title: Dendrimer Conjugate of [4-(Tetradecanoylamino)benzyl]phosphonic Acid (S32826) as an Autotaxin Inhibitor.
abstract: Autotaxin is an extracellular phospholipase D that catalyzes the hydrolysis of lysophosphatidyl choline (LPC) to bioactive lipid lysophosphatidic acid (LPA). LPA has been implicated in many pathological processes relevant to cancer, including cell migration and invasion, proliferation, and survival. The most potent autotaxin inhibitor described to date is the LPA analogue S32826 (IC50 5.6 nM). S32826 and many other autotaxin inhibitors are notably lipophilic, creating a need to improve their physical properties. Polymers are becoming an increasingly useful tool in the delivery of drugs and have the potential to improve the properties of small molecules. Herein we report the synthesis of a S32826 dendrimer conjugate and its biological evaluation. The conjugate was found to inhibit autotaxin activity using two different substrates and to decrease the migration of an ovarian cancer cell line modified to overexpress autotaxin. Furthermore, the conjugate potentiated activation of caspase 3/7 induced by carboplatin.
authors.affiliation: Institute for Science & Technology in Medicine and School of Pharmacy, Keele University, Guy Hilton Research Centre , Stoke-on-Trent, Staffordshire ST4 7QB, U.K. ; Synthesis and Medicinal Chemistry Cluster, Lennard-Jones Building, Keele University , Staffordshire ST5 5BG, U.K.
authors.forename: Natalie
authors.initials: N
authors.lastname: Fisher
authors.affiliation: Synthesis and Medicinal Chemistry Cluster, Lennard-Jones Building, Keele University , Staffordshire ST5 5BG, U.K.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hilton-Bolt
authors.affiliation: Synthesis and Medicinal Chemistry Cluster, Lennard-Jones Building, Keele University , Staffordshire ST5 5BG, U.K.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Edwards
authors.affiliation: Synthesis and Medicinal Chemistry Cluster, Lennard-Jones Building, Keele University , Staffordshire ST5 5BG, U.K.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Haxton
authors.affiliation: Charnwood Molecular Ltd, The Heritage Building, 7 Beaumont Court, Prince William Road, Loughborough LE11 5GA, U.K.
authors.forename: Michael
authors.initials: M
authors.lastname: McKenzie
authors.affiliation: School of Science and Technology, Nottingham Trent University , Clifton campus, Nottingham NG11 8NS, U.K.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Allin
authors.affiliation: Institute for Science & Technology in Medicine and School of Pharmacy, Keele University, Guy Hilton Research Centre , Stoke-on-Trent, Staffordshire ST4 7QB, U.K.
authors.forename: Alan
authors.initials: A
authors.lastname: Richardson
keywords: Autotaxin; S32826; dendrimer; ovarian cancer