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Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors.

ABSTRACT: The K+-sparing diuretic amiloride shows off-target anti-cancer effects in multiple rodent models. These effects arise from the inhibition of two distinct cancer targets: the trypsin-like serine protease urokinase-type plasminogen activator (uPA), a cell-surface mediator of matrix degradation and tumor cell invasiveness, and the sodium-hydrogen exchanger isoform-1 (NHE1), a central regulator of transmembrane pH that supports carcinogenic progression. In this study, we co-screened our library of 5- and 6-substituted amilorides against these two targets, aiming to identify single-target selective and dual-targeting inhibitors for use as complementary pharmacological probes. Closely related analogs substituted at the 6-position with pyrimidines were identified as dual-targeting (pyrimidine 24 uPA IC50 = 175 nM, NHE1 IC50 = 266 nM, uPA selectivity ratio = 1.5) and uPA-selective (methoxypyrimidine 26 uPA IC50 = 86 nM, NHE1 IC50 = 12,290 nM, uPA selectivity ratio = 143) inhibitors, while high NHE1 potency and selectivity was seen with 5-morpholino (29 NHE1 IC50 = 129 nM, uPA IC50 = 10,949 nM; NHE1 selectivity ratio = 85) and 5-(1,4-oxazepine) (30 NHE1 IC50 = 85 nM, uPA IC50 = 5715 nM; NHE1 selectivity ratio = 67) analogs. Together, these amilorides comprise a new toolkit of chemotype-matched, non-cytotoxic probes for dissecting the pharmacological effects of selective uPA and NHE1 inhibition versus dual-uPA/NHE1 inhibition.

SUBMITTER: Buckley BJ

PROVIDER: S-EPMC8000185 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors.

Buckley Benjamin J BJ Kumar Ashna A Aboelela Ashraf A Bujaroski Richard S RS Li Xiuju X Majed Hiwa H Fliegel Larry L Ranson Marie M Kelso Michael J MJ

International journal of molecular sciences 20210315 6

The K<sup>+</sup>-sparing diuretic amiloride shows off-target anti-cancer effects in multiple rodent models. These effects arise from the inhibition of two distinct cancer targets: the trypsin-like serine protease urokinase-type plasminogen activator (uPA), a cell-surface mediator of matrix degradation and tumor cell invasiveness, and the sodium-hydrogen exchanger isoform-1 (NHE1), a central regulator of transmembrane <i>p</i>H that supports carcinogenic progression. In this study, we co-screene ...[more]

PMID: 33804289

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Project description:Methylxanthines and their derivatives are of great interest due to their diverse biological activities. In this work, a new series of twenty-eight semisynthetic theobromine and theophylline derived compounds were designed and synthesized by applying a simple and efficient strategy. First, the corresponding methylxanthine was reacted with a dibromoalkane (n = 3, 5-8) and subsequently, the brominated intermediate was reacted with an amine, including pyrrolidine, piperidine, diethylamine, methylpiperazine, 1-(2-aminoethyl)pyrrolidine, 1-(2-aminoethyl)piperidine, 2-(1-methylpyrrolidin-2-yl)ethanamine, 1-benzylpiperidin-4-amine, 1-benzylpiperidin-4-yl-methanamine, and 2-(1-benzylpiperidin-4-yl)ethan-1-amine. The two synthetic steps were carried out in very short times using a microwave reactor. The biological activity of the new compounds was evaluated on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidases (MAO-A, MAO-B) and beta-secretase (BACE-1). The majority of the new derivatives showed potent and selective in vitro AChE inhibition. Compounds 21, 28 and 30 exhibited the strongest effect on both electric eel and human AChE enzyme, with IC50 values on the low nanomolar scale. The kinetic study of compound 28 in hAChE displayed a mixed inhibition mechanism, suggesting a simultaneous interaction with both the CAS and PAS of the enzyme. This experimental binding mode is consistent with the results of docking and molecular dynamics modelling studies, where it was observed that the piperidinium fragment of 16, 21, 28 and 32 was located at the CAS, whereas the xanthine fragment of each inhibitor interacted with Trp286 in the PAS. These results indicate that these novel xanthine analogues act as selective and potent AChE inhibitors that could also prevent the precipitation of the aberrant Aβ peptide. These properties, in conjunction with their in silico good pharmacokinetic profiles, make these molecules promising lead compounds for the development of new effective drugs against several forms of dementia.

Dataset Information

Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors.

Publications

Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors.

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