Nitric oxide inhibitory activity and antioxidant evaluations of 2-benzoyl-6-benzylidenecyclohexanone analogs, a novel series of curcuminoid and diarylpentanoid derivatives

Leong, Sze Wei; Faudzi, Siti Munirah Mohd; Abas, Faridah; Aluwi, Mohd Fadhlizil Fasihi Mohd; Rullah, Kamal; Lam, Kok Wai; Bahari, Mohd Nazri Abdul; Ahmad, Sadeem; Tham, Chau Ling; Shaari, Khozirah; Lajis, Nordin H.

doi:10.1016/j.bmcl.2015.05.056

Cited by 34 publications

(22 citation statements)

References 40 publications

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“…In another study, compound 40 belonging to 2-benzoyl-6-benzylidenecyclohexanone curcumin analogs series was evaluated for NO inhibition in LPS/IFN-induced RAW 264.7 macrophages model and was found to exhibit the highest activity with an IC 50 value of 4.2 ± 0.2 μM (Leong et al, 2015 ). Analogously, in a model of IFN-γ/LPS-activated RAW 264.7 cells, similar results have been seen when a series of 1, 5-diphenylpenta-2, 4-dien-1-one analogs was evaluated for anti-inflammatory activity by measuring their NO inhibition activity (Faudzi et al, 2015 ).…”

Section: Immunosuppression Of Natural αβ-Unsaturated Carbonyl-based mentioning

confidence: 99%

Immunosuppressive Effects of Natural α,β-Unsaturated Carbonyl-Based Compounds, and Their Analogs and Derivatives, on Immune Cells: A Review

et al. 2017

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The immune system is complex and pervasive as it functions to prevent or limit infections in the human body. In a healthy organism, the immune system and the redox balance of immune cells maintain homeostasis within the body. The failure to maintain the balance may lead to impaired immune response and either over activity or abnormally low activity of the immune cells resulting in autoimmune or immune deficiency diseases. Compounds containing α,β-unsaturated carbonyl-based moieties are often reactive. The reactivity of these groups is responsible for their diverse pharmacological activities, and the most important and widely studied include the natural compounds curcumin, chalcone, and zerumbone. Numerous studies have revealed the mainly immunosuppressive and anti-inflammatory activities of the aforesaid compounds. This review highlights the specific immunosuppressive effects of these natural α,β-unsaturated carbonyl-based compounds, and their analogs and derivatives on different types of immune cells of the innate (granulocytes, monocytes, macrophages, and dendritic cells) and adaptive (T cells, B cells, and natural killer cells) immune systems. The inhibitory effects of these compounds have been comprehensively studied on neutrophils, monocytes and macrophages but their effects on T cells, B cells, natural killer cells, and dendritic cells have not been well investigated. It is of paramount importance to continue generating experimental data on the mechanisms of action of α,β-unsaturated carbonyl-based compounds on immune cells to provide useful information for ensuing research to discover new immunomodulating agents.

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Section: Immunosuppression Of Natural αβ-Unsaturated Carbonyl-based mentioning

confidence: 99%

Immunosuppressive Effects of Natural α,β-Unsaturated Carbonyl-Based Compounds, and Their Analogs and Derivatives, on Immune Cells: A Review

et al. 2017

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“…The synthesis of diarylpentanoid analogues (AS1–32) has been described previously by Leong et al 22 In general, analogues were prepared by a series of chemical reactions involving benzoylation of cyclohexanone and aldol condensation of aromatic aldehydes. Briefly, cyclohexanone (20 mmol; 1.86 mL) was first reacted with pyrrolidine (20 mmol; 1.23 mL) in toluene (30 mL) to afford N -(1-cyclohexenyl)pyrrolidine, the essential enamine intermediate for benzoylation.…”

Section: Methodsmentioning

confidence: 99%

“…The greater biological activity of meta-substituted diarylpentanoid analogues in the present study was in concordance with the reported higher anti-inflammatory and anticancer properties of similarly meta-substituted curcuminoids. 22,26 Interestingly, dual additions and permutations of heteroatoms and hydroxyl and methoxy groups at the meta-(C3 or C5) and para-(C4) positions (AS10, AS15, AS17, AS18, AS19, and AS20) showed increased activity (IC 50 16-62 µM) in both isogenic pairs compared with their singly substituted counterpart (AS3 and AS4, AS6 and AS7, AS8 and AS9). In particular, we observed an increase in cell viability inhibition with the addition of two hydroxyl groups (HCT116 isogenic pairs: 19.4 ± 2.35 µM; AS10) compared with the addition of methoxy groups (29.1 ± 4.33 µM; AS15).…”

