The UVS9 Gene of Chlamydomonas Encodes an XPG Homolog with a New Conserved Domain

Publication date: Available online 19 November 2015
Source:DNA Repair
Author(s): Erin Deitsch, Erin M. Hibbard, Jason L. Petersen
Nucleotide excision repair (NER) is a key pathway for removing DNA damage that destabilizes the DNA double helix. During NER a protein complex coordinates to cleave the damaged DNA strand on both sides of the damage. The resulting lesion-containing oligonucleotide is displaced from the DNA and a replacement strand is synthesized using the undamaged strand as template. Ultraviolet (UV) light is known to induce two primary forms of DNA damage, the cyclobutane pyrimidine dimer and the 6-4 photoproduct, both of which destabilize the DNA double helix. The uvs9 strain of Chlamydomonas reinhardtii was isolated based on its sensitivity to UV light and was subsequently shown to have a defect in NER. In this work, the UVS9 gene was cloned through molecular mapping and shown to encode a homolog of XPG, the structure-specific nuclease responsible for cleaving damaged DNA strands 3′ to sites of damage during NER. 3′ RACE revealed that the UVS9 transcript is alternatively polyadenylated. The predicted UVS9 protein is nearly twice as long as other XPG homologs, primarily due to an unusually long spacer region. Despite this difference, amino acid sequence alignment of UVS9p with XPG homologs revealed a new conserved domain involved in TFIIH interaction.



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Development of 68Ga-Labeled Multivalent Nitroimidazole Derivatives for Hypoxia Imaging

Publication date: Available online 22 November 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Sudhakara Reddy Seelam, Ji Youn Lee, Yun-Sang Lee, Mi Kyung Hong, Young Joo Kim, Vinay Kumar Banka, Dong Soo Lee, June-Key Chung, Jae Min Jeong
Radiolabeled nitroimidazole (NI) derivatives have been extensively studied for imaging hypoxia. To increase the hypoxic tissue uptake, we developed ⁶⁸Ga-labeled agents based on mono-, bis-, and trisnitroimidazole conjugates with the chelating agent 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid] (TRAP). All the three agents showed high radiolabeling yields (>96%) and were found to be stable up to 4 h in prepared medium at room temperature and in human serum at 37 °C. The trivalent agent showed a significant increase in hypoxic to normoxic uptake ratio (p < 0.005) according to the in vitro cell uptake experiments. Immunohistochemical analysis confirmed the presence of hypoxia in xenografted CT26 tumor tissue. The trivalent derivative (⁶⁸Ga-3: 0.17 ± 0.04, ⁶⁸Ga-4: 0.33 ± 0.04, ⁶⁸Ga-5: 0.45 ± 0.09, and ⁶⁸Ga-6: 0.47 ± 0.05% ID/g) showed the highest uptake by tumor cells according to the biodistribution studies in CT-26 xenografted mice. All the nitroimidazole derivatives showed significantly higher uptake by tumor cells than the control agent (p < 0.05) at 1 h post-injection. The trivalent derivative (⁶⁸Ga-3: 0.10 ± 0.06; ⁶⁸Ga-4: 0.20 ± 0.06; ⁶⁸Ga-5: 0.33 ± 0.08; ⁶⁸Ga-6: 0.59 ± 0.09) also showed the highest standard uptake value for tumor cells at 1 h post-injection in animal PET studies using CT-26 xenografted mice. In conclusion, we successfully synthesized multivalent ⁶⁸Ga-labeled NI derivatives for imaging hypoxia. Among them, the trivalent agent showed the highest tumor uptake in biodistribution and animal PET studies.

Graphical abstract

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Synthesis and antitumor activity evaluation of PI3K inhibitors containing 3-substituted quinazolin-4(3H)-one moiety

Publication date: Available online 22 November 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Hao Zhang, Min-Hang Xin, Xiao-Xiao Xie, Shuai Mao, Sai-Jie Zuo, She-Min Lu, San-Qi Zhang
In present study, a series of N-(2-methoxy-5-(3-substituted quinazolin-4(3H)-one- 6-yl)-pyridin-3-yl)phenylsulfonamide were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against HCT116 and MCF-7 cancer cell lines. The SAR of title compounds was discussed. The compounds (S)-C5 and (S)-C8 displayed potent inhibitory activity against PI3Ks and mTOR, especially against PI3Kα. In addition, compound (S)-C5 can efficaciously inhibit tumor growth in a mice S-180 model. These findings suggest that our designed compounds can serve as potent PI3K inhibitors and effective anticancer agents.

