010. PMID 5793149. 
  8. ↑ "Schistosomiasis drug therapy and treatment considerations". Drugs 42 (3): 379–405. September 1991. doi:10.2165/00003495-199142030-00004. PMID 1720380. 
  9. ↑ "Anticholinergic properties of the antischistosomal drug hycanthone". The American Journal of Tropical Medicine and Hygiene 24 (5): 827–834. September 1975. doi:10.4269/ajtmh.1975.24.827. PMID 1190369. 
  10. ↑ "Biochemical Resemblance Between Endoparasites and Malignant Tumors". Priroda 39 (10): 22-27. 1950. https://www.cia.gov/readingroom/docs/CIA-RDP80-00809A000600380033-3.pdf. 
  11. ↑ "Effects of miracil D, amodiaquin, and a series of other 10-thiaxanthenones and 4-aminoquinolines against a variety of experimental tumors in vitro and in vivo". Journal of the National Cancer Institute 22 (3): 567–579. March 1959. PMID 13642019. 
  12. ↑ "Structure-activity studies on the mechanism of action of miracil D". Cancer Research 28 (3): 601–607. March 1968. PMID 4966649. 
  13. ↑ "The adjuvant effect of lucanthone (miracil D) in clinical radiation therapy". Radiology 114 (3): 729–731. March 1975. doi:10.1148/114.3.729. PMID 1118579. 
  14. ↑ "[Molecular mechanism of the antitumor action of lucanthone]". Voprosy Onkologii 24 (1): 91–94. 1978. PMID 205049. 
  15. ↑ "Analogues of hycanthone and lucanthone as antitumor agents". Journal of Medicinal Chemistry 26 (9): 1240–1246. September 1983. doi:10.1021/jm00363a007. PMID 6887199. 
  16. ↑ "Accelerated regression of brain metastases in patients receiving whole brain radiation and the topoisomerase II inhibitor, lucanthone". International Journal of Radiation Oncology, Biology, Physics 43 (1): 89–93. January 1999. doi:10.1016/s0360-3016(98)00374-5. PMID 9989518. 
  17. ↑ "Autophagy as a target for cancer therapy: new developments". Cancer Management and Research 4: 357–365. 2012. doi:10.2147/CMAR.S26133. PMID 23091399. 
  18. ↑ "Lucanthone Targets Lysosomes to Perturb Glioma Proliferation, Chemoresistance and Stemness, and Slows Tumor Growth In Vivo". Frontiers in Oncology 12. 2022. doi:10.3389/fonc.2022.852940. PMID 35494072. 
  19. ↑ "Lucanthone, a Potential PPT1 Inhibitor, Perturbs Stemness, Reduces Tumor Microtube Formation, and Slows the Growth of Temozolomide-Resistant Gliomas In Vivo". The Journal of Pharmacology and Experimental Therapeutics 389 (1): 51–60. March 2024. doi:10.1124/jpet.123.002021. PMID 38296645. 
  20. ↑ "Lucanthone inhibits the proliferation of lung cancer cells by suppressing the cuproptosis-related pathway". American Journal of Cancer Research 15 (11): 4857–4884. 2025. doi:10.62347/TVGD6582. PMID 41395284. 
  21. ↑ "Über basisch substituierte Xanthon- und Thioxanthon-Abkömmlinge; Miracil, ein neues Chemotherapeuticum". Chemische Berichte 81: 19–31. 1948. doi:10.1002/cber.19480810104. 
  22. ↑ "The Preparation of Some 1-Alkylamino- and Dialkylaminoalkylaminothiaxanthones1". Journal of the American Chemical Society 74 (17): 4296–4309. 1952. doi:10.1021/ja01137a017. 



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