Novel Non-steroidal Progesterone Receptor Ligands Based on <i>m</i>-Carborane Containing a Secondary Alcohol: Effect of Chirality on Ligand Activity

Abstract

The progesterone receptor (PR) controls various physiological processes, including the female reproductive system, and nonsteroidal PR ligands are considered to be drug candidates for treatment of various diseases without significant adverse effects. Here, we designed and synthesized m-carborane-based secondary alcohols and investigated their PR-ligand activity. All the synthesized alcohols exhibited PR-antagonistic activity at subnanomolar concentration. Among them, alcohols having a small alkyl side chain and a 4-cyanophenyl group also exhibited PR-agonistic activity in a relatively high concentration range. Optical resolution of secondary alcohols having a methyl side chain was performed, and the PR-ligand activity and PR-binding affinity of the purified enantiomers were examined. The chirality of the secondary alcohol appears to have a more significant influence on PR-agonistic activity than on antagonistic activity.Key words progesterone receptor; antagonist; carborane; chirality; lipase The progesterone receptor (PR) is a member of the nuclear receptor superfamily and plays important roles in many physiological processes, especially in the female reproductive system, via ligand-dependent transcriptional activation of various target genes.1) Progesterone (1, Fig. 1) is an endogenous PR agonist that regulates many physiological processes, [2][3][4][5] including uterine cell proliferation/differentiation, the ovulation cycle, and implantation. In addition, 1 modulates the activities of major physiological systems such as the cardiovascular , 6) immune, 7) and nervous systems. 8) Several synthetic PR agonists and antagonists have been developed for clinical use [9][10][11] in contraception, hormone replacement therapy, treatment of gynecological disorders, and abortion. For example, synthetic PR antagonist mifepristone (2, Fig. 1) is a representative abortifacient.12) It has also been suggested that 2 might be effective in the treatment of endometriosis, 13) uterine leiomyoma, 14) and breast cancer. 15,16) However, all PR ligands currently in clinical use, including 2, are steroid derivatives, and may have significant adverse effects because of their cross-activity toward other steroid hormone receptors. 17) In order to avoid these adverse effects, non-steroidal PR ligands are required, and indeed, several non-steroidal ligands have been developed, such as tanaproget (3) 18) and a sulfonamide derivative (4) 19) (Fig. 1). Results and DiscussionWe have reported non-steroidal PR ligands bearing boroncluster compounds (carborane) as their hydrophobic core structures. [20][21][22] Carboranes, more precisely dicarba-closododecaboranes (C 2 B 10 H 12 ), are carbon-containing boron clusters with icosahedral cage structure; there are three isomers depending upon the position of the two carbon atoms, that is, ortho-, meta-, and para-carborane [23][24][25] (Fig. 2a). Carboranes have high thermal and chemical stability, and exceptionally high hydrophobicity, [26][27][28][29] and we have applied them as hydrophobic core ...

Development of Boron-Cluster-Based Progesterone Receptor Antagonists Bearing a Pentafluorosulfanyl (SF₅) Group

“…18) On the other hand, compound 7 having an m-carborane core exhibited bidirectional PR ligand activity, namely, it showed PR-antagonistic activity in the low concentration range, and PR-agonistic activity in the high concentration range. 20) Compound 8 having a 3-trifluoromethyl substituent on the phenyl group showed only antagonistic activity. 20) These results indicate that the mode of PR ligand activity is affected by the nature and position of the polar functional group on the phenyl group.…”

“…20) Compound 8 having a 3-trifluoromethyl substituent on the phenyl group showed only antagonistic activity. 20) These results indicate that the mode of PR ligand activity is affected by the nature and position of the polar functional group on the phenyl group. Therefore, it is important to investigate the characteristics of a variety of polar functional groups of PR ligands.…”

“…15) In the previous study, we developed non-steroidal PR antagonists bearing a boron-cluster carborane as the hydrophobic core structure. [17][18][19][20] Carboranes, or more precisely dicarbacloso-dodecaboranes (C 2 B 10 H 12 ), are carbon-containing boron clusters with an icosahedral cage structure, and there are three isomers, depending on the positions of the two carbon atoms, that is, ortho-, meta-, and para-carborane. 21) Carboranes have high thermal and chemical stability, and exceptionally high hydrophobicity, [22][23][24] and we have applied them as hydrophobic core structures of various bioactive compounds, especially ligands of various nuclear receptors, such as retinoid receptors, 25) androgen receptor, 26) and vitamin D receptor.…”

“…2) exhibited PR-antagonistic activity. 18,20) A docking study of 5 with the PR-LBD indicated that the carborane moiety of 5 occupies the space corresponding to the steroid CD ring of progesterone (1). 18) In addition, the cyano group of 5 was suggested to interact with Gln725 and Arg766 in the PR-LBD, which also interact with 3-carbonyl group of progesterone (1).…”

m-Carborane as a Novel Core for Periphery-Decorated Macromolecules

“…On the other hand, the reactivity of m -carborane is less studied but for the C c -H vertexes, which are less acidic as compared to the C c -H vertexes of the o -isomer [ 10 , 26 ]. Using a similar strategy as for o -carborane, a wide variety of 1-R-1,7- closo -C 2 B 10 H 11 and 1,7-R 2 -1,7- closo -C 2 B 10 H 10 derivatives has been developed [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. To some extent, the current state of knowledge of the m -carborane functionalization through the B-H vertexes is in an odd situation.…”