Due to the high prostate cancer incidence worldwide, the development of different methods of treatment continues to be a hot research topic. Since its first clinical application at the beginning of the 2010s, abiraterone in the form of prodrug abiraterone acetate continues to be the most used hormone derivative in the treatment of castration-resistant prostate cancer. This is the reason behind the publication of many scientific results regarding its synthesis, biological activity, metabolism, novel designed steroid derivatives based on its structure, etc. A similar steroid compound with a heterocycle in the C17 position, called galeterone, also designed to treat prostate cancer, continues to be in clinical studies, which provides further proof of the importance of these steroid derivatives. Besides prostate cancer treatment, abiraterone showed indications for possible clinical application in the treatment of breast, ovarian, lung, kidney, salivary gland, and adrenocortical cancer, congenital adrenal hyperplasia, Cushing’s syndrome, and COVID-19, while galeterone is investigated for its use against prostate, pancreatic, and breast cancer. Herein, we report a review comprising methods of synthesis, possible clinical applications, and mechanisms of action, as well as structures and bioactivities of derivatives of these two important steroids.

Testolactone is structurally related to testosterone and belongs to the first generation of aromatase inhibitors. It is a non-selective irreversible aromatase enzyme inhibitor that was one of the first steroids used in the clinical treatment of breast cancer. The use of testolactone in the treatment of breast cancer started in 1970, although its ability to inhibit aromatase was not discovered until 1975. Its use was primarily based on the inhibition of estrogen synthesis, which was applied in the treatment of estrogen-dependent breast cancers, in the treatment of disorders of sex steroid excess, familial male-limited precocious puberty, or in the treatment of patients with McCune–Albright syndrome, etc. The weak inhibitory activity of testolactone, and the moderate clinical response, prevented its widespread use, which ultimately resulted in withdrawal from the drug market in 2008. This review paper is dedicated to testolactone, its rise in the second half of the 20th century, and its fall in the first decade of the 21st century. Regardless of withdrawal from the market, for many years testolactone was a drug that improved the quality of life of patients facing one of the most serious diseases today, and for this reason, this paper describes medicinal application, synthesis, and modifications of testolactone.

The estrogen receptor (ER) is a major therapeutic target in treating estrogen-related diseases, such as breast cancer. There is a need to develop potent ER ligands capable of selectively targeting cancer cells without affecting normal cells. Blocking ERα action by antagonists and inhibiting steroidogenic enzymes has been standard therapy in breast cancer treatment for many years. On the other hand, the ERβ isoform usually has antiproliferative and tumor-suppressive functions, so targeting ERβ with specific agonists represents a promising new approach not only in breast cancer but also in prostate cancer therapy. Besides the anticancer activity of ERβ agonists, their application is considered in treating depression, anxiety, and inflammation. To obtain potent antiproliferative agents, a triazole ring is often incorporated as a pharmacophore in the steroid skeleton. This study evaluates the binding affinity of novel N(2)-substituted D-condensed steroidal triazoles for ligand-binding domains (LBDs) of ERβ and androgen receptors using a yeast-based fluorescent assay. The LBD of the steroid receptor was expressed in-frame with a yellow fluorescent protein (YFP) in Saccharomyces cerevisiae. Upon ligand-binding induced dimerization, fluorescence resonance energy transfer (FRET) between YFP molecules was analyzed using fluorescence spectroscopy and microscopy. We identified new selective ERβ ligands without androgenic properties, but further experiments are required to determine whether their mechanism of action is agonistic or antagonistic. Considering the broad therapeutic potential of specific ERβ ligands, our findings indicate that steroid derivatives containing triazole are promising bioactive compounds in the field of anticancer agents.