{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T17:11:51Z","timestamp":1778087511001,"version":"3.51.4"},"reference-count":20,"publisher":"Elsevier BV","issue":"9","license":[{"start":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T00:00:00Z","timestamp":1588291200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T00:00:00Z","timestamp":1588291200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T00:00:00Z","timestamp":1588291200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T00:00:00Z","timestamp":1588291200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T00:00:00Z","timestamp":1588291200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T00:00:00Z","timestamp":1588291200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T00:00:00Z","timestamp":1588291200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Bioorganic & Medicinal Chemistry Letters"],"published-print":{"date-parts":[[2020,5]]},"DOI":"10.1016\/j.bmcl.2019.126933","type":"journal-article","created":{"date-parts":[[2020,1,2]],"date-time":"2020-01-02T12:14:36Z","timestamp":1577967276000},"page":"126933","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":2,"title":["Second basic pKa: An overlooked parameter in predicting phospholipidosis-inducing potential of diamines"],"prefix":"10.1016","volume":"30","author":[{"given":"Hiroki","family":"Sakai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidekazu","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Murata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuya","family":"Toba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naohiro","family":"Takemoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahiro","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeo","family":"Kawabata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.bmcl.2019.126933_h0005","first-page":"1","volume":"2","author":"Benjamin","year":"2018","journal-title":"Clin Neurol Neurosci"},{"key":"10.1016\/j.bmcl.2019.126933_h0010","doi-asserted-by":"crossref","first-page":"2332","DOI":"10.1016\/j.bmcl.2019.06.016","volume":"29","author":"Sakai","year":"2019","journal-title":"Bioorg Med Chem Lett"},{"key":"10.1016\/j.bmcl.2019.126933_b0010","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/7355_2013_34","volume":"9","author":"Hanumegowda","year":"2015","journal-title":"Top Med Chem"},{"key":"10.1016\/j.bmcl.2019.126933_b0015","unstructured":"See ref. 2 and references therein."},{"key":"10.1016\/j.bmcl.2019.126933_b0020","doi-asserted-by":"crossref","unstructured":"According to Ploemen\u2019s model, PLIP is predicted to be positive if (most basic pKa)2 + (ClogP)2 \u2265 90 and most basic pKa \u2265 8 and ClogP \u2265 1. It is predicted to be negative if even one of these requirements is not satisfied. Ploemen JP, Kelder J, Hafmans T, van de Sandt H, van Burgsteden JA, Salemink PJ, van Esch E. Exp Toxicol Pathol. 2004;55:347.","DOI":"10.1078\/0940-2993-00338"},{"key":"10.1016\/j.bmcl.2019.126933_b0025","doi-asserted-by":"crossref","unstructured":"Compounds with NC equal to 1.0 are more likely to cause phospholipidosis as ClogP increases. For those with NC above 1.0, phospholipidosis is induced regardless of ClogP. Tomizawa K, Sugano K, Yamada H, Horii I. J. Toxicol. Sci. 2006;31:315.","DOI":"10.2131\/jts.31.315"},{"key":"10.1016\/j.bmcl.2019.126933_b0030","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1093\/toxsci\/kfj067","volume":"90","author":"Kasahara","year":"2006","journal-title":"Toxicol Sci"},{"key":"10.1016\/j.bmcl.2019.126933_b0035","unstructured":"The stoichiometric ratio of amine and HCl has not been experimentally determined. We however consider that all basic nitrogen atoms are protonated under strong acidic conditions because previous studies have confirmed by elemental analysis that diamines form dihydrochloride when treated with hydrochloric acid(a) or saturated solution of hydrogen chloride in ethanol.(b),(c) (a) Reiter J, Trinka P, Bartha FL, Pongo L, Volk B, Simig G. Org Process Res Dev. 2012;16:1279. (b) Veselov IS, Trushkov IV, Zefirov NS, Grishina GV. Russ J Org Chem. 2009;45:1050. (c) Ganina OG, Veselov IS, Grishina GV, Fedorov AY, Beletskaya IP. Russ Chem Bull, Int Ed. 2006;55:1642."