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The conjugates of 5′-deoxy-5-fluorocytidine and hydroxycinnamic acids - synthesis, anti-pancreatic cancer activity and molecular docking studies
New amide conjugates 1-6 of hydroxycinnamic acids (HCA) and 5′-deoxy-5-fluorocytidine (5-dFCR), the prodrug of 5-fluorouracil (5-FU), were synthesized and tested in vitro against pancreatic cancer lines (PDAC). The compounds showed slightly higher efficacy against primary BxPC-3 cells (IC 50 values...
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| Published in: | RSC advances 2024-04, Vol.14 (19), p.13129-13141 |
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| container_title | RSC advances |
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| creator | Cybulski, Marcin Zaremba-Czogalla, Magdalena Trzaskowski, Bartosz Kubiszewski, Marek Tobiasz, Joanna Jaromin, Anna Krzeczy ski, Piotr Gubernator, Jerzy Michalak, Olga |
| description | New amide conjugates
1-6
of hydroxycinnamic acids (HCA) and 5′-deoxy-5-fluorocytidine (5-dFCR), the prodrug of 5-fluorouracil (5-FU), were synthesized and tested
in vitro
against pancreatic cancer lines (PDAC). The compounds showed slightly higher efficacy against primary BxPC-3 cells (IC
50
values of 14-45 μM) than against metastatic AsPC-1 (IC
50
values of 37-133 μM), and similar to that of 5-FU for both PDAC lines. Compound
1
, which has a
para
-(acetyloxy)coumaroyl substituent, was found to be the most potent (IC
50
= 14 μM) with a selectivity index of approximately 7 to normal dermal fibroblasts (IC
50
= 96 μM). The potential pharmacological profiles were discussed on the basis of the ADME data. Docking to the carboxylesterase CES2 showed that the synthesized compounds have the ability to bind
via
hydrogen bonding between a specific acetate group of the sugar moiety and Ser228, which belongs to the catalytic triad that causes hydrolysis. Docking to albumin, a major transport protein in the circulatory system, revealed a strong interaction of the conjugates at the binding site which is native to warfarin and responsible for its transport in the body.
New conjugates
1-6
containing 5-dFCR and selected hydroxycinnamic acids were synthesized and tested
in vitro
against pancreatic cancer (PDAC) lines. The ADME properties and molecular docking to CES2 or human albumin were discussed. |
| doi_str_mv | 10.1039/d4ra01683a |
| format | article |
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1-6
of hydroxycinnamic acids (HCA) and 5′-deoxy-5-fluorocytidine (5-dFCR), the prodrug of 5-fluorouracil (5-FU), were synthesized and tested
in vitro
against pancreatic cancer lines (PDAC). The compounds showed slightly higher efficacy against primary BxPC-3 cells (IC
50
values of 14-45 μM) than against metastatic AsPC-1 (IC
50
values of 37-133 μM), and similar to that of 5-FU for both PDAC lines. Compound
1
, which has a
para
-(acetyloxy)coumaroyl substituent, was found to be the most potent (IC
50
= 14 μM) with a selectivity index of approximately 7 to normal dermal fibroblasts (IC
50
= 96 μM). The potential pharmacological profiles were discussed on the basis of the ADME data. Docking to the carboxylesterase CES2 showed that the synthesized compounds have the ability to bind
via
hydrogen bonding between a specific acetate group of the sugar moiety and Ser228, which belongs to the catalytic triad that causes hydrolysis. Docking to albumin, a major transport protein in the circulatory system, revealed a strong interaction of the conjugates at the binding site which is native to warfarin and responsible for its transport in the body.
New conjugates
1-6
containing 5-dFCR and selected hydroxycinnamic acids were synthesized and tested
in vitro
against pancreatic cancer (PDAC) lines. The ADME properties and molecular docking to CES2 or human albumin were discussed.</description><identifier>ISSN: 2046-2069</identifier><identifier>EISSN: 2046-2069</identifier><identifier>DOI: 10.1039/d4ra01683a</identifier><identifier>PMID: 38655481</identifier><language>eng</language><publisher>England: Royal Society of Chemistry</publisher><subject>Binding sites ; Cancer ; Chemical synthesis ; Chemistry ; Circulatory system ; Conjugates ; Hydrogen bonding ; Hydroxycinnamic acid ; Molecular docking ; Pancreatic cancer</subject><ispartof>RSC advances, 2024-04, Vol.14 (19), p.13129-13141</ispartof><rights>This journal is © The Royal Society of Chemistry.