6003-11-8Relevant articles and documents
Characterization of TnmH as an O-Methyltransferase Revealing Insights into Tiancimycin Biosynthesis and Enabling a Biocatalytic Strategy to Prepare Antibody-Tiancimycin Conjugates
Adhikari, Ajeeth,Teijaro, Christiana N.,Yan, Xiaohui,Chang, Chin-Yuan,Gui, Chun,Liu, Yu-Chen,Crnovcic, Ivana,Yang, Dong,Annaval, Thibault,Rader, Christoph,Shen, Ben
, p. 8432 - 8441 (2020)
The enediynes are among the most cytotoxic molecules known, and their use as anticancer drugs has been successfully demonstrated by targeted delivery. Clinical advancement of the anthraquinone-fused enediynes has been hindered by their low titers and lack of functional groups to enable the preparation of antibody-drug conjugates (ADCs). Here we report biochemical and structural characterization of TnmH from the tiancimycin (TNM) biosynthetic pathway, revealing that (i) TnmH catalyzes regiospecific methylation at the C-7 hydroxyl group, (ii) TnmH exhibits broad substrate promiscuity toward hydroxyanthraquinones and S-alkylated SAM analogues and catalyzes efficient installation of reactive alkyl handles, (iii) the X-ray crystal structure of TnmH provides the molecular basis to account for its broad substrate promiscuity, and (iv) TnmH as a biocatalyst enables the development of novel conjugation strategies to prepare antibody-TNM conjugates. These findings should greatly facilitate the construction and evaluation of antibody-TNM conjugates as next-generation ADCs for targeted chemotherapy.
Laser flash photolysis study of the reaction mechanism in the photochromism of 1-(acyloxy)-2-methoxyanthraquinones
Gritsan,Kellmann,Tfibel,Klimenko
, p. 794 - 801 (1997)
Nanosecond laser flash photolysis has been used to study the primary processes in the photochromic reaction of five O-acylic derivatives of 1-hydroxy-2-methoxyanthraquinone with methyl (I), tolyl (II), phenyl (III), ethoxyl (IV), and diethylamino (V) groups in the migrating acyl. The triplet-triplet absorption spectra of the reactive triplet states of quinones IV and V were detected, and the rate constants of the primary photochemical step were measured. The temperature dependence of the rate constants of acyl migration in the triplet states of quinones IV and V was studied, and the Arrhenius parameters were determined. The rate constants of thermal acyl migration and their Arrhenius parameters were measured for compounds I-V. It was found that migrant nature significantly influences the activation energy of both thermal and photochemical reactions of acyl migration. The activation energy of thermal migration increases from 37.9 ± 0.2 kJ/mol for compound I up to 66.5 ± 0.7 kJ/mol for compound V. The photochemical process is characterized by considerably lower values of the activation energy (15.9 ± 0.8 and 26.0 ± 1.7 kJ/mol for compounds IV and V, respectively). It was confirmed in the present work that photochemical migration of acyl groups is an adiabatic process occurring on the triplet potential energy surface.
Inhibition of nitric oxide production in LPS-stimulated RAW264.7 macrophages and 15-LOX activity by anthraquinones from Pentas schimperi
Dzoyem, Jean Paul,Donfack, Arno R. N.,Tane, Pierre,McGaw, Lyndy J.,Eloff, Jacobus N.
, p. 1246 - 1251 (2016)
The anti-inflammatory activity of a coumarin and nine anthraquinone derivatives, 3-hydroxy-1-methoxy-2-methylanthraquinone (1), 2-hydroxymethyl anthraquinone (2), schimperiquinone B (3), cleomiscosin A (4), damnacanthal (5), 1,2-dihydroxy anthraquinone (6), damnacanthol (7), 3-hydroxy-2-hydroxymethyl anthraquinone (8), 1-hydroxy-2-methoxyanthraquinone (9), and 2-hydroxymethyl- 3-O-prenylanthraquinone (10), isolated from the roots of Pentas schimperi were determined. The anti-15-lipoxygenase activity and nitric oxide production inhibition on lipopolysaccharide-activated macrophages RAW 264.7 cells were determined as indicators of anti-inflammatory activity. The Griess assay was used to measure nitric oxide production and the ferrous oxidation-xylenol orange assay was used to determine the 15-lipoxygenase inhibitory activity. All the compounds significantly decreased nitrite + nitrate accumulation in lipopolysaccharide-stimulated RAW264.7 cells in a concentration-dependent manner with 85.67% to 119.75% inhibition of nitrite + nitrate production at 20 μg/mL. Most of the compounds had a moderate inhibitory effect on 15-lipoxygenase activity. Compounds 8 and 10 were the most potent inhibitor both in nitrite + nitrate production with respective IC50 values of 1.56μM and 6.80 μM. Compounds 2, 7, and 8 had good anti-15-lipoxygenase activity with respective IC50 values of 13.80 μM, 14.80 μM, and 15.80 μM compared to quercetin, which was used as a standard lipoxygenase inhibitor (IC50 of 16.80 μM). Our study revealed 3-hydroxy-2-hydroxymethyl anthraquinone and damnacanthol as potent inhibitors of both 15-lipoxygenase activity and nitric oxide production. Further studies are needed in order to envisage its possible future use as a therapeutic alternative against inflammatory diseases.
Palladium-Catalyzed Direct Acylation: One-Pot Relay Synthesis of Anthraquinones
Suchand, Basuli,Satyanarayana, Gedu
, p. 769 - 779 (2019/01/23)
A bis-acylation strategy to access functionalized anthraquinones via one-pot relay process, is presented. The first acylation was feasible under [Pd]-catalyzed intermolecular direct acylation reaction, while, the second acylation was accomplished by using intramolecular Friedel-Crafts acylation. Notably, benchtop aldehydes have been utilized as non-toxic acylation agents in the key [Pd]-catalyzed acylation.
