Biological activity of pyrazole and imidazole-dehydroepiandrosterone derivatives on the activity of 17β-hydroxysteroid dehydrogenase

Abstract

The enzyme type 5 17b-hydroxysteroid dehydrogenase 5 (17b-HSD5) catalyzes the transformation of androstenedione (4-dione) to testosterone (T) in the prostate. This metabolic pathway remains active in cancer patients receiving androgen deprivation therapy. Since physicians seek to develop advantageous and better new treatments to increase the average survival of these patients, we synthesized several different dehydroepiandrosterone derivatives. These compounds have a pyrazole or imidazole function at C-17 and an ester moiety at C-3 and were studied as inhibitors of 17b-HSD5. The kinetic parameters of this enzyme were determined for use in inhibition assays. Their pharmacological effect was also determined on gonadectomized hamsters treated with D 4 -androstenedione (4-dione) or testosterone (T) and/or the novel compounds. The results indicated that the incorporation of a heterocycle at C-17 induced strong 17b-HSD5 inhibition. These derivatives decreased flank organ diameter and prostate weight in castrated hamsters treated with T or 4-dione. Inhibition of 17b-HSD5 by these compounds could have therapeutic potential for the treatment of prostate cancer and benign prostatic hyperplasia.

Synthesis, characterization and in vitro biological evaluation of two matrine derivatives

“…Our results are also in a good agreement with the previous research 26 . Considering the structural features of matrine derivative 1, one may deduce that the introduction of indole to matrine skeleton could improve its permeability into cell membrane and then influence its bioactivity, hence resulting in increased lipophilicity of this derivative 12 , 33 , 34 . This explanation could also be applicable for matrine derivative 2, even though its lipophilicity is relatively lower than that of matrine derivative 1, but much higher than that of the parent matrine (Table 4 ).…”

Synthesis and Pharmacological Properties of Modified A- and D-Ring in Dehydroepiandrosterone (DHEA): A Review

“…Derivatives. Cabeza and co-workers reported the synthesis of various novel DHEA derivatives with pyrazole or imidazole moiety at C-17 and an ester moiety at C-3 (Scheme 10) in 2016, 19 which were tested as inhibitors of enzyme 17β-HSD5 (17β-hydroxysteroid dehydrogenase type 5). Inhibition of 17β-HSD5 by these DHEA derivatives could offer therapeutic potential for treating prostate cancer and benign prostatic hyperplasia.…”

“…Figure 6. Effect of the novel steroids on the activity of 17β-HSD5 enzyme IC 50 values shows the concentration for each compound, that inhibited the activity of 17β-HSD5 by 50% 19. …”