Chemistry of ecteinascidins. Part 3: preparation of 2'-N-acyl derivatives of ecteinascidin 770 and evaluation of cytotoxicity.

A three-step transformation of ecteinascidin 770 (1b) into 2'-N-indole-3-carbonyl derivative 3 via 18,6'-O-bisallyl-protected derivative 4a, which was shown to have higher cytotoxicity than 1b, is presented. In addition, a number of 2'-N amide derivatives of 1b have been prepared from 4a and their in vitro cytotoxicity were determined by measuring IC₅₀ values against human cell lines HCT116, QG56, and DU145. Benzoyl amide derivatives 7a-c showed similar in vitro cytotoxicity to 1b, whereas the nitrogen-containing heterocyclic derivatives 7d-h and cinnamoyl derivatives 9a-b showed higher cytotoxicity than 1b.

In vitro inhibitory effects of asiaticoside and madecassoside on human cytochrome P450.

The inhibitory effects and types of inhibition of asiaticoside and madecassoside on human CYPs were studied in vitro using recombinant human CYPs. The median inhibitory concentrations (IC50) of asiaticoside and madecassoside were determined for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Asiaticoside inhibited CYP2C19 (IC50 = 412.

A validated stability-indicating HPLC method for analysis of glabridin prodrugs in hydrolysis studies.

A simple, selective and precise stabilityindicating HPLC method for determination of glabridin diacetate and dihexanoate prodrugs was developed, validated and applied to the enzymatic and chemical hydrolysis studies. The chromatographic separation was achieved on a reverse phase C18 (Thermo Hypersil-Keystone, 250 × 4.6 mm, 5 micron) column using the mixture of acetonitrile and water as mobile phase.

Synthesis of glabridin derivatives as tyrosinase inhibitors.

A novel 3'',4''-dihydroglabridin was successfully prepared for studying on tyrosinase inhibitory activity. The result demonstrated that 3'',4''-dihydroglabridin exhibited higher activity than glabridin (IC(50) value = 11.40 microM), which is probably due to the 4-substituted resorcinol skeleton and the lacking of double bond between carbon atom 3'' and 4'' on its structure giving more conformational flexibily to interact with the enzyme more effectively.

Acute effects of N-(2-propylpentanoyl)urea on hippocampal amino acid neurotransmitters in pilocarpine-induced seizure in rats.

The present study aimed to investigate the anticonvulsant activity as well as the effects on the level of hippocampal amino acid neurotransmitters (glutamate, aspartate, glycine and GABA) of N-(2-propylpentanoyl)urea (VPU) in comparison to its parent compound, valproic acid (VPA). VPU was more potent than VPA, exhibiting the median effective dose (ED(50)) of 49 mg/kg in protecting rats against pilocarpine-induced seizure whereas the corresponding value for VPA was 322 mg/kg. In vivo microdialysis demonstrated that an intraperitoneal administration of pilocarpine induced a pronounced increment of hippocampal glutamate and aspartate whereas no significant change was observed on the level of glycine and GABA.