},{"key":"10.1016\/j.bmcl.2019.126933_b0040","unstructured":"Culture media used in the PLIP assay contains inorganic salts such as sodium bicarbonate or disodium phosphate, which compose acid-base buffering systems to keep the pH constant. The media also contains Phenol Red as a pH indicator. We have confirmed that the color of the media didn\u2019t change significantly between when free base was used and when HCl salt was used, indicating the difference between free base and HCl salt does not affect physiological pH of evaluated conditions. Detailed assay conditions are described in the supplementary material."},{"key":"10.1016\/j.bmcl.2019.126933_b0045","unstructured":"Diamines have two basic pKa. The first and second basic pKa of diamines are expressed as pKa1 and pKa2, respectively (see the scheme below). Unless otherwise noted, pKa values were calculated using ADMET predictor, Simulation.plus.inc. Version 7.2.0001."},{"key":"10.1016\/j.bmcl.2019.126933_b0050","doi-asserted-by":"crossref","unstructured":"In addition to Ploemen\u2019s model (see ref. 4) and Tomizawa\u2019s model (see ref. 5), modified Ploemen\u2019s model was used. Pelletier DJ, Gehlhaar D, Tilloy-Ellul A, Johnson TO, Greene N. J Chem Inf Model. 2007;47:1196.","DOI":"10.1021\/ci6004542"},{"key":"10.1016\/j.bmcl.2019.126933_b0055","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1002\/cmdc.200700059","volume":"2","author":"Morgenthaler","year":"2007","journal-title":"ChemMedChem"},{"key":"10.1016\/j.bmcl.2019.126933_b0060","unstructured":"The protonation behaviors are simulated by ADMET predictor, version 7.2.0001. All pKa1 and pKa2 values listed in Table 1 to 5 have been specified as shown in Figure 4."},{"key":"10.1016\/j.bmcl.2019.126933_b0065","unstructured":"Even though the basicities of two nitrogen atoms are similar to each other, pKa1 and pKa2 values are not necessarily close to each other. This is because pKa1 and pKa2 values do not represent the basicity of a particular nitrogen atom but the pH at which the whole positive charge of the compound is 0.5 or 1.5, respectively."},{"key":"10.1016\/j.bmcl.2019.126933_b0070","unstructured":"Experimentally measured pKa values, cited from the tabulation at http:\/\/www.zirchrom.com\/organic.htm and references therein. [Accessed: 1-Sep-2019]."},{"key":"10.1016\/j.bmcl.2019.126933_h0080","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0005-2736(97)00145-4","volume":"1330","author":"Andrew","year":"1997","journal-title":"Biochim Biophys Acta"},{"key":"10.1016\/j.bmcl.2019.126933_h0085","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1083\/jcb.90.3.656","volume":"90","author":"Ohkuma","year":"1981","journal-title":"J Cell Biol"},{"key":"10.1016\/j.bmcl.2019.126933_b0080","doi-asserted-by":"crossref","first-page":"5506","DOI":"10.1021\/cr100352k","volume":"111","author":"Grygorenko","year":"2011","journal-title":"Chem Rev"},{"key":"10.1016\/j.bmcl.2019.126933_b0085","unstructured":"http:\/\/www.enamine.net\/download\/catalogs\/Enamine_BicyclicAmines_2014.pdf [Accessed: 1-Sep-2019]."},{"key":"10.1016\/j.bmcl.2019.126933_b0090","doi-asserted-by":"crossref","first-page":"3451","DOI":"10.1021\/jm200187y","volume":"54","author":"Roughley","year":"2011","journal-title":"J Med Chem"}],"updated-by":[{"DOI":"10.1016\/j.bmcl.2020.127422","type":"erratum","label":"Erratum","source":"publisher","updated":{"date-parts":[[2020,9,15]],"date-time":"2020-09-15T00:00:00Z","timestamp":1600128000000}}],"container-title":["Bioorganic & Medicinal Chemistry Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0960894X19309163?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0960894X19309163?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T16:21:26Z","timestamp":1778084486000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0960894X19309163"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5]]},"references-count":20,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2020,5]]}},"alternative-id":["S0960894X19309163"],"URL":"https:\/\/doi.org\/10.1016\/j.bmcl.2019.126933","relation":{},"ISSN":["0960-894X"],"issn-type":[{"value":"0960-894X","type":"print"}],"subject":[],"published":{"date-parts":[[2020,5]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Second basic pKa: An overlooked parameter in predicting phospholipidosis-inducing potential of diamines","name":"articletitle","label":"Article Title"},{"value":"Bioorganic & Medicinal Chemistry Letters","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.bmcl.2019.126933","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2019 Elsevier Ltd. 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