Estimating the hydrophobicity extent of molecular fragments using reversed-phase liquid chromatography
A fast HPLC method was developed to study the hydrophobicity extent of pharmaceutically relevant molecular fragments. By this strategy, the reduced amount of sample available for physico-chemical evaluations in early-phase drug discovery programs does not represent a limiting factor. The sixteen aci...
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| Veröffentlicht in: | Journal of separation science 2023-09, Vol.46 (18), p.e2300346-e2300346 |
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| creator | Carotti, Andrea Varfaj, Ina Pruscini, Ilaria Abualzulof, Ghaid W A Mercolini, Laura Bianconi, Elisa Macchiarulo, Antonio Camaioni, Emidio Sardella, Roccaldo |
| description | A fast HPLC method was developed to study the hydrophobicity extent of pharmaceutically relevant molecular fragments. By this strategy, the reduced amount of sample available for physico-chemical evaluations in early-phase drug discovery programs does not represent a limiting factor. The sixteen acid fragments investigated were previously synthesized also determining potentiometrically their experimental log D values. For four fragments it was not possible to determine such property since their values were outside of the instrumental working range (2 |
| doi_str_mv | 10.1002/jssc.202300346 |
| format | Article |
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< 12). An RP-HPLC method was therefore optimized. For each scrutinized method, some derived chromatographic indices were calculated, and Pearson's correlation coefficient (r) allowed to select the so-called "φ
index" as the best correlating with the log D. The
was fixed at 3.5 and a modification of some variables [organic modifier (methanol vs. ACN), stationary phase (octyl vs. octadecyl), presence/absence of the additives n-octanol, n-butylamine, and n-octylamine], allowed to select the best correlation conditions, producing a r = 0.94 (p < 0.001). Importantly, the φ
index enabled the estimation of log D values for four fragments which were unattainable by potentiometric titration. Moreover, a series of molecular descriptors were calculated to identify the chemical characteristics of the fragments explaining the obtained φ
. The number of hydrogen bond donors and the index of cohesive interaction correlated with the experimental data.</description><identifier>ISSN: 1615-9306</identifier><identifier>EISSN: 1615-9314</identifier><identifier>DOI: 10.1002/jssc.202300346</identifier><identifier>PMID: 37438993</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Additives ; Correlation coefficients ; Estimation ; Fragments ; High performance liquid chromatography ; Hydrogen bonds ; Hydrophobicity ; Mathematical analysis ; Octanol ; Titration</subject><ispartof>Journal of separation science, 2023-09, Vol.46 (18), p.e2300346-e2300346</ispartof><rights>2023 The Authors. Journal of Separation Science published by Wiley-VCH GmbH.</rights><rights>2023. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c318t-769f08620d189484a8bf0d7fd65587e5d53abb566157bc186a0080908fbe366d3</cites><orcidid>0000-0001-9856-0230 ; 0000-0002-0644-9461</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,778,782,27907,27908</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37438993$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Carotti, Andrea</creatorcontrib><creatorcontrib>Varfaj, Ina</creatorcontrib><creatorcontrib>Pruscini, Ilaria</creatorcontrib><creatorcontrib>Abualzulof, Ghaid W A</creatorcontrib><creatorcontrib>Mercolini, Laura</creatorcontrib><creatorcontrib>Bianconi, Elisa</creatorcontrib><creatorcontrib>Macchiarulo, Antonio</creatorcontrib><creatorcontrib>Camaioni, Emidio</creatorcontrib><creatorcontrib>Sardella, Roccaldo</creatorcontrib><title>Estimating the hydrophobicity extent of molecular fragments using reversed-phase liquid chromatography</title><title>Journal of separation science</title><addtitle>J Sep Sci</addtitle><description>A fast HPLC method was developed to study the hydrophobicity extent of pharmaceutically relevant molecular fragments. By this strategy, the reduced amount of sample available for physico-chemical evaluations in early-phase drug discovery programs does not represent a limiting factor. The sixteen acid fragments investigated were previously synthesized also determining potentiometrically their experimental log D values. For four fragments it was not possible to determine such property since their values were outside of the instrumental working range (2 < pK
< 12). An RP-HPLC method was therefore optimized. For each scrutinized method, some derived chromatographic indices were calculated, and Pearson's correlation coefficient (r) allowed to select the so-called "φ
index" as the best correlating with the log D. The
was fixed at 3.5 and a modification of some variables [organic modifier (methanol vs. ACN), stationary phase (octyl vs. octadecyl), presence/absence of the additives n-octanol, n-butylamine, and n-octylamine], allowed to select the best correlation conditions, producing a r = 0.94 (p < 0.001). Importantly, the φ
index enabled the estimation of log D values for four fragments which were unattainable by potentiometric titration. Moreover, a series of molecular descriptors were calculated to identify the chemical characteristics of the fragments explaining the obtained φ