</rights><rights>Copyright Royal Society of Chemistry 2024</rights><rights>This journal is © The Royal Society of Chemistry 2024 The Royal Society of Chemistry</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c388t-8d02e3e363581bf80c6671a99cdf470bbc2cf2c7100eff4b592dbd6a483890833</cites><orcidid>0000-0001-5925-8178 ; 0000-0002-4560-9317 ; 0000-0003-0182-7299 ; 0000-0002-7921-8007 ; 0000-0002-1067-4223 ; 0000-0003-2385-1476 ; 0000-0002-6144-2211 ; 0000-0002-4978-5887</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11036175/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11036175/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38655481$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cybulski, Marcin</creatorcontrib><creatorcontrib>Zaremba-Czogalla, Magdalena</creatorcontrib><creatorcontrib>Trzaskowski, Bartosz</creatorcontrib><creatorcontrib>Kubiszewski, Marek</creatorcontrib><creatorcontrib>Tobiasz, Joanna</creatorcontrib><creatorcontrib>Jaromin, Anna</creatorcontrib><creatorcontrib>Krzeczy ski, Piotr</creatorcontrib><creatorcontrib>Gubernator, Jerzy</creatorcontrib><creatorcontrib>Michalak, Olga</creatorcontrib><title>The conjugates of 5′-deoxy-5-fluorocytidine and hydroxycinnamic acids - synthesis, anti-pancreatic cancer activity and molecular docking studies</title><title>RSC advances</title><addtitle>RSC Adv</addtitle><description>New amide conjugates
1-6
of hydroxycinnamic acids (HCA) and 5′-deoxy-5-fluorocytidine (5-dFCR), the prodrug of 5-fluorouracil (5-FU), were synthesized and tested
in vitro
against pancreatic cancer lines (PDAC). The compounds showed slightly higher efficacy against primary BxPC-3 cells (IC
50
values of 14-45 μM) than against metastatic AsPC-1 (IC
50
values of 37-133 μM), and similar to that of 5-FU for both PDAC lines. Compound
1
, which has a
para
-(acetyloxy)coumaroyl substituent, was found to be the most potent (IC
50
= 14 μM) with a selectivity index of approximately 7 to normal dermal fibroblasts (IC
50
= 96 μM). The potential pharmacological profiles were discussed on the basis of the ADME data. Docking to the carboxylesterase CES2 showed that the synthesized compounds have the ability to bind
via
hydrogen bonding between a specific acetate group of the sugar moiety and Ser228, which belongs to the catalytic triad that causes hydrolysis. Docking to albumin, a major transport protein in the circulatory system, revealed a strong interaction of the conjugates at the binding site which is native to warfarin and responsible for its transport in the body.
New conjugates
1-6
containing 5-dFCR and selected hydroxycinnamic acids were synthesized and tested
in vitro
against pancreatic cancer (PDAC) lines. The ADME properties and molecular docking to CES2 or human albumin were discussed.</description><subject>Binding sites</subject><subject>Cancer</subject><subject>Chemical synthesis</subject><subject>Chemistry</subject><subject>Circulatory system</subject><subject>Conjugates</subject><subject>Hydrogen bonding</subject><subject>Hydroxycinnamic acid</subject><subject>Molecular docking</subject><subject>Pancreatic cancer</subject><issn>2046-2069</issn><issn>2046-2069</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNpdks9u1DAQxiMEolXphTvIEheECNhx4nVOaFXKH6kSEirnyBmPd70k9mI7FbnxDDwKj9QnwdstS8GXGen76fPY3xTFY0ZfMcrb17oOijIhubpXHFe0FmVFRXv_Tn9UnMa4ofmIhlWCPSyOuBRNU0t2XPy8XCMB7zbTSiWMxBvSXP_4VWr03-eyKc0w-eBhTlZbh0Q5TdazDlkE65waLRAFVkdSkji7tMZo48uMJVtulYOAKmUEcoshk8le2TTf2Ix-QJgGFYj28NW6FYlp0hbjo-KBUUPE09t6Unx5d3559qG8-PT-49nyogQuZSqlphVy5II3kvVGUhBiwVTbgjb1gvY9VGAqWDBK0Zi6b9pK91qoWnLZUsn5SfFm77ud-hE1oEtBDd022FGFufPKdv8qzq67lb_qWP54wRZNdnh-6xD8twlj6kYbAYdBOfRT7HiOoGFS0N1lz_5DN34KLr9vR7UVzXG0mXqxpyD4GAOawzSMdru4u7f15-VN3MsMP707_wH9E24GnuyBEOGg_t0X_hvxHbMF</recordid><startdate>20240422</startdate><enddate>20240422</enddate><creator>Cybulski, Marcin</creator><creator>Zaremba-Czogalla, Magdalena</creator><creator>Trzaskowski, Bartosz</creator><creator>Kubiszewski, Marek</creator><creator>Tobiasz, Joanna</creator><creator>Jaromin, Anna</creator><creator>Krzeczy ski, Piotr</creator><creator>Gubernator, Jerzy</creator><creator>Michalak, Olga</creator><general>Royal Society of Chemistry</general><general>The Royal Society of Chemistry</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SR</scope><scope>8BQ</scope><scope>8FD</scope><scope>JG9</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5925-8178</orcidid><orcidid>https://orcid.org/0000-0002-4560-9317</orcidid><orcidid>https://orcid.org/0000-0003-0182-7299</orcidid><orcidid>https://orcid.org/0000-0002-7921-8007</orcidid><orcidid>https://orcid.org/0000-0002-1067-4223</orcidid><orcidid>https://orcid.org/0000-0003-2385-1476</orcidid><orcidid>https://orcid.org/0000-0002-6144-2211</orcidid><orcidid>https://orcid.org/0000-0002-4978-5887</orcidid></search><sort><creationdate>20240422</creationdate><title>The conjugates of 5′-deoxy-5-fluorocytidine and