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Biotechnological Production of Prenylated Xanthones for Pharmaceutical Use
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Mariam Gaid, Poonam Singh, Islam El-Awaad, Mohamed Nagia, Ludger Beerhues
Studies unraveled that synthetic chiral derivatives of xanthones (CDXs, Table 4.4) possess interesting biological activities. Fernandes et al. (2012) synthesized and assessed the biological activities of (S)-N-(1-hydroxy-3-methylbutan-2-yl)-6-methoxy-9-oxo-9H-xanthene-2-carboxamide (CDX1), (S)-N-(1-hydroxy-4-methylpentan-2-yl)-6-methoxy-9-oxo-9H-xanthene-2-carboxamide (CDX2) and (S)-6-methoxy-9-oxo-N-(1-(p-tolyl)ethyl)-9H-xanthene-2-carboxamide (CDX3) as nerve conduction blockers. They reported that the CDXs blocked the conduction in isolated rat sciatic nerves through their action on Na+ ionic currents when used in the low concentration range (0.1–3.0 μM) and mimicked the effect ofdibucaine, a prototypical local anesthetic. Another CDX, N-((1R,2S)-2-hydroxy-1,2-diphenylethyl)-6-methoxy-9-oxo-9H-xanthene-2-carboxamide (CDX4), possessed anti-tumor activity against human tumor cell lines with GI50 of 32.15 ± 2.03 μM, 22.55 ± 1.99 μM and 14.05 ± 1.82 μM for A375-C5 (melanoma), MCF-7 (breast adenocarcinoma), and NCI-H460 (non-small cell lung cancer), respectively. CDXs with aryl substitution in chiral moiety displayed significant anti-tumor potency. The number of aryl substitutions affected the anti-tumor potency. CDXs with two aryl substitutions in chiral moiety (CDX4, Table 4.4) exhibited better activity than the ones with one aryl group (CDX3 and CDX5, GI50 > 42.62 μM). In addition, the size of the alkyl group in the CDX chiral moiety modulated the anti-tumor activity. The growth inhibition effect decreased with the decrease in the size of the alkyl group. The growth inhibitory effects in some cases were dependent on the stereochemistry of the CDXs. For example, the enantiomers (R)-6-methoxy-9-oxo-N-(1-(p-tolyl)ethyl)-9H-xanthene-2-carboxamide (CDX5) and (S)-6-methoxy-9-oxo-N-(1-(p-tolyl)ethyl)-9H-xanthene-2-carboxamide (CDX3) demonstrated high stereoselectivity for MCF-7 and NCI-H460 cell lines. While the R enantiomer exhibited little inhibitory activity (GI50 = 85.88 ± 5.30 μM), the S enantiomer inhibited the NCI-H460 cell line with a GI50 = 42.62 ± 1.77 μM. In the MCF-7 cell line, the R enantiomer was inactive (GI50 > 150 μM), while the S enantiomer presented a weak activity (GI50 = 91.91 ± 6.27 μM). Both enantiomers were unable to inhibit the growth of the cell line A375-C5, indicating the occurrence of cell-type selectivity (Fernandes et al., 2014). In addition, Fernandes et al. (2017) reported CDXs that exert anti-inflammatory activity by inhibiting cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), however, 20 times less than the positive control indomethacin.
Splenic tyrosine kinase (SYK) inhibitors and their possible use in acute myeloid leukemia
Published in Expert Opinion on Investigational Drugs, 2018
Sushma Bartaula-Brevik, Marte Karen Lindstad Brattås, Tor Henrik Anderson Tvedt, Håkon Reikvam, Øystein Bruserud
Previous studies of murine AML suggest that Hoxa9/Hoxa10 (see discussion earlier) are involved in leukemogenesis through their effects on the expression of αvβ3 integrins and SYK expression/activation [48] (see also Section 5.3). Furthermore, studies of human AML suggest that Hox genes are important in leukemogenesis and high Hox expression seems to identify a distinct patient subset [49,50]. Similar to the murine AML models [48], Hox expression seems to be associated with high expression of FGF2, αvβ3 integrins, and Cdx4, and such patients are also characterized by a higher proliferative GM-CSF response and a stronger antiproliferative effect of FGF2 and SYK inhibition [48]. Thus, the Hox/FGF2/β-catenin/Cdx4 together with the Hox/αvβ3/SYK cooperation first identified in murine AML models seem important also in human leukemogenesis at least for a subset of patients, especially patients with intermediate cytogenetics [49].