A chemical investigation of secondary metabolites (SMs) from Aspergillus nidulans resulted in the identification of five novel dioxopiperazine (DKP)-diphenyl ether hybrids, designated as diphenylemestrins A-E (1-5). These compounds 1-5 represent the first known dimers combining DKP and diphenyl ether structures, with compound 4 featuring an uncommon dibenzofuran as the diphenyl ether component. The structural elucidation and determination of absolute stereochemistry were accomplished through spectroscopic analysis and electronic circular dichroism (ECD) calculations. Notably, diphenylemestrin C (3) exhibited moderate cytostatic activity against NB4 cells, with a half maximal inhibitory concentration (IC₅₀) value of 21.99 μmol·L^-1, and induced apoptosis at higher concentrations.
Aspergillus nidulans/metabolism* ; Diketopiperazines/pharmacology* ; Molecular Structure ; Phenyl Ethers/pharmacology* ; Humans ; Apoptosis/drug effects* ; Cell Line, Tumor

One new sorbicillin derivative, 2-deoxy-sohirnone C (1), one new diketopiperazine alkaloid, 5S-hydroxynorvaline-S-Ile (2), and two naturally occurring diketopiperazines, 3S-hydroxylcyclo(S-Pro-S-Phe) (3) and cyclo(S-Phe-S-Gln) (4), together with three known compounds were isolated from the Chinese mangrove endophytic fungus Penicillium sp. GD6. Their structures were determined on the basis of extensive spectroscopic analyses and by comparison with literature data. The absolute configuration of 3-hydroxyl moiety in 3 was determined by Mosher's method, while the absolute stereochemistry of 2 and 4 was established by comparison with the CD spectra of natural and synthesized diketopiperazines. Compound 1 showed moderate antibacterial activity against Methicillin-resistant Staphylococcus aureus with a MIC value of 80 μg·mL.
Alkaloids ; chemistry ; isolation & purification ; Anti-Bacterial Agents ; chemistry ; isolation & purification ; pharmacology ; China ; Circular Dichroism ; Diketopiperazines ; chemistry ; isolation & purification ; Methicillin-Resistant Staphylococcus aureus ; drug effects ; Microbial Sensitivity Tests ; Molecular Structure ; Nuclear Magnetic Resonance, Biomolecular ; Penicillium ; chemistry ; Resorcinols ; chemistry ; isolation & purification ; pharmacology ; Rhizophoraceae ; microbiology ; Wetlands

OBJECTIVETo evaluate whether ursolic acid can inhibit breast cancer resistance protein (BCRP)-mediated transport of rosuvastatin in vivo and in vitro.

METHODSFirstly, we explored the pharmacokinetics of 5-fluorouracil (5-FU, a substrate of BCRP) in rats in the presence or absence of ursolic acid. Secondly, we studied the pharmacokinetics of rosuvastatin in rats in the presence or absence of ursolic acid or Ko143 (inhibitor of BCRP). Finially, the concentration-dependent transport of rosuvastatin and the inhibitory effects of ursolic acid and Ko143 were examined in Madin-Darby Canine Kidney (MDCK) 2-BCRP421CC (wild type) cells and MDCK2-BCRP421AA (mutant type) cells.

RESULTSAs a result, significant changes in pharmacokinetics parameters of 5-FU were observed in rats following pretreatment with ursolic acid. Both ursolic acid and Ko143 could significantly affect the pharmacokinetics of rosuvastatin. The rosuvastatin transport in the BCRP overexpressing system was increased in a concentration-dependent manner. However, there was no statistical difference in BCRP-mediated transport of rosuvastatin betweent the wild type cells and mutant cells. The same as Ko143, ursolic acid inhibited BCRP-mediated transport of rosuvastatin in vitro.

CONCLUSIONUrsolic acid appears to be a potent modulator of BCRP that affects the pharmacokinetic of rosuvastatin in vivo and inhibits the transport of rosuvastatin in vitro.

ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; physiology ; Adenosine ; analogs & derivatives ; pharmacology ; Animals ; Biological Transport ; drug effects ; Diketopiperazines ; Heterocyclic Compounds, 4 or More Rings ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Rosuvastatin Calcium ; pharmacokinetics ; Triterpenes ; pharmacology

S1-M1-80 cells, derived from human colon carcinoma S1 cells, are mitoxantrone-selected ABCG2-overexpressing cells and are widely used in in vitro studies of multidrug resistance(MDR). In this study, S1-M1-80 cell xenografts were established to investigate whether the MDR phenotype and cell biological properties were maintained in vivo. Our results showed that the proliferation, cell cycle, and ABCG2 expression level in S1-M1-80 cells were similar to those in cells isolated from S1-M1-80 cell xenografts (named xS1-M1-80 cells). Consistently, xS1-M1-80 cells exhibited high levels of resistance to ABCG2 substrates such as mitoxantrone and topotecan, but remained sensitive to the non-ABCG2 substrate cisplatin. Furthermore, the specific ABCG2 inhibitor Ko143 potently sensitized xS1-M1-80 cells to mitoxantrone and topotecan. These results suggest that S1-M1-80 cell xenografts in nude mice retain their original cytological characteristics at 9 weeks. Thus, this model could serve as a good system for further investigation of ABCG2-mediated MDR.
ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; antagonists & inhibitors ; metabolism ; Adenosine ; analogs & derivatives ; pharmacology ; Animals ; Antineoplastic Agents ; pharmacology ; Cell Cycle ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; drug effects ; Cisplatin ; pharmacology ; Colonic Neoplasms ; metabolism ; pathology ; Diketopiperazines ; Doxorubicin ; metabolism ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Female ; Heterocyclic Compounds, 4 or More Rings ; Humans ; Inhibitory Concentration 50 ; KB Cells ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitoxantrone ; pharmacology ; Neoplasm Proteins ; antagonists & inhibitors ; metabolism ; Neoplasm Transplantation ; Rhodamine 123 ; metabolism ; Topotecan ; pharmacology

Aspergillus fumigatus, a type of endophytic fungi from Erthrophleum fordii, was fermented with GPY culture medium. Fermented liquid and mycelium were extracted from fermented products after freezing and thawing treatment. After alcohol extraction, mycelium was extracted with ethyl acetate and n-butyl alcohol, respectively. According to the results of cytotoxity of tumor cells, ethyl acetate extracts were studied for their chemical constituents. Five diketopiperazine compounds were separated and purified with silica gel, MCI and Sephadex LH-20 column chromatography, reversed-phase chromatographic column and preparative HPLC, their structures were identified as cyclo- (R-Pro-R-Phe) (1), cyclo- (trans-4-OH-D-Pro-D-Phe) (2), cyclo- (R-Tyr-S-Ile) (3), cyclo-(R-Phe-S-Ile) (4), and cyclo-(R-Val-S-Tyr) (5) by using spectral methods.
Aspergillus fumigatus ; chemistry ; growth & development ; metabolism ; Cell Line, Tumor ; Diketopiperazines ; chemistry ; isolation & purification ; metabolism ; pharmacology ; Endophytes ; chemistry ; growth & development ; metabolism ; Fabaceae ; microbiology ; Humans ; Mycelium ; chemistry ; growth & development ; metabolism