Synthesis and antibacterial activity evaluation of octapeptin derivatives / 药学学报

Octapeptin has strong antibacterial activity against Gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii, while it also has activity against some Gram-positive bacteria. This study used natural octapeptin A3 and B3 as lead compounds for structural modification. Twenty-one peptide derivatives (including A3 and B3) containing eight amino acid residues were prepared by solid-phase synthesis, and evaluated for antibacterial activity and renal cytotoxicity. Among them, three compounds 6, 7 and 17 exhibited broad-spectrum antibacterial activity and significantly enhanced the activity for Gram-positive bacteria while maintaining the activity of Gram-negative bacteria. Several compounds improved the activity for Pseudomonas aeruginosa. Compound 7 was active against all test strains and had relatively low renal cytotoxicity. The results provide a basis for the further development of novel polypeptide antibiotics.

Structure modification and antimicrobial activity of novel cationic melittin analogues / 药学学报

Melittin exhibits high antibacterial potency against drug-resistant bacteria. However, the clinical utility of melittin is limited by its serious hemolytic activity. Thus, the need for developing novel melittin analogues with high antimicrobial activity and low hemolytic activity has grown. We designed, synthesized, and evaluated 20 novel melittin analogues with varying hydrophobic, polar or positively charged amino acids. The results showed that 8 compounds had antimicrobial activity (MIC: 1-4 μg·mL-1) against gram-positive pathogens equal to or better than that of melittin, and 16 compounds had low hemolytic activity (HC50 ≥ 11.9 μg·mL-1). Compounds 13 (MIC: 2-4 μg·mL-1) and 15 (MIC: 1-2 μg·mL-1) showed equal or better antimicrobial activity against both susceptible and resistant strains of Staphylococcus aureus and Enterococcus faecium compared to melittin (MIC: 4 μg·mL-1). Compound 13 (HC50: 24.0 ± 4.3 μg·mL-1) displayed noticeably decreased hemolytic activity compared to melittin (HC50: 5.3 ± 0.4 μg·mL-1). This work established a base for further study on the structure-activity relationships and structure-toxicity relationships of melittin.

Design, synthesis, and biological evaluation of novel polymyxin B analogues / 药学学报

Polymyxin B and polymyxin E (colistin) are increasingly used as last-resort drugs for treatment of infections caused by multidrug-resistant gram-negative pathogens. Unfortunately, the application was limited due to the serious side effects, especially nephrotoxicity. Very recently, the need for developing more tolerated and more effective polymyxin analogues has grown. This study details the design, synthesis, and evaluation of two classes of polymyxin B analogues with varying hydrophobicity and bulkiness at the N-terminal fatty acyl chain or position 6 amino acid. 20 polymyxin B analogues were synthesized and the chemical structures of the analogues were confirmed by HR-MS and 1H NMR spectra. Compounds 7e (MIC: 0.5-4 μg·mL-1) and 7l (MIC: 0.25-2 μg·mL-1) showed similar or better antimicrobial activity against both susceptible and resistant strains of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa compared to polymyxin B (MIC: 0.5-2 μg·mL-1). Besides, compound 7l (CC50: 217.1±13.2 μg·mL-1) displayed noticeably decreased renal cytotoxicity compared to polymyxin B (CC50: 120.3±6.0 μg·mL-1). This work establishes the base of further study on the structure-activity relationship of polymyxin B.

In vitro metabolism and drug-drug interaction potential of IG-105, a novel antimicrotubule agent / 药学学报

IG-105, N-(2,6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide, a novel antimicrotubule agent, showed potent anticancer activity in a variety of human tumor cells in vitro and in vivo. In order to characterize the metabolism and the possible drug-drug interaction of IG-105, we carried out a series of experiments. Drug metabolizing enzymes involved in IG-105 metabolism were investigated by using pooled human liver microsomes (HLMs) and recombinant cytochrome P450 isoforms (rP450s) respectively. The possible metabolites were analyzed by liquid chromatography-orbitrap-mass spectrometry (LC-Orbitrap-MS). The inhibitory effect of IG-105 on main P450 enzymes was also evaluated. The results showed that IG-105 can be metabolized by a series of rP450s, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5, with the major contribution enzymes being CYP1A2, CYP2B6, CYP2C19, and CYP3A. Three metabolites (M1-M3) were identified and demethylation was the major phase I metabolic reaction for IG-105. IG-105 moderately inhibited CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A enzyme activities with IC50 values of 6.42, 23.64, 0.39, 1.4, and 3.14 μmol·L-1, respectively. Since the biotransformation of IG-105 involves multiple enzymatic pathways, the compound is less likely to be a victim of a concomitantly used medicine which inhibits activity of one of the CYPs. However, as IG-105 showed medium to strong inhibition on CYP1A2, CYP2D6, CYP3A, and CYP2C19, caution is particularly needed when IG-105 is co-administrated with other anticancer drugs which are mainly metabolized by the above enzymes.

