Oxaliplatin and [Pt(R,R-DACH)(panobinostat-2H)] show nanomolar cytotoxicity towards diffuse intrinsic pontine glioma (DIPG)
<p>We report the synthesis of two novel platinum(<small>II</small>) complexes which incorporate histone deacetylase (HDAC) inhibitors: [Pt<small><sup>II</sup></small>(<em>R</em>,<em>R</em>-DACH)(Sub<small><sub>-H</sub&g...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
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Royal Society of Chemistry
2020
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| _version_ | 1826277919376277504 |
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| author | Boulet, MHC Marsh, LK Howarth, A Woolman, A Farrer, NJ |
| author_facet | Boulet, MHC Marsh, LK Howarth, A Woolman, A Farrer, NJ |
| author_sort | Boulet, MHC |
| collection | OXFORD |
| description | <p>We report the synthesis of two novel platinum(<small>II</small>) complexes which incorporate histone deacetylase (HDAC) inhibitors: [Pt<small><sup>II</sup></small>(<em>R</em>,<em>R</em>-DACH)(Sub<small><sub>-H</sub></small>)] (<strong>1</strong>), [Pt<small><sup>II</sup></small>(<em>R</em>,<em>R</em>-DACH)(panobinostat<small><sub>-2H</sub></small>)] (<strong>2</strong>), where SubH = suberoyl-bis-hydroxamic acid; DACH = (1<em>R</em>,2<em>R</em>)-(–)-1,2-diaminocyclohexane and panobinostat = (<em>E</em>)-<em>N</em>-hydroxy-3-[4-[[2-(2-methyl-1<em>H</em>-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enamide. Complexes <strong>1</strong> and <strong>2</strong> were characterised by <small><sup>1</sup></small>H, <small><sup>13</sup></small>C, <small><sup>195</sup></small>Pt NMR spectroscopy and ESI-MS. Whilst oxaliplatin demonstrated considerable cytotoxicity in two patient-derived low-passage paediatric glioma DIPG cell lines (IC<small><sub>50</sub></small> values of 0.333 μM in SU-DIPG-IV, and 0.135 μM in SU-DIPG-XXI), complex <strong>2</strong> showed even greater cytotoxicities, with IC<small><sub>50</sub></small> values of 0.021 μM (SU-DIPG-IV), 0.067 μM (BIOMEDE 194) and 0.009 μM (SU-DIPG-XXI). Complex <strong>2</strong> also demonstrated superior aqueous solubility in comparison to panobinostat. Complex <strong>2</strong> released free intact panobinostat under HPLC conditions, as determined by ESI-MS. Incubation of solutions of oxaliplatin (H<small><sub>2</sub></small>O) and panobinostat (DMF) resulted in instantaneous reactivity and precipitation of a panobinostat derivative which was not a platinum complex; the same reactivity was not observed between carboplatin and panobinostat.</p> |
| first_indexed | 2024-03-06T23:36:09Z |
| format | Journal article |
| id | oxford-uuid:6dbc187d-e203-405d-86bc-1a938bc910fb |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:36:09Z |
| publishDate | 2020 |
| publisher | Royal Society of Chemistry |
| record_format | dspace |
