Autotaxin (ATX) is an autocrine motility factor that promotes cancer cell invasion, cell migration and angiogenesis. ATX, originally discovered as a nucleotide phosphodiesterase, is known now to be responsible for the lysophospholipid-preferring phospholipase D activity in plasma. As such, it catalyzes the production of lysophosphatidic acid (LPA) from lysophophatidylcholine (LPC). ATX is thus an attractive drug target; small molecular inhibitors might be efficacious in slowing the spread of cancers. With this study we have generated a series of beta-keto and beta-hydroxy phosphonate derivatives of LPA, some of which are potent ATX inhibitors. KeywordsAutotaxin; ATX; Phosphonate; Choline; LPA The autocrine motility factor autotaxin (ATX) was originally isolated from melanoma cell supernatants as a 125-kD glycoprotein that stimulated tumor cell motility. 1 In vivo experiments documented that forced expression of ATX augments tumor cell invasion and metastasis. 2 Further, ATX promotes angiogenesis and may act in concert with other angiogenic factors to facilitate new blood vessel formation. 3 These biological properties require enzymatic activity.ATX belongs to the nucleotide pyrophosphatase and phosphodiesterase (NPP) family of enzymes, which hydrolyze phosphodiester and diphosphate bonds, typically found in ATP and ADP. 4 Interest in ATX was stimulated by the identification of this enzyme as the long elusive plasma lysophospholipase D activity, which is responsible for the cleavage of choline group of lysophophatidylcholine (LPC) to form lysophosphatidic acid (LPA) ( Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 1). 5,6 This is a major pathway of biosynthesis of LPA in plasma. 7,8 LPA is an intercellular lipid mediator that influences many biochemical processes including cell proliferation, smooth muscle contraction, platelet aggregation and apoptosis. [9][10][11] For example, LPA is the "ovarian cancer activating factor" in ascitic fluid characteristic of ovarian cancer patients. Elevated levels of LPA are present both at early and late stages in ovarian cancer and may play a role in tumor cell proliferation and invasion. 12,13 LPA mediates its effects through the activation of G protein-coupled receptors (GPCR). 14 Thus, great efforts have been made on the study of LPA receptor antagonists and agonists due to their therapeutic potential. [15][16][17][18][19][20][21] In aggregate, these data suggest that ATX is an attractive pharmacological target; blockage of LPA produ...
Autotaxin (ATX) is an attractive pharmacological target due to its lysophospholipase D activity which leads to the production of lysophosphatidic acid (LPA). Blockage of ATX produced LPA by small molecules could be a potential anticancer chemotherapy. In our previous study, we have identified the two beta-hydroxy phosphonate analogs of LPA (compounds f17 and f18) as ATX inhibitors. With this work, we investigated alpha- and beta-substituted phosphonate analogs of LPA and evaluated them for ATX inhibitory activity. The stereochemistry of beta-hydroxy phosphonates was also studied.
BackgroundThe clinical utility for mefloquine has been eroded due to its association with adverse neurological effects. Better-tolerated alternatives are required. The objective of the present study was the identification of lead compounds that are as effective as mefloquine, but exhibit physiochemical properties likely to render them less susceptible to passage across the blood-brain barrier.MethodsA library of drug-like non-piperidine analogs of mefloquine was synthesized. These compounds are diverse in structure and physiochemical properties. They were screened in appropriate in vitro assays and evaluated in terms of their potential as lead compounds. The correlation of specific structural attributes and physiochemical properties with activity was assessed.ResultsThe most potent analogs were low molecular weight unconjugated secondary amines with no heteroatoms in their side-chains. However, these compounds were more metabolically labile and permeable than mefloquine. In terms of physiochemical properties, lower polar surface area, lower molecular weight, more freely rotatable bonds and fewer H-bond acceptors were associated with greater potency. There was no such relationship between activity and LogP, LogD or the number of hydrogen bond donors (HBDs). The addition of an H-bond donor to the side-chain yielded a series of active diamines, which were as metabolically stable as mefloquine but showed reduced permeability.ConclusionsA drug-like library of non-piperidine analogs of mefloquine was synthesized. From amongst this library an active lead series of less permeable, but metabolically stable, diamines was identified.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.