Research progress of HCV NS5A complex inhibitors / 药学学报

Direct acting antivirals against the hepatitis C virus (HCV) have been developed and the field has been under a rapid progress in recent years. Especially, HCV inhibitors targeting nonstructural 5A (NS5A) protein are attracting much attention due to the potent antiviral activity, fast viral clearance and broad antiviral spectrum. This article is prepared to cover the main progress of HCV NS5A complex inhibitors in the market since 2010. The pharmaceutical characteristics of diverse compounds are described and summarized according to their different chemotypes.

Synthesis and biological activity of substituted xanthines as DPP-IV inhibitors / 药学学报

In order to find more potential DPP-IV inhibitor, a series of xanthine-scaffold analogs of linagliptin, an approved antidiabetes drug, were designed and synthesized for SAR study. All compounds with a concentration of 50 nmol·L-1 showed the inhibitory activity against DPP-IV enzyme in vitro, and the inhibition rate of compounds 1a, 1d and 1f was over 50%. Virtual docking was also performed to facilitate the SAR analysis of these substituted xanthines.

Synthesis and antiviral activities of geldanamycin analog TC-GM in vitro / 药学学报

In order to find antiviral compounds with novel structures, geldanamycin and lamivudine with different antiviral mechanisms were conjunctively synthesized to acquire a new compound TC-GM, and the antiviral activity of TC-GM was measured. The antiviral activity against HIV-1 was examined by p24 antigen ELISA kit. The activity against HBV was examined by dotblot. The activity against HSV and CoxB virus was examined by CPE. TC-GM exhibited broad-spectrum antiviral activities similarly like geldanamycin. TC-GM inhibited the replication of different viruses, including HIV-1, HBV, HSV 1 and 2, CoxB6. TC-GM showed more potent inhibitory activity against HIV-1 and HBV than other detected virus.

Antiviral activities of cycloheximide and its derivatives / 药学学报

Cycloheximide (CHX) inhibits protein synthesis in most eukaryotic cells and it is a well-known tool commonly used in biochemical research. In this paper, the antiviral spectrum of CHX against several DNA and RNA viruses have been evaluated. CHX showed strong inhibitory activities against several RNA viruses such as HIV-1, influenza viruses, coxsackie B virus, enterovirus (EV71) and several DNA viruses such as HSV and HCMV. Especially the strong inhibitory activities of CHX against coxsackie B virus and enterovirus caught our attention, since effective drugs available in clinic are limited. The SAR of CHX derivatives also has been discussed in the paper. The hydroxyl group at C-2' and carbonyl group at C-2" of CHX are essential for its antiviral activity. And modification to these groups results its derivatives' antiviral activities reduced or lost.

Synthesis and neuroprotective activity in cell culture of aminoadamantane analogues / 药学学报

Seven novel derivatives of aminoadamantane with 1-aminosubstituted group were synthesized from amantadine or memantine individually in order to find new neuroprotective agent. Six of them are amides of two precursors, one is a 1-amino derivative of memantine substituted with 2-hydroxy propyl. Their chemical structures were confirmed by 1H NMR and HRMS. The neuroprotective activity in vitro was evaluated primarily with 500 micromol x L(-1) glutamate damaged SY5Y cell by measurement of MTT metabolic rate and LDH leakage rate. Glutamate reduced MTT metabolic rate, but increased LDH leakage rate significantly. The addition of new derivatives elevated the MTT value with their certain concentration, reduced cell death rate. Especially as for 3d and 4c, they fully normalized LDH leakage rate with concentration of 20 micromol x L(-1) during LDH measurement. These data indicated that 3d and 4c have significant protective effect on nerve cell against glutamate injury, deserved to be further tested and maybe helpful for treatment of neurodegenerative disease.

Studies on polyphenolic chemical constitutents from root of Salvia yunnansis / 中国中药杂志

<p><b>OBJECTIVE</b>To study the chemical constituents in the root of Salvia yunnansis.</p><p><b>METHOD</b>Compounds were isolated and purified by Diaion HP20, Sephadex LH - 20, ODS chromatography. Their structures were determined by spectral analysis and chemical evidence.</p><p><b>RESULT</b>Twelve compounds were isolated and identified from the root of S. yunnansis protocatechaldehyde (1), caffeic acid (2), ferulic acid (3), rosmarinic acid (4), salvianolic acid A (5), salvianolic acid C (6), lithospermicacid (7), lithospermicacid B (8), 9'-methyl lithospermate B (9), 9"'-methyl lithospermate B (10), 9',9'''-dimethyl lithospermate B (11), 9'-ethyl lithospermate B (12).</p><p><b>CONCLUSION</b>The compounds 1, 2, 3, 5, 6, 9, 10, 11 and 12 were first isolated from S. yunnanensis.</p>