Characterization of Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitors as Stimulators of Steroidogenesis

Abstract

Inhibition of GSK-3β has been well documented to account for the behavioral actions of the mood stabilizer lithium in various animal models of mood disorders. Recent studies have showed that genetic or pharmacological inhibition of GSK-3β resulted in anxiolytic-like and pro-social behavior. In our ongoing efforts to develop GSK-3β inhibitors for the treatment of mood disorders, SAR studies on maleimide-based compounds were undertaken. We present herein for the first time that some of these GSK-3β inhibitors, in particular analogs 1 and 9, were able to stimulate progesterone production in the MA-10 mouse tumor Leydig cell model of steroidogenesis without any significant toxicity. These two compounds were tested in the SmartCube® behavioral assay and showed anxiolytic-like signatures following daily dose administration (50 mg/kg, i.p.) for 13 days. Taken together, these results support the hypothesis that GSK-3β inhibition could influence neuroactive steroid production thereby mediating the modulation of anxiety-like behavior in vivo.

Structural and in Vivo Characterization of Tubastatin A, a Widely Used Histone Deacetylase 6 Inhibitor

“…The behavioral signatures of mice were captured by a digital video camera, analyzed by computer algorithms, and further compared with a database of behavioral signatures obtained using a set of diverse reference drugs clinically used in treatments of psychiatric diseases. 41,42 As shown in Figure 5, the behavioral signatures of TubA at 60 mg/kg (IP) after 15 min of pretreatment revealed anxiolytic, antidepressant, antipsychotic, and cognitive effects with minor side-effects.…”

New N‐benzhydrylpiperazine/1,3,4‐oxadiazoles conjugates inhibit the proliferation, migration, and induce apoptosis in HeLa cancer cells via oxidative stress–mediated mitochondrial pathway

“…23 1,3,4-Oxadiazoles, is another important scaffold demonstrating various pharmacological significances. The anticancer activities of 1,3,4-oxadiazole derivatives is contributed to their potential concerning the inhibition of telomerase, 24 histone deacetylase (HDAC), 25 thymidylate synthase (TS), 26 glycogen synthase kinase (GSK3), 27 vascular endothelial growth factor (VEGF), 28 and epidermal growth factor (EGFR) 29 involve in proliferation of cancer cells. Also, substitution at C-2 of 1,3,4-oxadiazoles by an acyl, or alkyl substrate further improves the biological profile.…”

