Title: Construction of a new lipase- and xylanase-producing oleaginous yeast consortium capable of reactive azo dye degradation and detoxification Ali SS, Al-Tohamy R, Xie R, El-Sheekh MM, Sun J Ref: Bioresour Technol, 313:123631, 2020 : PubMed
A new oleaginous yeast consortium Y-BC-SH which stands for molecularly identified species Yarrowia sp., Barnettozyma californica and Sterigmatomyces halophilus was successfully constructed in this study. This multipurpose oleaginous yeast consortium was developed based on its higher ability to accumulate large amounts of lipids in the form of triacylglycerol, grow on xylose, produce lipase and xylanase and it could rapidly decolorize and degrade commonly-used textile reactive azo dyes. The specific enzyme activities of lipase, xylanase, xylan esterase, beta-xylosidase, CMCase, beta-glucosidase and cellobiohydrolase produced by Y-BC-SH were significantly higher than that of individual strains. As chemical oxygen demand reduction had occurred in the dye mixture solutions, it was evidence of their color removal and mineralization by Y-BC-SH. The significant induction of oxidoreductive enzymes by Y-BC-SH was probably due to the coordinated metabolic interactions of the individual strains. Phytotoxicity assay confirmed that metabolites generated after dye degradation by Y-BC-SH are non-toxic.
Title: Design, Synthesis and Insecticide Activity of Novel Acetylcholinesterase Inhibitors: Triazolinone and Phthalimide Heterodimers Xie R, Mei X, Ning J Ref: Chem Pharm Bull (Tokyo), 67:345, 2019 : PubMed
Based on the "cluster effect" and the structure characters of acetylcholinesterase (AChE; EC 3.1.1.7), a new series of 1,2,4-triazolin-3-one and phthalimide heterodimers were designed, synthesized, and evaluated as potent dual acetylcholinesterase inhibitors (AChEIs). Most of the synthesized compounds showed good in vitro inhibitory activities towards both Drosophila melanogaster acetylcholinesterase (DmAChE) and Musca domestica acetylcholinesterase (MdAChE). Among them, 5g was found to be the most potent anti-AChE derivate (5g, IC50 = 8.07 microM to DmAChE, IC50 = 32.24 microM to MdAChE). It was 2.31- and 1.35-fold more active than the positive control ethion (CP, IC50 = 18.62 microM to DmAChE, IC50 = 43.56 microM to MdAChE). The docking model study revealed that 5g possessed the fitted spatial structure and bound to the central pocket and peripheral site of DmAChE. Moreover, most compounds demonstrated high insecticidal activity to Lipaphis erysimi and Tetranychus cinnabarinus at the concentration of 300 mg/L.
Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 A from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.
Title: Design, synthesis and biological evaluation of organophosphorous-homodimers as dual binding site acetylcholinesterase inhibitors Xie R, Zhao Q, Zhang T, Fang J, Mei X, Ning J, Tang Y Ref: Bioorganic & Medicinal Chemistry, 21:278, 2013 : PubMed
The cluster effect is an effective strategy to explore new lead compounds, and has been successfully applied in rational drug design and screening. A series of novel organophosphorous-homodimers were designed and synthesized based on the dual-site structure characteristics of acetylcholinesterase (AChE). The compounds were evaluated in vitro for their inhibitory activity to AChE extracted from Drosophila melanogaster and Musca domestic. Compound 4H showed an excellent inhibitor activity to both Drosophila melanogaster and Musca domestic with the corresponding IC(50) values of 23 and 168nM, respectively. Meanwhile, its activities against Drosophila melanogaster and Musca domestic AChE were more than 10,00,000 and 100,000-fold higher compared with the parent compound (MH), and was up to 245 and 107-fold higher than those of the positive control omethoate. The molecular docking study revealed that 4H possessed an optimal spacer length and can perfectly fit into the central pocket, active gorge, and peripheral site of DmAChE, and consequently exhibited highly improved inhibitor potency to DmAChE. The bioassay tests showed that 4 series compounds showed prominent insecticidal activities against both Lipaphser erysimi and Tetranychus cinnbarinus at a concentration of 200mg/L. The insecticide activity of compound 4H was particularly significant that can cause 96% mortality to Tetranychus cinnbarinus after 24h of treatment.
Title: Homo- and hetero-dimers of inactive organophosphorous group binding at dual sites of AChE Zhao Q, Xie R, Zhang T, Fang J, Mei X, Ning J, Tang Y Ref: Bioorganic & Medicinal Chemistry Lett, 21:6404, 2011 : PubMed
Homo- and hetero-dimers of inactive organophosphorous group(s) dramatically enhanced the acetylcholinesterase (AChE; EC 3.1.1.7) inhibiting potency, with the highest potency observed at a tether length of 6 methylene groups (6d) for the homodimers, and 7 methylene groups (8e) for the heterodimers. The docking model of Drosophila melanogaster AChE suggested that 6d and 8e bound at the catalytic and peripheral sites of AChE, in which two organophosphorous groups of 6d individually oriented towards TRP83 of catalytic sites and TRP321 of peripheral sites, and phthalicimide group of 8e was appropriately arranged for a pi-pi interaction with the phenyl ring of TYR330, furthermore, the organophosphorous group introduced hydrophobic interaction with TRP83. The compounds prepared in this work demonstrated high insecticidal activity to Lipaphis erysimi and Tetranychus cinnbarinus at the concentration 300mg/L.
PURPOSE: The purpose was to explore the relationships between irinotecan disposition and allelic variants of genes coding for adenosine triphosphate binding cassette transporters and enzymes of putative relevance for irinotecan. EXPERIMENTAL DESIGN: Irinotecan was administered to 65 cancer patients as a 90-min infusion (dose, 200-350 mg/m(2)), and pharmacokinetic data were obtained during the first cycle. All patients were genotyped for variants in genes encoding MDR1 P-glycoprotein (ABCB1), multidrug resistance-associated proteins MRP-1 (ABCC1) and MRP-2 (canalicular multispecific organic anion transporter; ABCC2), breast cancer resistance protein (ABCG2), carboxylesterases (CES1, CES2), cytochrome p450 isozymes (CYP3A4, CYP3A5), UDP glucuronosyltransferase (UGT1A1), and a DNA-repair enzyme (XRCC1), which was included as a nonmechanistic control. RESULTS: Eighteen genetic variants were found in nine genes of putative importance for irinotecan disposition. The homozygous T allele of the ABCB1 1236C>T polymorphism was associated with significantly increased exposure to irinotecan (P = 0.038) and its active metabolite SN-38 (P = 0.031). Pharmacokinetic parameters were not related to any of the other multiple variant genotypes, possibly because of the low allele frequency. The extent of SN-38 glucuronidation was slightly impaired in homozygous variants of UGT1A1*28, although differences were not statistically significant (P = 0.22). CONCLUSIONS: It is concluded that genotyping for ABCB1 1236C>T may be one of the factors assisting with dose optimization of irinotecan chemotherapy in cancer patients. Additional investigation is required to confirm these findings in a larger population and to assess relationships between irinotecan disposition and the rare variant genotypes, especially in other ethnic groups.
