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.

Hilaire Playa ¹, Timothy A Lewis ², Amal Ting ², Byung-Chul Suh ², Benito Muñoz ², Robert Matuza ³, Brent J Passer ³, Stuart L Schreiber ², John K Buolamwini ⁴

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.

PMID: 25454272 DOI: 10.1016/j.bmcl.2014.10.026

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.

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