. The number of hydrogen bond donors and the index of cohesive interaction correlated with the experimental data.</description><subject>Additives</subject><subject>Correlation coefficients</subject><subject>Estimation</subject><subject>Fragments</subject><subject>High performance liquid chromatography</subject><subject>Hydrogen bonds</subject><subject>Hydrophobicity</subject><subject>Mathematical analysis</subject><subject>Octanol</subject><subject>Titration</subject><issn>1615-9306</issn><issn>1615-9314</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNpdkb1PwzAQxS0EoqWwMiJLLCwp5zjxx4hQ-ZAqscAcObHdpErq1E4Q_e9x1dKB6U6n3z3dvYfQLYE5AUgf1yFU8xRSCkAzdoamhJE8kZRk56ce2ARdhbAGIFxIuEQTyjMqpKRTZBdhaDo1NJsVHmqD6532rq9d2VTNsMPmZzCbATuLO9eaamyVx9arVRenAY9hv-bNt_HB6KSvVTC4bbZjo3FVexd13cqrvt5dowur2mBujnWGvl4Wn89vyfLj9f35aZlUlIgh4UxaECwFTYTMRKZEaUFzq1meC25ynVNVljmLf_GyIoIpAAEShC0NZUzTGXo46PbebUcThqJrQmXaVm2MG0ORCsoE5ymDiN7_Q9du9Jt4XaQYl0SKaOsMzQ9U5V0I3tii99EvvysIFPsEin0CxSmBuHB3lB3LzugT_mc5_QWLkYLh</recordid><startdate>20230901</startdate><enddate>20230901</enddate><creator>Carotti, Andrea</creator><creator>Varfaj, Ina</creator><creator>Pruscini, Ilaria</creator><creator>Abualzulof, Ghaid W A</creator><creator>Mercolini, Laura</creator><creator>Bianconi, Elisa</creator><creator>Macchiarulo, Antonio</creator><creator>Camaioni, Emidio</creator><creator>Sardella, Roccaldo</creator><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U5</scope><scope>8FD</scope><scope>L7M</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-9856-0230</orcidid><orcidid>https://orcid.org/0000-0002-0644-9461</orcidid></search><sort><creationdate>20230901</creationdate><title>Estimating the hydrophobicity extent of molecular fragments using reversed-phase liquid chromatography</title><author>Carotti, Andrea ; Varfaj, Ina ; Pruscini, Ilaria ; Abualzulof, Ghaid W A ; Mercolini, Laura ; Bianconi, Elisa ; Macchiarulo, Antonio ; Camaioni, Emidio ; Sardella, Roccaldo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c318t-769f08620d189484a8bf0d7fd65587e5d53abb566157bc186a0080908fbe366d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Additives</topic><topic>Correlation coefficients</topic><topic>Estimation</topic><topic>Fragments</topic><topic>High performance liquid chromatography</topic><topic>Hydrogen bonds</topic><topic>Hydrophobicity</topic><topic>Mathematical analysis</topic><topic>Octanol</topic><topic>Titration</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Carotti, Andrea</creatorcontrib><creatorcontrib>Varfaj, Ina</creatorcontrib><creatorcontrib>Pruscini, Ilaria</creatorcontrib><creatorcontrib>Abualzulof, Ghaid W A</creatorcontrib><creatorcontrib>Mercolini, Laura</creatorcontrib><creatorcontrib>Bianconi, Elisa</creatorcontrib><creatorcontrib>Macchiarulo, Antonio</creatorcontrib><creatorcontrib>Camaioni, Emidio</creatorcontrib><creatorcontrib>Sardella, Roccaldo</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Technology Research Database</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of separation science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Carotti, Andrea</au><au>Varfaj, Ina</au><au>Pruscini, Ilaria</au><au>Abualzulof, Ghaid W A</au><au>Mercolini, Laura</au><au>Bianconi, Elisa</au><au>Macchiarulo, Antonio</au><au>Camaioni, Emidio</au><au>Sardella, Roccaldo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Estimating the hydrophobicity extent of molecular fragments using reversed-phase liquid chromatography</atitle><jtitle>Journal of separation science</jtitle><addtitle>J Sep Sci</addtitle><date>2023-09-01</date><risdate>2023</risdate><volume>46</volume><issue>18</issue><spage>e2300346</spage><epage>e2300346</epage><pages>e2300346-e2300346</pages><issn>1615-9306</issn><eissn>1615-9314</eissn><abstract>A fast HPLC method was developed to study the hydrophobicity extent of pharmaceutically relevant molecular fragments. By this strategy, the reduced amount of sample available for physico-chemical evaluations in early-phase drug discovery programs does not represent a limiting factor. The sixteen acid fragments investigated were previously synthesized also determining potentiometrically their experimental log D values. For four fragments it was not possible to determine such property since their values were outside of the instrumental working range (2 < pK
< 12). An RP-HPLC method was therefore optimized. For each scrutinized method, some derived chromatographic indices were calculated, and Pearson's correlation coefficient (r) allowed to select the so-called "φ
index" as the best correlating with the log D. The
was fixed at 3.5 and a modification of some variables [organic modifier (methanol vs. ACN), stationary phase (octyl vs. octadecyl), presence/absence of the additives n-octanol, n-butylamine, and n-octylamine], allowed to select the best correlation conditions, producing a r = 0.94 (p < 0.001). Importantly, the φ
index enabled the estimation of log D values for four fragments which were unattainable by potentiometric titration. Moreover, a series of molecular descriptors were calculated to identify the chemical characteristics of the fragments explaining the obtained φ
. The number of hydrogen bond donors and the index of cohesive interaction correlated with the experimental data.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>37438993</pmid><doi>10.1002/jssc.202300346</doi><orcidid>https://orcid.org/0000-0001-9856-0230</orcidid><orcidid>https://orcid.org/0000-0002-0644-9461</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Additives Correlation coefficients Estimation Fragments High performance liquid chromatography Hydrogen bonds Hydrophobicity Mathematical analysis Octanol Titration |
| title | Estimating the hydrophobicity extent of molecular fragments using reversed-phase liquid chromatography |
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