{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T12:13:09Z","timestamp":1783685589209,"version":"3.55.0"},"reference-count":55,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T00:00:00Z","timestamp":1657756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MNERT","award":["CNRS-UMR 7273"],"award-info":[{"award-number":["CNRS-UMR 7273"]}]},{"name":"MNERT","award":["ANR ROS Signal\u2014N\u00b0 ANR-09-BLAN-005-03"],"award-info":[{"award-number":["ANR ROS Signal\u2014N\u00b0 ANR-09-BLAN-005-03"]}]},{"name":"MNERT","award":["ANR JCJC MitoDiaPM\u2014N\u00b0 ANR-17-CE34-0006-01"],"award-info":[{"award-number":["ANR JCJC MitoDiaPM\u2014N\u00b0 ANR-17-CE34-0006-01"]}]},{"name":"Yelen Analytics","award":["CNRS-UMR 7273"],"award-info":[{"award-number":["CNRS-UMR 7273"]}]},{"name":"Yelen Analytics","award":["ANR ROS Signal\u2014N\u00b0 ANR-09-BLAN-005-03"],"award-info":[{"award-number":["ANR ROS Signal\u2014N\u00b0 ANR-09-BLAN-005-03"]}]},{"name":"Yelen Analytics","award":["ANR JCJC MitoDiaPM\u2014N\u00b0 ANR-17-CE34-0006-01"],"award-info":[{"award-number":["ANR JCJC MitoDiaPM\u2014N\u00b0 ANR-17-CE34-0006-01"]}]},{"name":"Agence Nationale de la Recherche","award":["CNRS-UMR 7273"],"award-info":[{"award-number":["CNRS-UMR 7273"]}]},{"name":"Agence Nationale de la Recherche","award":["ANR ROS Signal\u2014N\u00b0 ANR-09-BLAN-005-03"],"award-info":[{"award-number":["ANR ROS Signal\u2014N\u00b0 ANR-09-BLAN-005-03"]}]},{"name":"Agence Nationale de la Recherche","award":["ANR JCJC MitoDiaPM\u2014N\u00b0 ANR-17-CE34-0006-01"],"award-info":[{"award-number":["ANR JCJC MitoDiaPM\u2014N\u00b0 ANR-17-CE34-0006-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In order to discover new 31P NMR markers for probing subtle pH changes (&lt;0.2 pH unit) in biological environments, fifteen new conformationally constrained or sterically hindered \u03b1-aminophosphonates derived from diethyl(2-methylpyrrolidin-2-yl)phosphonate were synthesized and tested for their pH reporting and cytotoxic properties in vitro. All compounds showed near-neutral pKas (ranging 6.28\u20136.97), chemical shifts not overlapping those of phosphorus metabolites, and spectroscopic sensitivities (i.e., chemical shifts variation \u0394\u03b4ab between the acidic and basic forms) ranging from 9.2\u201310.7 ppm, being fourfold larger than conventional endogenous markers such as inorganic phosphate. X-ray crystallographic studies combined with predictive empirical relationships and ab initio calculations addressed the inductive and stereochemical effects of substituents linked to the protonated amine function. Satisfactory correlations were established between pKas and both the 2D structure and pyramidalization at phosphorus, showing that steric crowding around the phosphorus is crucial for modulating \u0394\u03b4ab. Finally, the hit 31P NMR pH probe 1b bearing an unsubstituted 1,3,2-dioxaphosphorinane ring, which is moderately lipophilic, nontoxic on A549 and NHLF cells, and showing pKa = 6.45 with \u0394\u03b4ab = 10.64 ppm, allowed the first clear-cut evidence of trans-sarcolemmal pH gradients in normoxic Dictyostelium discoideum cells with an accuracy of &lt;0.05 pH units.<\/jats:p>","DOI":"10.3390\/molecules27144506","type":"journal-article","created":{"date-parts":[[2022,7,15]],"date-time":"2022-07-15T01:57:11Z","timestamp":1657850231000},"page":"4506","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel Sterically Crowded and Conformationally Constrained \u03b1-Aminophosphonates with a Near-Neutral pKa as Highly Accurate 31P NMR pH Probes. Application to Subtle pH Gradients Determination in Dictyostelium discoideum Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"Caroline","family":"Delehedde","sequence":"first","affiliation":[{"name":"Aix Marseille Univ, CNRS, ICR, UMR 7273, SMBSO, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7255-7591","authenticated-orcid":false,"given":"Marcel","family":"Culcasi","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, CNRS, ICR, UMR 7273, SMBSO, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3950-0884","authenticated-orcid":false,"given":"Emilie","family":"Ricquebourg","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, CNRS, ICR, UMR 7273, SMBSO, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Cassien","sequence":"additional","affiliation":[{"name":"Yelen Analytics, 10 Boulevard Temp\u00eate, 13820 Ensu\u00e8s-la-Redonne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1561-7233","authenticated-orcid":false,"given":"Didier","family":"Siri","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, CNRS, ICR, UMR 7273, CT, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Blaive","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, CNRS, ICR, UMR 7273, SMBSO, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Pietri","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, CNRS, ICR, UMR 7273, SMBSO, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0924-1180","authenticated-orcid":false,"given":"Sophie","family":"Th\u00e9tiot-Laurent","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, CNRS, ICR, UMR 7273, SMBSO, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nrm2820","article-title":"Sensors and regulators of intracellular pH","volume":"11","author":"Casey","year":"2010","journal-title":"Nat. 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