Polyheteroaryl Oxazole/Pyridine-Based Compounds Selected in Vitro as G‑Quadruplex Ligands Inhibit Rock Kinase and Exhibit Antiproliferative Activity
Heptaheteroaryl compounds comprised of oxazole and pyridine units (TOxaPy) are quadruplex DNA (G4)-interactive compounds. Herein, we report on the synthesis of parent compounds bearing either amino side chains (TOxaPy-1–5) or featuring an isomeric oxazole-pyridine central connectivity (iso-TOxapy, i...
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| Veröffentlicht in: | Journal of medicinal chemistry 2018-12, Vol.61 (23), p.10502-10518 |
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| container_title | Journal of medicinal chemistry |
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| creator | Verga, Daniela N’Guyen, Chi-Hung Dakir, Malika Coll, Jean-Luc Teulade-Fichou, Marie-Paule Molla, Annie |
| description | Heptaheteroaryl compounds comprised of oxazole and pyridine units (TOxaPy) are quadruplex DNA (G4)-interactive compounds. Herein, we report on the synthesis of parent compounds bearing either amino side chains (TOxaPy-1–5) or featuring an isomeric oxazole-pyridine central connectivity (iso-TOxapy, iso-TOxapy 1–3) or a bipyridine core (iso-TOxabiPy). The new isomeric series showed significant G4-binding activity in vitro, and remarkably, three compounds (iso-TOxaPy, iso-TOxaPy-1, and iso-TOxabiPy) exhibited high antiproliferative activity toward a tumor panel of cancer cell lines. However, these compounds do not behave as typical G-quadruplex (G4) binders, and the kinase profiling assay revealed that the best antiproliferative molecule iso-TOxaPy selectively inhibited Rock-2. The targeting of Rock kinase was confirmed in cells by the dephosphorylation of Rock-2 substrates, the decrease of stress fibers, and peripheral focal adhesions, as well as the induction of long neurite-like extensions. Remarkably, two of these molecules were able to inhibit the growth of cells organized as spheroids. |
| doi_str_mv | 10.1021/acs.jmedchem.8b01023 |
| format | Article |
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Herein, we report on the synthesis of parent compounds bearing either amino side chains (TOxaPy-1–5) or featuring an isomeric oxazole-pyridine central connectivity (iso-TOxapy, iso-TOxapy 1–3) or a bipyridine core (iso-TOxabiPy). The new isomeric series showed significant G4-binding activity in vitro, and remarkably, three compounds (iso-TOxaPy, iso-TOxaPy-1, and iso-TOxabiPy) exhibited high antiproliferative activity toward a tumor panel of cancer cell lines. However, these compounds do not behave as typical G-quadruplex (G4) binders, and the kinase profiling assay revealed that the best antiproliferative molecule iso-TOxaPy selectively inhibited Rock-2. The targeting of Rock kinase was confirmed in cells by the dephosphorylation of Rock-2 substrates, the decrease of stress fibers, and peripheral focal adhesions, as well as the induction of long neurite-like extensions. Remarkably, two of these molecules were able to inhibit the growth of cells organized as spheroids.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.8b01023</identifier><identifier>PMID: 30457335</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Chemical Sciences ; Medicinal Chemistry ; Organic chemistry ; Other</subject><ispartof>Journal of medicinal chemistry, 2018-12, Vol.61 (23), p.10502-10518</ispartof><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a428t-20e3e0b20d53426bfe497a331c32372d58f3ff35ca4c8125eefbf19aa4ff0d5e3</citedby><cites>FETCH-LOGICAL-a428t-20e3e0b20d53426bfe497a331c32372d58f3ff35ca4c8125eefbf19aa4ff0d5e3</cites><orcidid>0000-0002-9859-8682 ; 0000-0002-2053-7513 ; 0000-0002-7555-6033</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.8b01023$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01023$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30457335$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-02392101$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Verga, Daniela</creatorcontrib><creatorcontrib>N’Guyen, Chi-Hung</creatorcontrib><creatorcontrib>Dakir, Malika</creatorcontrib><creatorcontrib>Coll, Jean-Luc</creatorcontrib><creatorcontrib>Teulade-Fichou, Marie-Paule</creatorcontrib><creatorcontrib>Molla, Annie</creatorcontrib><title>Polyheteroaryl Oxazole/Pyridine-Based Compounds Selected in Vitro as G‑Quadruplex Ligands Inhibit Rock Kinase and Exhibit Antiproliferative Activity</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Heptaheteroaryl compounds comprised of oxazole and pyridine units (TOxaPy) are quadruplex DNA (G4)-interactive compounds. Herein, we report on the synthesis of parent compounds bearing either amino side chains (TOxaPy-1–5) or featuring an isomeric oxazole-pyridine central connectivity (iso-TOxapy, iso-TOxapy 1–3) or a bipyridine core (iso-TOxabiPy). The new isomeric series showed significant G4-binding activity in vitro, and remarkably, three compounds (iso-TOxaPy, iso-TOxaPy-1, and iso-TOxabiPy) exhibited high antiproliferative activity toward a tumor panel of cancer cell lines. However, these compounds do not behave as typical G-quadruplex (G4) binders, and the kinase profiling assay revealed that the best antiproliferative molecule iso-TOxaPy selectively inhibited Rock-2. The targeting of Rock kinase was confirmed in cells by the dephosphorylation of Rock-2 substrates, the decrease of stress fibers, and peripheral focal adhesions, as well as the induction of long neurite-like extensions. 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Med. Chem</addtitle><date>2018-12-13</date><risdate>2018</risdate><volume>61</volume><issue>23</issue><spage>10502</spage><epage>10518</epage><pages>10502-10518</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Heptaheteroaryl compounds comprised of oxazole and pyridine units (TOxaPy) are quadruplex DNA (G4)-interactive compounds. Herein, we report on the synthesis of parent compounds bearing either amino side chains (TOxaPy-1–5) or featuring an isomeric oxazole-pyridine central connectivity (iso-TOxapy, iso-TOxapy 1–3) or a bipyridine core (iso-TOxabiPy). The new isomeric series showed significant G4-binding activity in vitro, and remarkably, three compounds (iso-TOxaPy, iso-TOxaPy-1, and iso-TOxabiPy) exhibited high antiproliferative activity toward a tumor panel of cancer cell lines. However, these compounds do not behave as typical G-quadruplex (G4) binders, and the kinase profiling assay revealed that the best antiproliferative molecule iso-TOxaPy selectively inhibited Rock-2. The targeting of Rock kinase was confirmed in cells by the dephosphorylation of Rock-2 substrates, the decrease of stress fibers, and peripheral focal adhesions, as well as the induction of long neurite-like extensions. Remarkably, two of these molecules were able to inhibit the growth of cells organized as spheroids.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>30457335</pmid><doi>10.1021/acs.jmedchem.8b01023</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-9859-8682</orcidid><orcidid>https://orcid.org/0000-0002-2053-7513</orcidid><orcidid>https://orcid.org/0000-0002-7555-6033</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Chemical Sciences Medicinal Chemistry Organic chemistry Other |
| title | Polyheteroaryl Oxazole/Pyridine-Based Compounds Selected in Vitro as G‑Quadruplex Ligands Inhibit Rock Kinase and Exhibit Antiproliferative Activity |
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