scholarly journals Design and synthesis of selective inhibitors of Placental Alkaline Phosphatase

2010 ◽  
Vol 18 (2) ◽  
pp. 573-579 ◽  
Author(s):  
Marion Lanier ◽  
Eduard Sergienko ◽  
Ana Maria Simão ◽  
Ying Su ◽  
Thomas Chung ◽  
...  
2019 ◽  
Vol 16 (3) ◽  
pp. 256-272
Author(s):  
Uzma Salar ◽  
Khalid Mohammed Khan ◽  
Syeda Abida Ejaz ◽  
Abdul Hameed ◽  
Mariya al-Rashida ◽  
...  

Background: Alkaline Phosphatase (AP) is a physiologically important metalloenzyme that belongs to a large family of ectonucleotidase enzymes. Over-expression of tissue non-specific alkaline phosphatase has been linked with ectopic calcification including vascular and aortic calcification. In Vascular Smooth Muscles Cells (VSMCs), the high level of Reactive Oxygen Species (ROS) resulted in the up-regulation of TNAP. Accordingly, there is a need to identify highly potent and selective inhibitors of APs for treatment of disorders related to hyper activity of APs. </P><P> Methods: Herein, a series of coumarinyl alkyl/aryl sulfonates (1-40) with known Reactive Oxygen Species (ROS) inhibition activity, was evaluated for alkaline phosphatase inhibition against human Tissue Non-specific Alkaline Phosphatase (hTNAP) and Intestinal Alkaline Phosphatase (hIAP). </P><P> Results: With the exception of only two compounds, all other compounds in the series exhibited excellent AP inhibition. For hIAP and hTNAP inhibition, IC50 values were observed in the range 0.62-23.5 &#181;M, and 0.51-21.5 &#181;M, respectively. Levamisole (IC50 = 20.21 &#177; 1.9 &#181;M) and Lphenylalanine (IC50 = 100.1 &#177; 3.15 &#181;M) were used as standards for hIAP and hTNAP inhibitory activities, respectively. 4-Substituted coumarinyl sulfonate derivative 23 (IC50 = 0.62 &#177; 0.02 &#181;M) was found to be the most potent hIAP inhibitor. Another 4-substituted coumarinyl sulfonate derivative 16 (IC50 = 0.51 &#177; 0.03 &#181;M) was found to be the most active hTNAP inhibitor. Some of the compounds were also found to be highly selective inhibitors of APs. Detailed Structure-Activity Relationship (SAR) and Structure-Selectivity Relationship (SSR) analysis were carried out to identify structural elements necessary for efficient and selective AP inhibition. Molecular modeling and docking studies were carried out to rationalize the most probable binding site interactions of the inhibitors with the AP enzymes. In order to evaluate drug-likeness of compounds, in silico ADMETox evaluation was carried out, most of the compounds were found to have favorable ADME profiles with good predicted oral bioavailability. X-ray crystal structures of compounds 38 and 39 were also determined. </P><P> Conclusion: Compounds from this series may serve as lead candidates for future research in order to design even more potent, and selective inhibitors of APs.


2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii329-iii329
Author(s):  
Hiroki Yamada ◽  
Tomohiro Abiko ◽  
Hirokazu Fujiwara ◽  
Kazunari Yoshida ◽  
Hikaru Sasaki

Abstract INTRODUCTION Germ cell tumors in the central nervous system (CNS) typically arise either at suprasellar and/or pineal region, and occasionally at basal ganglia. We report a case of diagnostically challenging, recurrent germ cell tumor presented with diffuse intraaxial abnormality in and across the lower brainstem, which was diagnosed by the elevated placental alkaline phosphatase (PLAP) level in cerebrospinal fluid (CSF). CASE DESCRIPTION: A 28-year-old man had been treated by chemoradiotherapy at the previous hospital for bifocal suprasellar and pineal lesions with the provisional diagnosis of germinoma without histological confirmation. Three years later, he presented with progressive weakness of bilateral extremities for weeks. Magnetic resonance imaging showed a diffuse, bilaterally symmetric high intensity lesion on T2-weighted image with slight contrast enhancement across the ventral side of the medulla oblongata to the upper cervical spinal cord. Serum and CSF hCG, hCG-β, and AFP were all negative. Since the image findings were atypical for recurrent germ cell tumor, some kind of myelitis was initially suspected. Therefore, steroid pulse therapy was administered. However, the patient’s symptom was still gradually progressing. Then, the CSF PLAP turned out to be positive, indicating the recurrence of germinoma. Accordingly, platinum-based chemotherapy was administered, and the imaging findings, patient’s symptoms, and CSF PLAP began to improve. The patient is to be treated with radiotherapy following chemotherapy. CONCLUSION We report a rare case of CNS germ cell tumor that presented with diffuse intraaxial lesion in the lower brainstem in which examination of CSF PLAP was extremely useful.


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