Graphical abstract

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SAR Studies Directed Toward the Pyridine Moiety of the Sap-Feeding Insecticide Sulfoxaflor (Isoclast™ active)

Publication date: Available online 22 November 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Michael R. Loso, Zoltan Benko, Ann Buysse, Timothy C. Johnson, Benjamin M. Nugent, Richard B. Rogers, Thomas C. Sparks, Nick X. Wang, Gerald B. Watson, Yuanming Zhu
Sap-feeding insect pests constitute a major insect pest complex that includes a range of aphids, whiteflies, planthoppers and other insect species. Sulfoxaflor (Isoclast™ active), a new sulfoximine class insecticide, targets sap-feeding insect pests including those resistant to many other classes of insecticides. A structure activity relationship (SAR) investigation of the sulfoximines insecticides revealed the importance of a 3-pyridyl ring and a methyl substituent on the methylene bridge linking the pyridine and the sulfoximine moiety to achieving strong Myzus persicae activity. A more in depth QSAR investigation of pyridine ring substituents revealed a strong correlation with the calculated log octanol/water partition coefficient (SLogP). Model development resulted in a highly predictive model for a set of 18 sufoximines including sulfoxaflor. The model is consistent with and helps explain the highly optimized pyridine substitution pattern for sulfoxaflor.

Graphical abstract

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Synthesis of tetravalent LacNAc-glycoclusters as high-affinity cross-linker against Erythrina cristagalli agglutinin

Publication date: Available online 22 November 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Makoto Ogata, Yasushi Chuma, Yoshinori Yasumoto, Takashi Onoda, Myco Umemura, Taichi Usui, Enoch Y. Park
Four kinds of tetravalent double-headed glycoclusters [(LacNAc)4-DHGs] were designed with linkers of varying lengths consisting of alkanedionic carboxyamido groups (C6, C12, C18 and C24) between two bi-antennary LacNAc-glycosides. These glycoclusters served as high-affinity cross-linking ligands for the LacNAc-binding lectin Erythrina cristagalli agglutinin (ECA). The binding activity and cross-linking between each ligand and ECA were characterized by a hemagglutination inhibition (HI) assay, isothermal titration calorimetry (ITC), a quantitative precipitation assay and dynamic light scattering (DLS). For the precipitation assay and DLS measurement, the synthesized (LacNAc)4-DHGs were found to be capable of binding and precipitating the ECA as multivalent ligands. ITC analysis indicated the binding of (LacNAc)4-DHGs was driven by a favorable enthalpy change. Furthermore, the entropy penalty from binding (LacNAc)4-DHGs clearly decreased in a spacer length-dependent manner. The binding affinities of flexible (LacNAc)4-DHGs (C18 and C24) with long spacers were found to be more favorable than those of the clusters having short spacers (C6 and C12). These results were supported by molecular dynamics simulations with explicit water molecules for the tetravalent glycoclusters with ECA. We concluded that the subtle modification in the epitope-presenting scaffolds exerts the significant effect in the recognition efficiency involved in the LacNAc moieties by ECA.

Graphical abstract

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Characterization of Childhood Obesity and Behavioral Factors

Childhood obesity is a major public health threat in the United States. Recent data indicate that 34.2% of children ages 6 to 11 years are overweight or obese. The purpose of this study is to describe childhood obesity levels and identify risk behaviors in two school-based health centers in Michigan, one urban and one rural.

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Use of a Pediatric Bleeding Questionnaire in the Screening of Von Willebrand Disease in Young Females at Menarche in the Primary Care Setting

Von Willebrand disease (VWD), the most common inherited bleeding disorder, is caused by deficiency or dysfunction in von Willebrand factor. Assessment of hemorrhagic symptoms is essential for early diagnosis, although bleeding histories are taken in a nonstandardized manner. Validated bleeding assessment tools provide objectivity in evaluating bleeding patterns of females at menarche and may improve provider confidence in screening for VWD. Utilizing a pretest/posttest design, in this project we implemented and evaluated the use of a pediatric bleeding questionnaire in eight pediatric primary care clinics for 3 months.

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