Triphenylmethanol Conjugates of Leuprorelin as Anti-Cancer Prodrugs

Kaleh Karim, Tennessee State University


Leuprorelin (LEP) is a synthetic analogue of gonadotropin-releasing hormone (GnRH). It was first approved by the FDA for the treatment of prostate cancer and breast cancer in 1985. The initial effect of LEP is that it stimulates the pituitary secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH) however, after prolonged stimulation the pituitary gland becomes insensitive to the action of GnRH. This reduces the level of gonadotropin in the blood, resulting in decreased levels of reproductive hormones to post castration or menopausal levels. Although these effects are reversible, improving the biological activity of LEP by increasing the cellular uptake and retention is a beneficial remedy. In this study, the hydrophobicity of LEP was optimized using dodecanedioic acid linker attached to triphenylmethanol derivatives followed by the conjugation of Leuprorelin to increase cellular uptake of LEP. We hypothesize that by creating a prodrug system which increases lipophilicity, the cellular uptake will also increase. Hence, comparative cell cytotoxicity assays between LEP-triphenylmethanol conjugates and the corresponding non-covalent physical mixtures of the triphenylmethanol derivatives and LEP were performed against human invasive ductal carcinoma BT­549 (ATCC® HTB­122™) cells, human prostate carcinoma (PC3) cells, human lung cancer A549 cells and mouse pre-adipocytes (3T3-L1) cells. LEP-triphenylmethanol conjugates had slightly higher cell cytotoxicity against BT549, PC3 an 3T3 cell at concentrations 5-100 µM after 24h incubation period than when treated with Leuprorelin alone. However, cell cytotoxicity seemed to increase significantly when using LEP-TPM CO2CH3 . Cell proliferation data suggests that cell proliferation was inhibited by approximately 20 percent more when using LEP-TPM CO2CH3 than when using Leuprorelin. These data suggest that LEP-triphenylmethanol derivatives have optimized hydrophobicity of LEP thereby improving the biological activity of LEP presumably by enhancing the cellular delivery and retention of LEP among reproductive cancer cell lines.

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Recommended Citation

Kaleh Karim, "Triphenylmethanol Conjugates of Leuprorelin as Anti-Cancer Prodrugs" (2017). ETD Collection for Tennessee State University. Paper AAI10267504.