Dilazep analogues for the study of equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2)

Hilaire Playa; Timothy A Lewis; Amal Ting; Byung-Chul Suh; Benito Muñoz; Robert Matuza; Brent J Passer; Stuart L Schreiber; John K Buolamwini

doi:10.1016/j.bmcl.2014.10.026

Dilazep analogues for the study of equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2)

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5801-5804. doi: 10.1016/j.bmcl.2014.10.026. Epub 2014 Oct 28.

Authors

Hilaire Playa¹, Timothy A Lewis², Amal Ting², Byung-Chul Suh², Benito Muñoz², Robert Matuza³, Brent J Passer³, Stuart L Schreiber², John K Buolamwini⁴

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Ste 327 Johnson, 847, Monroe, Memphis, TN 38163, USA.
² Center for the Science of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
³ Neurosurgery Department, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
⁴ Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Ste 327 Johnson, 847, Monroe, Memphis, TN 38163, USA. Electronic address: john.buolamwini@rosalindfranklin.edu.

Abstract

As ENT inhibitors including dilazep have shown efficacy improving oHSV1 targeted oncolytic cancer therapy, a series of dilazep analogues was synthesized and biologically evaluated to examine both ENT1 and ENT2 inhibition. The central diamine core, alkyl chains, ester linkage and substituents on the phenyl ring were all varied. Compounds were screened against ENT1 and ENT2 using a radio-ligand cell-based assay. Dilazep and analogues with minor structural changes are potent and selective ENT1 inhibitors. No selective ENT2 inhibitors were found, although some analogues were more potent against ENT2 than the parent dilazep.

Keywords: Dilazep; Equilibrative nucleoside transporters (ENTs); hENT1; hENT2; rENT2.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Biological Transport / drug effects
Cell Line
Dilazep / analogs & derivatives*
Dilazep / chemical synthesis
Dilazep / pharmacology
Equilibrative Nucleoside Transporter 1 / antagonists & inhibitors*
Equilibrative Nucleoside Transporter 1 / genetics
Equilibrative Nucleoside Transporter 1 / metabolism
Equilibrative-Nucleoside Transporter 2 / antagonists & inhibitors*
Equilibrative-Nucleoside Transporter 2 / genetics
Equilibrative-Nucleoside Transporter 2 / metabolism
Humans
Protein Binding
Rats
Recombinant Proteins / biosynthesis
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Swine

Substances

Equilibrative Nucleoside Transporter 1
Equilibrative-Nucleoside Transporter 2
Recombinant Proteins
Dilazep

Abstract

Publication types

MeSH terms

Substances

Grants and funding