Search

HS-23, an extract of the dried flower buds of Lonicera japonica, is a new botanical drug currently being evaluated in a phase I clinical study in Korea for the treatment of sepsis. The in vitro induction and inhibition potentials of HS-23 on the drug-metabolizing enzymes using human hepatocytes and liver microsomes were assessed to evaluate herb–drug interaction according to botanical drug guideline and drug interaction guidance of FDA. HS-23 slightly inhibited CYP2A6, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 enzyme activities in human liver microsomes with IC50 values of 80.6, 160.7, 169.5, 85.4, and 76.6 μg/mL, respectively. HS-23 showed negligible inhibition of CYP1A2, CYP2C8, CYP2D6, UGT1A1, UGT1A4, UGT1A9, and UGT2B7 activities in human liver microsomes. Based on these results, HS-23 may not inhibit the metabolism of CYP2A6, CYP2B6, CYP2C9, CYP2C19, and CYP3A4-catalyzed drugs in humans. HS-23 did not affect the mRNA expression of CYP1A2, CYP2B6, and CYP3A4 after 48 h treatment at three concentrations (0.5, 5, and 50 μg/mL) in three independent human hepatocytes, indicating that HS-23 has no effect on herb–drug interactions that up- or down-regulate CYP1A2, CYP2B6, and CYP3A4. These results indicate that the administration of HS-23 in human may not cause clinically relevant inhibition and induction of these cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes and HS-23 may be promising therapeutic agent for treatment of sepsis.

Chiral phosphinoimidazolidine 3 was used as an excellent ligand in Pd-catalyzed asymmetric allylic alkylation of racemic 1,3-diphenyl-2-propenyl acetate 5 with dimethyl malonate. Outstanding enantioselectivity of up to 99% and remarkable catalytic activity were observed. The ligand was also found to be effective in the asymmetric allylic amination of 5 with benzylamine.

Optically active amino thiocyanate derivatives of (−)-norephedrine were found to act as effective aprotic ligands for enantioselective addition of diethylzinc to aldehydes. This reaction provided optically active secondary alcohols with ee up to 96%.

Protein aggregation is a major stability problem of therapeutic proteins. We investigated whether a novel stabilizing peptide [acidic tail of synuclein (ATS) peptide] could be generally used to make a more stable and soluble form of therapeutic proteins, particularly those having solubility or aggregation problems. We produced ATS fusion proteins by fusing the stabilizing peptide to three representative therapeutic proteins, and then compared the stress-induced aggregation profiles, thermostability, and solubility of them. We also compared the in vivo stability of these ATS fusion proteins by studying their pharmacokinetics in rats. The human growth hormone–ATS (hGH–ATS) and granulocyte colony-stimulating factor–ATS (G-CSF–ATS) fusion proteins were fully functional as determined by cell proliferation assay, and the ATS fusion proteins seemed to be very resistant to agitation, freeze/thaw, and heat stresses. The introduction of the ATS peptide significantly increased the storage and thermal stabilities of hGH and G-CSF. The human leptin–ATS fusion protein also seemed to be very resistant to aggregation induced by agitation, freeze/thaw, and heat stresses. Furthermore, the ATS peptide greatly increased the solubility of the fusion proteins. Finally, pharmacokinetic studies in rats revealed that the ATS fusion proteins are also more stable in vivo. Our data demonstrate that a more stable and soluble form of therapeutic proteins can be produced by fusing the ATS peptide.

School of Chemical Science & Engineering, Inha University, Inchon 402-751, KoreaReceived February 23, 2004Key Words : Enantioselective addition, Polymer-supported ligand, Amino thioacetate, DiethylzincEnantioselective addition of dialkylzinc to aldehydes inthe presence of a catalytic amount of chiral ligands is knownto be one of the most important methods for the synthesis ofoptically active secondary alcohols.

Enantioselective addition, Amino thiocyanate, Diethylzinc, AldehydeAsymmetric metal catalysis is now recognized as the mostpromising area in the synthesis of optically active organiccompounds. One attractive method that leads to theformation of optically active secondary alcohols is catalyticenantioselective addition of organozinc reagent to aldehyde.

Asymmetric carbon-carbon bond-forming reaction is one of the most valuable processes for construction of enantiomerically enriched molecules. Considerable research has been done on Pd-catalyzed asymmetric allylic alkylation. In particular, the search of new chiral ligands is an important chapter in the area and remains an area of intense research. We have previously found that phosphinooxazolidines 1 bearing sp nitrogen donor are useful ligands in the asymmetric allylic alkylation. The oxazolidines obtainable by simple synthetic route seem to be potential ligands for the asymmetric catalysis. As part of our continuing interest in oxazolidines, we herein disclose the preparation of new chiral pyridinyloxazolidines and their application in asymmetric allylic alkylation. The oxazolidines 2-4 were obtained through condensation of commercially available 2-pyridinecarboxaldehyde and optically pure (S)-N-methylalaninol, (S)-N-methylvalinol and (1R,2S)-ephedrine in good yields of 80%, 84%, and 90% respectively. The reaction leads to the formation of new