Xu X.,Ningxia Medical University |
Xu X.,Shanghai University |
Wu Y.,Shanghai University |
Wu Y.,Shanghai Institute of Technology |
And 13 more authors.
Chemical Biology and Drug Design | Year: 2016
Homocamptothecin is emerging as an important topoisomerase I inhibitor originating in natural product camptothecin. We report the modifications and SAR of homocamptothecin on position C10 to develop potent topoisomerase I inhibitors for anticancer drug discovery. Based on click chemistry, twenty-one 1,2,3-triazole-substituted homocamptothecin derivatives were readily synthesized in two steps. For A549, cycloalkyl- and alkyl-substituted compounds 6j, 6l, and 6o revealed highly antiproliferative inhibitory activities with IC50 value of 30, 30, and 50 nm, respectively. In addition, cyclopropyl 6j exhibited greater Topo I inhibitory activity than 20(S)-Camptothecin, which indicated suitability for further drug development. © 2016 John Wiley & Sons A/S
PubMed | WuXi Applied Tec Co. and Shanghai JiaoTong University
Type: | Journal: Scientific reports | Year: 2016
The ostium secundum atrial septal defect (ASDII) is the most common type of congenital heart disease and is characterized by a left to right shunting of oxygenated blood caused by incomplete closure of the septum secundum. We identified a familial form of isolated ASDII that affects four individuals in a family of five and shows autosomal dominant inheritance. By whole genome sequencing, we discovered a new mutation (c.*1784T>C) in the 3-untranslated region (3UTR) of ACTC1, which encodes the predominant actin in the embryonic heart. Further analysis demonstrated that the c.*1784T>C mutation results in a new target site for miRNA-139-5p, a microRNA that is involved in cell migration, invasion, and proliferation. Functional analysis demonstrated that the c.*1784T>C mutation specifically downregulates gene expression in a luciferase assay. Additionally, miR-139-5p mimic causes further decrease, whereas miR-139-5p inhibitor can dramatically rescue the decline in gene expression caused by this mutation. These findings suggest that the familial ASDII may be a result of an ACTC1 3UTR gain-of-function mutation caused by the introduction of a new miR-139-5p target site. Our results provide the first evidence of a pathogenic mutation in the ACTC1 3UTR that may be associated with familial isolated ASDII.
Park H.-K.,University of Ulsan |
Jo W.,University of Ulsan |
Choi H.-J.,University of Ulsan |
Kim B.,University of Ulsan |
And 9 more authors.
Journal of Applied Toxicology | Year: 2015
Many systemic drugs can induce ocular toxicity and several ocular side-effects have been identified in clinical studies. However, it is difficult to detect ocular toxicity in preclinical studies because of the lack of appropriate evaluation methods. Optical coherence tomography (OCT) is useful because it can provide real-time images throughout a study period, whereas histopathology only provides images of sacrificed animals. Using OCT alongside histopathology, attempts were made to find effective approaches for screening of drug-induced ocular toxicity in monkeys. Such approaches could be used in preclinical studies prior to human trials. Six male cynomolgus monkeys (Macaca fascicularis Raffles) were orally administered one of six candidate MAPK/ERK kinase (MEK) inhibitors. Central serous chorioretinopathy, a known side-effect of such inhibitors, was identified in four monkeys by OCT. Artifacts generated during tissue processing meant that histopathology could not detect edematous changes. Thus, OCT is a useful tool to detect ocular toxicity which cannot be detected by histopathology in preclinical studies. © 2014 John Wiley & Sons, Ltd.
Le P.T.,Pfizer |
Richardson P.F.,Pfizer |
Sach N.W.,Pfizer |
Xin S.,WuXi Applied Tec Co. |
And 3 more authors.
Organic Process Research and Development | Year: 2015
A robust process for the preparation of multigram quantities of 4-aminopyrimidin-5-ol (5) in good yield from an inexpensive and readily available pyrimidine starting material is described. An initial evaluation of the reported literature route for this material utilizing a de novo pyrimidine synthesis provided safety concerns over the scalability of several intermediates. In addition, a number of steps proceeded in mediocre yield, and involved chromatographic separations for the desired products. The newly developed route mitigates the safety concerns, reduces the number of steps from five to three, avoids column chromatography, leads to an 8-fold improvement in yield, and utilizes reagents, which are recognized to be more environmentally benign. © 2015 American Chemical Society.
Scales S.,Pfizer |
Johnson S.,Pfizer |
Hu Q.,Pfizer |
Do Q.-Q.,Pfizer |
And 11 more authors.
Organic Letters | Year: 2013
Differences in regioselectivity were observed during the SNAr reaction of amines with unsymmetrical 3,5-dichloropyrazines. This study revealed that when the 2-position of the pyrazine was occupied with an electron-withdrawing group (EWG), nucleophilic attack occurred preferentially at the 5-position. When the 2-position was substituted with an electron-donating group (EDG), nucleophilic attack occurred preferentially at the 3-position. These results are reported along with a computational rationale for the experimental observations based on the Fukui index at the reacting centers. © 2013 American Chemical Society.