Oxadiazole isomers: all bioisosteres are not created equal

Sphingosine 1-phosphate (S1P) is a potent growth-signaling lipid that has been implicated in cancer progression, inflammation, sickle cell disease, and fibrosis. Two sphingosine kinases (SphK1 and 2) are the source of S1P; thus, inhibitors of the SphKs have potential as targeted cancer therapies and will help to clarify the roles of S1P and the SphKs in other hyperproliferative diseases. Recently, we reported a series of amidinebased inhibitors with high selectivity for SphK1 and potency in the nanomolar range. However, these inhibitors display a short half-life. With the goal of increasing metabolic stability and maintaining efficacy, we designed an analogous series of molecules containing oxadiazole moieties. Generation of a library of molecules resulted in the identification of the most selective inhibitor of SphK1 reported to date (705-fold selectivity over SphK2), and we found that potency and selectivity vary significantly depending on the particular oxadiazole isomer employed. The best inhibitors were subjected to in silico molecular dynamics docking analysis, which revealed key insights into the binding of amidine-based inhibitors by SphK1. Herein, the design, synthesis, biological evaluation, and docking analysis of these molecules are described. KEYWORDS: Sphingosine 1-phosphate, sphingosine kinase, cancer, inhibitor, oxadiazoles S phingosine 1-phosphate (S1P) is a potent signaling lipid that acts on five membrane-bound receptors (S1P1−5) 1 and various intracellular targets. 2 S1P has been shown to regulate a host of processes that affect the growth and fate of cells, 3 and aberrant S1P signaling has been linked to numerous diseases including cancer, 2,4 asthma, 5 fibrosis, 6 and sickle cell disease. 7 Cellular synthesis of S1P is exclusively dependent on the action of two sphingosine kinases (SphK1 and 2) that directly phosphorylate sphingosine (Sph). 3 As the sole sources of cellular S1P, the SphKs influence cell survival 8,9 and have been identified as targets of interest in pharmacology and the pharmaceutical industry. 4,10 Therefore, SphK inhibitors, by affecting S1P levels, have therapeutic potential and are necessary to clarify the many roles of S1P and each SphK in physiology and disease. 10−12 S1P signaling is complex, and the roles of SphK1 and 2 in various pathways differ significantly. These differences are due, in large part, to subcellular compartmentalization; SphK2 possesses an N-terminal nuclear localization sequence not present in SphK1. 13 Indeed, SphK2 is located primarily in the nucleus and other organelles and may influence gene expression through S1P-dependent inhibition of histone deacetylase 1 and 2 (HDAC1 and 2). 14 Additionally, S1P produced by SphK2 in the endoplasmic reticulum and mitochondria has the effect of stimulating apoptosis. 15 In contrast, SphK1 is located primarily in the cytosol, and SphK1-derived S1P generally elicits prosurvival and proliferative effects through interactions with S1P1−5. Upon phosphorylation by the extracellular-regulated kinases, Sp...

show abstract

“…33 For each oxadiazole subtype, both meta-and para-substituted variants were synthesized (Schemes SI-3 and SI-4).…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Structural Requirements and Docking Analysis of Amidine-Based Sphingosine Kinase 1 Inhibitors Containing Oxadiazoles

Houck

Dawson

Kennedy

et al. 2016

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

show abstract

“…The methylene carbon appeared at 35.6 ppm. 1 H-NMR of compounds 2-7 showed the NH signal around 11.50 ppm. 1 H-NMR of 8 and 9 displayed the NH group at 12.00 and 8.92 ppm.…”

Section: Structure Confirmationmentioning

confidence: 97%

“…It has four isomers 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole ( Figure 1). 1,2,3-oxadiazole isomer is unstable and ring-opens to form the diazoketone tautomer but the other isomers are stable and known [1].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and characterization of new 5-(4-chlorobenzyl)-1,3,4-oxadiazol-2-amine derivatives

Salama

2020

Egypt. J. Chem.

View full text Add to dashboard Cite

“…15) and based on the model microtubule destabilizer chalcone MDL-27048 (47) [122] natural products (as for example 46) were selected from a pharmacophore search [123] or synthesized as cyclopropylcarboxamide analogues, (48) [124] but in both instances only weak potencies were observed. Similarly, incorporation of pyridine rings on 1,2,4-oxadiazole and related scaffolds [125][126][127][128][129] Fig. (15).…”

Section: Replacement Of the Phenyl Rings By Azinesmentioning

confidence: 99%

Pyridine Based Antitumour Compounds Acting at the Colchicine Site

Álvarez¹,

Aramburu²,

Puebla³

et al. 2016

CMC

View full text Add to dashboard Cite

Antimitotics binding at the colchicine site of tubulin are important antitumour and vascular disrupting agents. Pyridines and azines are privileged scaffolds in medicinal chemistry and in recent years many colchicine site ligands (CSL) have incorporated them into their structures with the aim of improving their pharmacokinetic and pharmacodynamics properties. CSL have been classified according to their chemical structures and the chemical structures of the pyridine and azine containing antimitotic compounds are described. The designed principles behind the structural modifications and the achieved effect on the biological activity upon inclusion of these heterocycles are also discussed. Lessons from the achievements and failures have been extracted and future perspectives delineated.

show abstract

Oxadiazole isomers: all bioisosteres are not created equal

Cited by 33 publications

References 28 publications

Structural Requirements and Docking Analysis of Amidine-Based Sphingosine Kinase 1 Inhibitors Containing Oxadiazoles

Structural Requirements and Docking Analysis of Amidine-Based Sphingosine Kinase 1 Inhibitors Containing Oxadiazoles

Synthesis and characterization of new 5-(4-chlorobenzyl)-1,3,4-oxadiazol-2-amine derivatives

Pyridine Based Antitumour Compounds Acting at the Colchicine Site

Contact Info

Product

Resources

About