“…-benzhydryl-4-((5-(4-methylphenyl)-1,3, 4-oxadiazol-2-yl)methyl)piperazine (4e) Yield: 51.06%; mp: 143 to 145°C; Anal Calcd for C27 H 28 N 4 O: C,76.39, H, 6.65, N, 13.20; found C, 76.40, H, 6.64, N, 13.21; IR (ν max cm −1 ): 3301 (NH stretch), 3289, 3123 (Ar-H), 2900, 2885 (piperazine ring), 1618, 1458 (C=N, C=C), 1242, 1117 (C-O-C), 1263 (C-N); 1 H-NMR (DMSO-d 6 ) δ (ppm): 7.38 to 7.37 (d, 4H, Ar-H, J = 6.6 Hz), 7.33 to 7.31 (t, 4H, Ar-H, J = 6.7 Hz), 7.24 to 7.19 (m, 5H, phenyl), 7.13 to 7.12 (d, 2H, Ar-H, J = 6.6 Hz), 4.81 (s, 2H, -CH 2 ), 4.47 (s, 1H, -CH), 3.23 (br, s, 4H, -CH 2 -N-CH 2 , piperazine ring), 2.46 (br, s, 4H, -CH 2 -N-CH 2 , piperazine ring) 13 C-NMR (DMSO-d 6 ) δ (ppm) 172.25, 164.53, 151.52, 143.52, 134.45, 132.11, 129.36, 127.48, 126.73, 122.28, 117.12, 114.21, 112.45, 67.94, 64.32, 45.85, 41.31; ESI-MS m/z: [M + H] + 425.54.N-benzhydryl-4-((5-(4-tertbutylphenyl)-1,3, 4-oxadiazol-2-yl)methyl)piperazine (4f) Yield: 47.34%; mp: 161 to 163°C; Anal Calcd for C 30 H 34 N 4 O: C,77.22, H, 7.34, N, 12.01; found C, 77.21, H, 7.33, N, 12.02; IR (ν max cm −1 ): 3388 (NH stretch), 3206, 3101 (Ar-H), 2900, 2865 (piperazine ring), 1623, 1515 (C=N, C=C), 1276, 1106 (C-O-C), 1253 (C-N); 1 H-NMR (CDCl 3 ) δ (ppm): 7.32 to 7.31 (d, 4H, Ar-H, J = 6.6 Hz), 7.28 to 7.26 (t, 4H, Ar-H, J = 6.7 Hz), 7.20 to 7.15 (m, 5H, phenyl), 7.10 to 7.09 (d, 2H, Ar-H, J = 6.6 Hz), 4.76 (s, 2H, -CH 2 ), 4.47 (s, 1H, -CH), 3.19 (br, s, 4H, -CH 2 -N-CH 2 , piperazine ring), 2.44 (br, s, 4H, -CH 2 -N-CH 2 , piperazine ring) 13 C-NMR (DMSO-d 6 ) δ (ppm) 170.56, 165.30, 153.67, 141.82, 135.75, 132.11, 130.96, 128.98, 127.03, 123.18, 116.82, 113.82, 111.56, 65.74, 63.72, 44.09, 40.90; ESI-MS m/z: [M + H] + 467.62. N-benzhydryl-4-((5-(2-nitrophenyl)-1,3, 4-oxadiazol-2-yl)methyl)piperazine (4g) Yield: 38.12%; mp: 173 to 175°C; Anal Calcd for C 26 H 25 N 5 O 3 : C,68.56, H, 5.53, N, 15.37; found C, 68.55, H, 5.54, N, 15.38; IR (ν max cm −1 ): 3309 (NH stretch), 3275, 3112 (Ar-H), 2900, 2812 (piperazine ring), 1626, 1523 (C=N, C=C), 1246, 1123 (C-O-C), 1234 (C-N) 1 H-NMR (CDCl 3 ) δ (ppm): 7.36 to 7.35 (d, 4H, Ar-H, J = 6.6 Hz), 7.26 to 7.24 (t, 4H, Ar-H, J = 6.7 Hz), 7.15 to 7.10 (m, 5H, phenyl), 7.12 to 7.11 (d, 2H, Ar-H, J = 6.6 Hz), 4.86 (s, 2H, -CH 2 ), 4.56 (s, 1H, -CH), 3.46 (br, s, 4H, -CH 2 -N-CH 2 , piperazine ring), 2.83 (br, s, 4H, -CH 2 -N-CH 2 , piperazine ring) 13 C-NMR (CDCl 3 ) δ (ppm) 172.40, 163.32, 152.87, 140.45, 134.23, 132.46, 129.32, 128.12, 123.31, 121.32, 115.21, 114.23, 112.98, 64.10, 62.39, 42.13, 41.45; ESI-MS m/z: [M + H] + 456.51.…”

A Rational Design, Synthesis, Biological Evaluation and Structure–Activity Relationship Study of Novel Inhibitors against Cyanobacterial Fructose-1,6-bisphosphate Aldolase

“…10 To find a specific inhibitor against Cy-FBA-II, a series of novel maleimide derivatives have been successfully designed and synthesized by means of a structure-based drug design strategy. Indeed, the biological activities of maleimide derivatives have been documented, such as glycogen synthase kinase-3 inhibitors, 12 monoglyceride lipase inhibitors, 13 cyclooxygenase inactivators, 14 antibiotics, 15 and topoisomerase IIα inhibitors. 16 To further understand the influence of different substituents of maleimide derivatives on the Cy-FBA-II inhibitory activity, comparative molecular field analysis (CoMFA) was also performed.…”