Author: Qu, Ying ; Cao, Hao ; Wang, Shenglin ; Li, Dahong ; Ma, Yongzhi ; Feng, Dongyan ; Hua, Huiming ; Zheng, Chao ; Wang, Weirenbo ; Wang, Siyu ; Li, Haonan ; Yang, Hangao ; Liang, Chaowei ; Cheng, Maosheng

SIRT6 promotes the progression of breast cancer by inducing drug resistance by reinforcing DNA damage repair mechanisms. This study utilized a combination of high-throughput virtual screening and FLUOR DE LYS assays. Hit 14 which features a novel β-carboline skeleton as a potent SIRT6 inhibitor was found. Subsequent structure-guided optimization led to the synthesis of 60 3,6,9-position modified derivatives based on the differences analysis of SIRTs family proteins. Of which, 10d inhibited the deacetylase activity of SIRT6, with an IC₅₀ of 5.81 μM and more than 27 times subtype selectivity. Phe64, Met157, and Ser56 were identified as the key residues. Moreover, 10d suppressed breast cancer cell proliferation, migration, invasion, and induced apoptosis in MCF-7 cells by disrupting the DNA damage repair pathway. Additionally, 10d demonstrated a safe and effective antibreast cancer effect in vivo, presenting a promising strategy for the treatment of breast cancer by targeting SIRT6.

01 Dec 2024·Behavioural Pharmacology

Norharmane potentiated anxiolytic- and antidepressant-like responses induced by imipramine and citalopram: an isobologram analysis

Article

Author: Khakpai, Fatemeh

β-carboline compounds display a therapeutic property for treating depression and anxiety behaviors. Imipramine and citalopram play an important role in the modulation of anxiety and depression behaviors. We investigated the effects of norharmane, imipramine, and citalopram on anxiety- and depression-like effects and their interactions. Elevated plus maze and forced swimming test were used for the assessment of anxiety- and depression-like behaviors in male mice. The results revealed that intraperitoneal (i.p.) administration of norharmane (10 mg/kg) increased percentage of open arm time (%OAT) in the elevated plus maze test and decreased immobility time in the forced swimming test, proposing anxiolytic- and antidepressant-like effects. Injection of imipramine (5 mg/kg; i.p.) enhanced %OAT and decreased immobility time, suggesting anxiolytic- and antidepressant-like effects. Moreover, norharmane potentiated the anxiolytic- and antidepressant-like responses induced by imipramine by increasing %OAT and decreasing immobility time. The results revealed additive anxiolytic- and antidepressant-like effects between norharmane and imipramine in mice. Alone, the administration of citalopram (5 mg/kg; i.p.) enhanced %OAT and reduced immobility time, causing anxiolytic- and antidepressant-like effects. When citalopram and norharmane were coinjected, norharmane augmented the anxiolytic- and antidepressant-like effects induced by citalopram by increasing %OAT and reducing immobility time. These results indicated additive anxiolytic- and antidepressant-like effects between norharmane and antidepressant drugs such as imipramine and citalopram on the modulation of anxiety and depression processes in mice.

01 Dec 2024·Pharmacological Reports

Correction: β-Carboline derivatives are potent against acute myeloid leukemia in vitro and in vivo

Author: Bueno, Maura Lima Pereira ; Sarragiotto, Maria Helena ; Roversi, Fernanda Marconi ; Saad, Sara T Olalla ; Foglio, Mary Ann ; de Oliveira, Aline Rufino ; Baréa, Paula ; Saad, Sara T. Olalla

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	Malaysia	Universiti Sains Malaysia	-

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