Section: Sar Analysis Of 2-benzoyl-6-(23-benzylidene)-cyclohexenol Smentioning

confidence: 99%

Novel 2-Benzoyl-6-(2,3-Dimethoxybenzylidene)-Cyclohexenol Confers Selectivity toward Human MLH1 Defective Cancer Cells through Synthetic Lethality

Song

Leong

et al. 2019

SLAS Discovery

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DNA mismatch repair (MMR) deficiency has been associated with a higher risk of developing colorectal, endometrial, and ovarian cancer, and confers resistance in conventional chemotherapy. In addition to the lack of treatment options that work efficaciously on these MMR-deficient cancer patients, there is a great need to discover new drug leads for this purpose. In this study, we screened through a library of commercial and semisynthetic natural compounds to identify potential synthetic lethal drugs that may selectively target MLH1 mutants using MLH1 isogenic colorectal cancer cell lines and various cancer cell lines with known MLH1 status. We identified a novel diarylpentanoid analogue, 2-benzoyl-6-(2,3-dimethoxybenzylidene)-cyclohexenol, coded as AS13, that demonstrated selective toxicity toward MLH1-deficient cancer cells. Subsequent analysis suggested AS13 induced elevated levels of oxidative stress, resulting in DNA damage where only the proficient MLH1 cells were able to be repaired and hence escaping cellular death. While AS13 is modest in potency and selectivity, this discovery has the potential to lead to further drug development that may offer better treatment options for cancer patients with MLH1 deficiency.

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“…Cyclic monocarbonyl diarylpentanoids are one of the bioactive families that are derived from curcumin by eliminating the reactive β-diketone moiety. Apart from showing improved chemical and metabolic stability, these diketone-free curcuminoids were also found to exhibit better medicinal potential than that of curcumin, particularly as anti-cancer agents [ 21 , 22 ]. Many studies reported that cyclic monocarbonyl diarylpentanoids possess potent anti-cancer properties based on their superior inhibitory activity against the growth of various cancer cell lines including breast, lung, colon and prostate cancer cells [ 13 , 23 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells

et al. 2020

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In the present study, we investigated the in-vitro anti-cancer potential of six diarylpentanoids against a panel of BRAF- and KRAS-mutated colorectal cancer cell lines including T84, SW620, LoVo, HT29, NCI-H508, RKO, and LS411N cells. Structure–activity relationship study suggested that the insertions of tetrahydro-4H-thiopyran-4-one and brominated phenyl moieties are essential for better cytotoxicity. Among the evaluated analogs, 2e has been identified as the lead compound due to its low IC50 values of approximately 1 µM across all cancer cell lines and high chemotherapeutic index of 7.1. Anti-proliferative studies on LoVo cells showed that 2e could inhibit cell proliferation and colony formations by inducing G2/M cell cycle arrest. Subsequent cell apoptosis assay confirmed that 2e is a Bcl-2 inhibitor that could induce intrinsic cell apoptosis by creating a cellular redox imbalance through its direct inhibition on the Bcl-2 protein. Further molecular docking studies revealed that the bromophenyl moieties of 2e could interact with the Bcl-2 surface pocket through hydrophobic interaction, while the tetrahydro-4H-thiopyran-4-one fragment could form additional Pi-sulfur and Pi-alkyl interactions in the same binding site. In all, the present results suggest that 2e could be a potent lead that deserves further modification and investigation in the development of a new Bcl-2 inhibitor.

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Nitric oxide inhibitory activity and antioxidant evaluations of 2-benzoyl-6-benzylidenecyclohexanone analogs, a novel series of curcuminoid and diarylpentanoid derivatives

Cited by 34 publications

References 40 publications

Immunosuppressive Effects of Natural α,β-Unsaturated Carbonyl-Based Compounds, and Their Analogs and Derivatives, on Immune Cells: A Review

Immunosuppressive Effects of Natural α,β-Unsaturated Carbonyl-Based Compounds, and Their Analogs and Derivatives, on Immune Cells: A Review

Novel 2-Benzoyl-6-(2,3-Dimethoxybenzylidene)-Cyclohexenol Confers Selectivity toward Human MLH1 Defective Cancer Cells through Synthetic Lethality

In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells

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