Methylation, Glucuronidation, and Sulfonation of Daphnetin in Human Hepatic Preparations In Vitro: Metabolic Profiling, Pathway Comparison, and Bioactivity Analysis

The human UDP-glucuronosyltransferase 1A6 (UGT1A6) plays important roles in elimination of many xenobiotics, including drugs. We have experimentally assessed inhibitory properties of 46 compounds toward UGT1A6 catalyzing the glucuronidation of 1-naphthol and built models for predicting compounds interactions with the enzyme. The tested compounds were divided into a training set (n = 31; evaluated by 10-fold cross-validation) and an external test set (n = 15), both of which yielded similar accuracies (80–81%) and Matthews correlation coefficients (0.61–0.63) when classified using support vector machines. Comparative molecular similarity index analysis (CoMSIA) modeling was conducted for nine methods of compound alignment. The most predictive CoMSIA model was analyzed in the light of a homology modeled UGT1A6 structure, with leave-one-out cross-validation, yielding a q2 of 0.62 and r2 of 0.91 on the training set and a r2pred of 0.82 on the test set. The CoMSIA contour plots highlighted the importance of H-b...

SVM classification and CoMSIA modeling of UGT1A6 interacting molecules.

In Vitro Evaluation of the Effect of 7‐Methyl Substitution on Glucuronidation of Daphnetin: Metabolic Stability, Isoform Selectivity, and Bioactivity Analysis

Daphnetin (7,8-dihydroxycoumarin (7,8-DHC)) and its C-4 derivatives have multiple pharmacological activities, but the poor metabolic stability of these catechols has severely restricted their application in the clinic. Methylation plays important roles in catechol elimination, although thus far the effects of structural modifications on the metabolic selectivity and the catalytic efficacy of human catechol- O -methyltransferase (COMT) remain unclear. This study was aimed at exploring the structure–methylation relationship of daphnetin and its C-4 derivatives, including 4-methyl, 4-phenyl and 4-acetic acid daphnetin. It was achieved by identifying the methylated products generated and by careful characterization of the reaction kinetics. These catechols are selectively metabolized to the corresponding 8- O -methyl conjugates, and this regioselective methylation could be elucidated by flexible docking, in which all the 8-OH groups of these catechols are much closer than the 7-OH groups to catalytic residue LYS144 and methyl donor AdoMet. The results of the kinetic analyses revealed that the Cl int values of the compounds could be strongly affected by the C-4 substitutions, which could be partially explained by the electronic effects of the C-4 substituents and the coordination modes of 7,8- dihydroxycoumarins in the active site of COMT. These findings provide helpful guidance for further structural modification of 7,8-DHCs to improve metabolic stability.

https://royalsocietypublishing.org/doi/pdf/10.1098/rsos.171271

In vitro evaluation of the effect of C-4 substitution on methylation of 7,8-dihydroxycoumarin: metabolic profile and catalytic kinetics.

The invention belongs to the field of chemical pharmaceuticals, and more specifically relates to 7-oxy, thio or imino substituted coumarin with a structure represented by formula 8 or 12, and derivatives and antineoplastic activity thereof. The results of antineoplastic activity and pharmacological target experiments show that 7-oxy, thio or imino substituted coumarin derivatives possess inhibitory activity on the growth of nasopharyngeal carcinoma cells and drug-resistant tumor strains of nasopharyngeal carcinoma cells, lung cancer cells and prostatic cancer cells; and the results of pharmacological research show that 7-oxy, thio or imino substituted coumarin is capable of promoting cell apoptosis and influencing cell division cycle G2/M. 7-oxygen, sulfur or nitrogen substituted coumarin is novel in structure, and is capable of providing basis for intensive study on target sports and related pharmacological mechanisms such as reversing drug-resistance mechanism. X is selected from oxygen, sulfur or nitrogen atoms; R2 is selected from alkyl, alkoxy, halogenated alkyl groups or ester group; and R3 is selected from alkyl, and substituted aromatic heterocyclic compounds including 6-chloropyridine and substituted aralkyl.

7-oxy, thio or imino substituted coumarin, and derivatives and applications thereof

The invention relates to an application of cephalomannine chemical derivation method in taxol preparation, comprising the following steps that: cephalomannine analogues having an alpha-beta unsaturated ketone structure are converted into a single-halogen single-hydroxyl or single-halogen single-alkyl product through addition reaction, and then taxol is obtained through column separation. The process is also suitable for the separation of 10-deacetylated cephalomannine, 10-deacetylated taxol, 10-deacetylated-7-xylose cephalomannine and 10-deacetylated-7-xylose taxol. The application has the advantage of applying an NBS addition method to the separation of taxol and cephalomannine (or analogues of the two) successfully, and using a conventional cheap silica gel column to realize the separation of taxol and cephalomannine so as to achieve the aim of purifying taxol. The method is suitable for the taxol mixtures with different purity and can be used for the separation of other cephalomannine type compounds and analogues. Due to the process of the invention, the taxol with the purity more than 99 percent can be obtained; the overall yield can be up to 80 percent; the overall yield of cephalomannine addition products is over 90 percent.

Method for separating and preparing paclitaxel

The invention relates to a coumarin compound acidulated by glucal and application thereof. The compound has a structure showed in the right formular, wherein R is one of-H, -OH, -CH3, -OCH3, -NH2 or ester group; and R1, R2, R3 and R4 are one of -H, -OH, -CH3, -SH, -OCH3, -NH2 or glucal acid group. The coumarin compound acidulated by the glucal has the activities of resisting arthritic and tumor.

Coumarin compound acidulated by glucal and application thereof

Detection and Identification of the Metabolites of Daphnetin in Rat Plasma by LC-ESI Tandem Mass Spectrometry

The present invention relates to a method which prepares a taxane xyloside compound from regeneratable taxus resources. By utilizing the regeneratable taxuses of the high-yielding taxane xyloside compound, such as the plant of Taxus Chinesis var mairei, or cell culture or microbial leavening as materials, the taxane xyloside compound is prepared by solvent extraction, liquid-liquid extraction, chromatographic separation and crystallization purification. The obtained taxane xyloside compound can be converted into a semi-synthetic material 10-deacetylbaccatin III of taxol or polyene taxol.

Mixture containing taxanes xyloside compounds and preparation method thereof

The present invention relates to a preparation method of the paclitaxel and taxane, specifically a method of the selective acylation of the hydroxyl of the taxane. In the method, the halide of metal elements or the trifluoroacetic sulfonate is used as the catalyst; the acidic anhydride is used as the acylating agent to handle the C (10)-deacylation taxane so as to get the C (10) acylated taxane. The present invention particularly relates to a method of preparing the C (10) hydroxyl acylated taxane compound through the selective acylation reaction when the C(10) and C(2') of the taxane both have the hydroxyl at the same time.

Guangbo Ge

Papers

Method for separating and preparing paclitaxel

Coumarin compound acidulated by glucal and application thereof

Detection and Identification of the Metabolites of Daphnetin in Rat Plasma by LC-ESI Tandem Mass Spectrometry

Mixture containing taxanes xyloside compounds and preparation method thereof

Method for selectively acylating taxone C(10) hydroxy