| spelling | oxford-uuid:6dbc187d-e203-405d-86bc-1a938bc910fb2022-03-26T19:19:43ZOxaliplatin and [Pt(R,R-DACH)(panobinostat-2H)] show nanomolar cytotoxicity towards diffuse intrinsic pontine glioma (DIPG)Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6dbc187d-e203-405d-86bc-1a938bc910fbEnglishSymplectic ElementsRoyal Society of Chemistry2020Boulet, MHCMarsh, LKHowarth, AWoolman, AFarrer, NJ<p>We report the synthesis of two novel platinum(<small>II</small>) complexes which incorporate histone deacetylase (HDAC) inhibitors: [Pt<small><sup>II</sup></small>(<em>R</em>,<em>R</em>-DACH)(Sub<small><sub>-H</sub></small>)] (<strong>1</strong>), [Pt<small><sup>II</sup></small>(<em>R</em>,<em>R</em>-DACH)(panobinostat<small><sub>-2H</sub></small>)] (<strong>2</strong>), where SubH = suberoyl-bis-hydroxamic acid; DACH = (1<em>R</em>,2<em>R</em>)-(–)-1,2-diaminocyclohexane and panobinostat = (<em>E</em>)-<em>N</em>-hydroxy-3-[4-[[2-(2-methyl-1<em>H</em>-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enamide. Complexes <strong>1</strong> and <strong>2</strong> were characterised by <small><sup>1</sup></small>H, <small><sup>13</sup></small>C, <small><sup>195</sup></small>Pt NMR spectroscopy and ESI-MS. Whilst oxaliplatin demonstrated considerable cytotoxicity in two patient-derived low-passage paediatric glioma DIPG cell lines (IC<small><sub>50</sub></small> values of 0.333 μM in SU-DIPG-IV, and 0.135 μM in SU-DIPG-XXI), complex <strong>2</strong> showed even greater cytotoxicities, with IC<small><sub>50</sub></small> values of 0.021 μM (SU-DIPG-IV), 0.067 μM (BIOMEDE 194) and 0.009 μM (SU-DIPG-XXI). Complex <strong>2</strong> also demonstrated superior aqueous solubility in comparison to panobinostat. Complex <strong>2</strong> released free intact panobinostat under HPLC conditions, as determined by ESI-MS. Incubation of solutions of oxaliplatin (H<small><sub>2</sub></small>O) and panobinostat (DMF) resulted in instantaneous reactivity and precipitation of a panobinostat derivative which was not a platinum complex; the same reactivity was not observed between carboplatin and panobinostat.</p> |
| spellingShingle | Boulet, MHC Marsh, LK Howarth, A Woolman, A Farrer, NJ Oxaliplatin and [Pt(R,R-DACH)(panobinostat-2H)] show nanomolar cytotoxicity towards diffuse intrinsic pontine glioma (DIPG) |
| title | Oxaliplatin and [Pt(R,R-DACH)(panobinostat-2H)] show nanomolar cytotoxicity towards diffuse intrinsic pontine glioma (DIPG) |
| title_full | Oxaliplatin and [Pt(R,R-DACH)(panobinostat-2H)] show nanomolar cytotoxicity towards diffuse intrinsic pontine glioma (DIPG) |
| title_fullStr | Oxaliplatin and [Pt(R,R-DACH)(panobinostat-2H)] show nanomolar cytotoxicity towards diffuse intrinsic pontine glioma (DIPG) |
| title_full_unstemmed | Oxaliplatin and [Pt(R,R-DACH)(panobinostat-2H)] show nanomolar cytotoxicity towards diffuse intrinsic pontine glioma (DIPG) |
| title_short | Oxaliplatin and [Pt(R,R-DACH)(panobinostat-2H)] show nanomolar cytotoxicity towards diffuse intrinsic pontine glioma (DIPG) |
| title_sort | oxaliplatin and pt r r dach panobinostat 2h show nanomolar cytotoxicity towards diffuse intrinsic pontine glioma dipg |
| work_keys_str_mv | AT bouletmhc oxaliplatinandptrrdachpanobinostat2hshownanomolarcytotoxicitytowardsdiffuseintrinsicpontinegliomadipg AT marshlk oxaliplatinandptrrdachpanobinostat2hshownanomolarcytotoxicitytowardsdiffuseintrinsicpontinegliomadipg AT howartha oxaliplatinandptrrdachpanobinostat2hshownanomolarcytotoxicitytowardsdiffuseintrinsicpontinegliomadipg AT woolmana oxaliplatinandptrrdachpanobinostat2hshownanomolarcytotoxicitytowardsdiffuseintrinsicpontinegliomadipg AT farrernj oxaliplatinandptrrdachpanobinostat2hshownanomolarcytotoxicitytowardsdiffuseintrinsicpontinegliomadipg |