A Novel N-Tert-Butyl Derivatives of Pseudothiohydantoin as Potential Target in Anti-Cancer Therapy

Abstract

Tumors are currently more and more common all over the world; hence, attempts are being made to explain the biochemical processes underlying their development. The search for new therapeutic pathways, with particular emphasis on enzymatic activity and its modulation regulating the level of glucocorticosteroids, may contribute to the development and implementation of new therapeutic options in the treatment process. Our research focuses on understanding the role of 11β-HSD1 and 11β-HSD2 as factors involved in the differentiation and proliferation of neoplastic cells. In this work, we obtained the 9 novel N-tert-butyl substituted 2-aminothiazol-4(5H)-one (pseudothiohydantoin) derivatives, differing in the substituents at C-5 of the thiazole ring. The inhibitory activity and selectivity of the obtained derivatives in relation to two isoforms of 11β-HSD were evaluated. The highest inhibitory activity for 11β-HSD1 showed compound 3h, containing the cyclohexane substituent at the 5-position of the thiazole ring in the spiro system (82.5% at a conc. 10 µM). On the other hand, the derivative 3f with the phenyl substituent at C-5 showed the highest inhibition of 11β-HSD2 (53.57% at a conc. of 10 µM). A low selectivity in the inhibition of 11β-HSD2 was observed but, unlike 18β-glycyrrhetinic acid, these compounds were found to inhibit the activity of 11β-HSD2 to a greater extent than 11β-HSD1, which makes them attractive for further research on their anti-cancer activity.

Novel 2-(Adamantan-1-ylamino)Thiazol-4(5H)-One Derivatives and Their Inhibitory Activity towards 11β-HSD1—Synthesis, Molecular Docking and In Vitro Studies

“…The change of the reaction conditions allowed obtaining compounds 3e-3f with isolated yields of 15.8-18.7%. Our previous research on the synthesis of 2-aminothiazol-4(5H)-one derivatives containing the spiro thiazole and alicyclic ring system showed that compounds of that type could be obtained by prolonged heating of the reactants in ethanol in the presence of N,N-diisopropylethylamine [30][31][32][33]. After 7 days for 3j and 14 days for 3i, a complete conversion of substrate to product was observed.…”

“…High percent inhibition (76.40-69.22%) was also shown by derivatives containing isopropyl (3e), propyl (3d), and ethyl (3c) substituents, for which IC 50 was 1.19, 3.23, and 5.44 µM, respectively. On the basis of the obtained results, it can be concluded that in comparison with the derivatives containing chain substituents at the nitrogen atom [30][31][32][33], 2-(adamantan-1-ylamino)thiazol-4 (5H)-ones show a higher activity towards the inhibition of 11β-HSD1. In vitro studies showed that all the derivatives obtained also inhibit the activity of enzyme isoform 2, yet to a lesser extent (all analyzed compounds inhibited the activity of 11β-HSD2 by less than 50%).…”

“…Our previous research has also shown that some of the thiazolone derivatives may be selective inhibitors over one of the 11β-HSD isoforms (Figure 2) [30][31][32][33][34]. Our previous research has also shown that some of the thiazolone derivatives may be selective inhibitors over one of the 11β-HSD isoforms (Figure 2) [30][31][32][33][34]. On the other hand, a group of compounds of interest from the pharmacological point of view includes the adamantane (tricyclo [3.3.1.13.7]-decane) derivatives.…”

“…Thiazole derivatives are also found as new enzyme inhibitors, for example Biovitrum BVT-2733, Biovitrum BVT-14225, AMG-221, and Amgen 2922 can inhibit 11β-hydroxysteroid dehydrogenase type 1 (Figure 1) [22][23][24][25][26][27][28][29]. Our previous research has also shown that some of the thiazolone derivatives may be selective inhibitors over one of the 11β-HSD isoforms (Figure 2) [30][31][32][33][34]. On the other hand, a group of compounds of interest from the pharmacological point of view includes the adamantane (tricyclo [3.3.1.13.7]-decane) derivatives.…”

“…These include adamantine triazoles such as the Merck compound 544 [36], amides from Abbott [37,38], sulfone, sulfonamide [39], pyrrolidine carboxamide [40], and adamantyl ethanone derivatives [41]. Our previous research has also shown that some of the thiazolone derivatives may be selective inhibitors over one of the 11β-HSD isoforms (Figure 2) [30][31][32][33][34]. Our previous research has also shown that some of the thiazolone derivatives may be selective inhibitors over one of the 11β-HSD isoforms (Figure 2) [30][31][32][33][34].…”