hydroxycinnamic acids - synthesis, anti-pancreatic cancer activity and molecular docking studies</title><author>Cybulski, Marcin ; Zaremba-Czogalla, Magdalena ; Trzaskowski, Bartosz ; Kubiszewski, Marek ; Tobiasz, Joanna ; Jaromin, Anna ; Krzeczy ski, Piotr ; Gubernator, Jerzy ; Michalak, Olga</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c388t-8d02e3e363581bf80c6671a99cdf470bbc2cf2c7100eff4b592dbd6a483890833</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Binding sites</topic><topic>Cancer</topic><topic>Chemical synthesis</topic><topic>Chemistry</topic><topic>Circulatory system</topic><topic>Conjugates</topic><topic>Hydrogen bonding</topic><topic>Hydroxycinnamic acid</topic><topic>Molecular docking</topic><topic>Pancreatic cancer</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cybulski, Marcin</creatorcontrib><creatorcontrib>Zaremba-Czogalla, Magdalena</creatorcontrib><creatorcontrib>Trzaskowski, Bartosz</creatorcontrib><creatorcontrib>Kubiszewski, Marek</creatorcontrib><creatorcontrib>Tobiasz, Joanna</creatorcontrib><creatorcontrib>Jaromin, Anna</creatorcontrib><creatorcontrib>Krzeczy ski, Piotr</creatorcontrib><creatorcontrib>Gubernator, Jerzy</creatorcontrib><creatorcontrib>Michalak, Olga</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Engineered Materials Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Materials Research Database</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>RSC advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cybulski, Marcin</au><au>Zaremba-Czogalla, Magdalena</au><au>Trzaskowski, Bartosz</au><au>Kubiszewski, Marek</au><au>Tobiasz, Joanna</au><au>Jaromin, Anna</au><au>Krzeczy ski, Piotr</au><au>Gubernator, Jerzy</au><au>Michalak, Olga</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The conjugates of 5′-deoxy-5-fluorocytidine and hydroxycinnamic acids - synthesis, anti-pancreatic cancer activity and molecular docking studies</atitle><jtitle>RSC advances</jtitle><addtitle>RSC Adv</addtitle><date>2024-04-22</date><risdate>2024</risdate><volume>14</volume><issue>19</issue><spage>13129</spage><epage>13141</epage><pages>13129-13141</pages><issn>2046-2069</issn><eissn>2046-2069</eissn><abstract>New amide conjugates
1-6
of hydroxycinnamic acids (HCA) and 5′-deoxy-5-fluorocytidine (5-dFCR), the prodrug of 5-fluorouracil (5-FU), were synthesized and tested
in vitro
against pancreatic cancer lines (PDAC). The compounds showed slightly higher efficacy against primary BxPC-3 cells (IC
50
values of 14-45 μM) than against metastatic AsPC-1 (IC
50
values of 37-133 μM), and similar to that of 5-FU for both PDAC lines. Compound
1
, which has a
para
-(acetyloxy)coumaroyl substituent, was found to be the most potent (IC
50
= 14 μM) with a selectivity index of approximately 7 to normal dermal fibroblasts (IC
50
= 96 μM). The potential pharmacological profiles were discussed on the basis of the ADME data. Docking to the carboxylesterase CES2 showed that the synthesized compounds have the ability to bind
via
hydrogen bonding between a specific acetate group of the sugar moiety and Ser228, which belongs to the catalytic triad that causes hydrolysis. Docking to albumin, a major transport protein in the circulatory system, revealed a strong interaction of the conjugates at the binding site which is native to warfarin and responsible for its transport in the body.
New conjugates
1-6
containing 5-dFCR and selected hydroxycinnamic acids were synthesized and tested
in vitro
against pancreatic cancer (PDAC) lines. The ADME properties and molecular docking to CES2 or human albumin were discussed.</abstract><cop>England</cop><pub>Royal Society of Chemistry</pub><pmid>38655481</pmid><doi>10.1039/d4ra01683a</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0001-5925-8178</orcidid><orcidid>https://orcid.org/0000-0002-4560-9317</orcidid><orcidid>https://orcid.org/0000-0003-0182-7299</orcidid><orcidid>https://orcid.org/0000-0002-7921-8007</orcidid><orcidid>https://orcid.org/0000-0002-1067-4223</orcidid><orcidid>https://orcid.org/0000-0003-2385-1476</orcidid><orcidid>https://orcid.org/0000-0002-6144-2211</orcidid><orcidid>https://orcid.org/0000-0002-4978-5887</orcidid><oa>free_for_read</oa></addata></record> |
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| source | PubMed Central (Training) |
| subjects | Binding sites Cancer Chemical synthesis Chemistry Circulatory system Conjugates Hydrogen bonding Hydroxycinnamic acid Molecular docking Pancreatic cancer |
| title | The conjugates of 5′-deoxy-5-fluorocytidine and hydroxycinnamic acids - synthesis, anti-pancreatic cancer activity and molecular docking studies |
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