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  • Goel et al reported study of diacetoxy methylcoumarin DAMC

    2020-11-12

    Goel et al. reported study of 7,8-diacetoxy-4-methylcoumarin (DAMC) 63 and its thiocoumarin derivative 7,8-diacetoxy-4-methylthiocoumarin (DAMTC) for their effect on human non-small cell lung cancer A549 cells. The study suggested that the 7,8-diacetoxy-4-methylcoumarin (DAMC) 63 downregulates Bcl-xl, Cox-2 and mitogen activated protein kinase pathway and upregulatesof p53, Akt, and NF-κB pathway in the underlying molecular mechanism of apoptosis induction by DAMC and DAMTC in A549 MRS 1220 [101]. Further Goel et al. investigated apoptosis caused by 7,8-dihydroxy-4-methylcoumarin 64 (DHMC) caused in A549 human non-small cell lung carcinoma cells (NSCLC) Although an increase in the levels of reactive oxygen species (ROS) was observed, pre-treatment with antioxidant showed no protective effect against DHMC-induced apoptosis. Additionally, immunoblot data revealed that DHMC treatment led to down-regulation of Bcl-xl, Bax, p21, COX-2, p53 and upregulation of c-Myc. Indicating for the first time suggest that DHMC induces apoptosis in human lung A549 cells through partial inhibition of ERK/MAPK signaling [102] (see Fig. 10). Kontogiorgis et al. synthesis and in vivo/in vitro anti-inflammatory /antioxidant activities of several new coumarin derivative with a 7-azomethine linkage. (E)-4-methyl-2-oxo-2H-chromene-7-carbaldehyde oxime 65 was found to potently inhibit cyclooxygenase-1 (COX-1) 78.9% at 1mM and the yeast-induced rat paw edema 44.3% at 1mM. (E)-4-methyl-2-oxo-2H-chromene-7-carbaldehyde oxime 65 was found to significantly protect the rats from adjuvant-induced [103]. The authors further reported several coumarin Mannich bases, the compounds however showed better activity against LOX rather than COX-1 [104]. Grover et al. have synthesized a series of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones 66 and evaluated for in vitro COX inhibitory potential. Within this series, seven compounds were identified as potential and selective COX-2 inhibitors (COX-2 IC50′s in 1.79–4.35μM range; COX-2 selectivity index (SI)=6.8–16.7 range). Coumarin analogue (R2=OMe, R1=H) emerged as most potent (COX-2 IC50=1.79μM; COX-1 IC50>30μM) and selective COX-2 inhibitor (SI>16.7). Further, Coumarin analogue (R2=OMe, R1=H) displayed superior anti-inflammatory activity (59.86% inhibition of edema at 5h) in comparison to celecoxib (51.44% inhibition of edema at 5h) in carrageenan-induced rat paw edema assay. Structure-activity relationship studies suggested that N-phenyl ring substituted with p-CF3 substituent lead to more selective inhibition of COX-2, Further molecular docking study revealed that coumarin analogue (R2=OMe, R1=H) showed stronger binding interaction with COX-2 as compared to COX-1 [105] (Fig. 11). Song et al. studied 7-hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-coumarin (IMM-H004) 67, a novel compound the anti-inflammatory effects of IMM-H004 were investigated in lipopolysaccharide (LPS)-treated BV2 microglia. It was observed that treatment with IMM-H004 significantly inhibited BV2 microglia activation, protected PC12 cells and primary neurons against indirect toxicity mediated by exposure to conditioned medium (CM) from LPS-treated BV2 cells. Additionally, IMM-H004 significantly suppressed the release of TNF-α, IL-1β and NO, and suppressed the expression of pro-inflammatory mediators and cytokines such as iNOS, COX- 2, and IL-6 in LPS-stimulated BV2 microglia [106] (see Fig. 12). Togna et al. reported anti-inflammatory properties of two 4-methylcoumarin derivatives, 7,8-dihydroxy-3-ethoxycarbonylmethyl-4-methylcoumarin (DHEMC) 68 and 7,8-diacetoxy-3-ethoxycarbonylmethyl-4-methylcoumarin (DAEMC) 69LPS-induced production of nitric oxide and other pro-inflammatory mediators, thromboxane (TX) B2 and prostaglandin (PGE2), as well as tumor necrosis factor (TNF)-α were inhibited in the presence of 100μM DHEMC and DAEMC. DAEMC was able to significantly inhibit NO, TXB2 and TNF-α production also at 50μM. Both compounds at 100μM significantly lowered cyclooxygenase-2 (COX-2) protein expression in LPS-stimulated microglial cells measured by Western blot, but only DAEMC showed an inhibitory effect on inducible nitric oxide synthase (iNOS) protein expression at 100μM [107].