Synthesis and antiproliferative activities of doxorubicin thiol conjugates and doxorubicin-SS-cyclic peptide
Myocardial toxicity and drug resistance caused by drug efflux are major limitations of doxorubicin (Dox)-based chemotherapy. Dox structure modification could be used to develop conjugates with an improved biological profile, such as antiproliferative activity and higher cellular retention. Thus, Dox...
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| Veröffentlicht in: | European journal of medicinal chemistry 2019-01, Vol.161, p.594-606 |
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| creator | Darwish, Shaban Sadeghiani, Neda Fong, Shirley Mozaffari, Saghar Hamidi, Parinaz Withana, Thimanthi Yang, Sun Tiwari, Rakesh Kumar Parang, Keykavous |
| description | Myocardial toxicity and drug resistance caused by drug efflux are major limitations of doxorubicin (Dox)-based chemotherapy. Dox structure modification could be used to develop conjugates with an improved biological profile, such as antiproliferative activity and higher cellular retention. Thus, Dox thiol conjugates, Dox thiol (Dox-SH), thiol-reactive Dox-SS-pyridine (SS = disulfide), and a Dox-SS-cell-penetrating cyclic peptide, Dox-SS-[C(WR)4K], were synthesized. Dox was reacted with Traut's reagent to generate Dox-SH. The thiol group was activated by the reaction with dithiodipyridine to afford the corresponding Dox-SS-Pyridine (Dox-SS-Pyr). A cyclic cell-penetrating peptide containing a cysteine residue [C(WR)4K] was prepared using Fmoc solid-phase strategy. Dox-SS-Py was reacted with the free sulfhydryl of cysteine in [C(WR)4K] to generate Dox-SS-[C(WR)4K] as a Dox-cyclic peptide conjugate. Cytotoxicity of the compounds was examined in human embryonic kidney (HEK-293), human ovarian cancer (SKOV-3), human fibrosarcoma (HT-1080), and human leukemia (CCRF-CEM) cells. Dox-SH and Dox-SS-pyridine were found to have significantly higher or comparable cytotoxicity when compared to Dox in HEK-293, HT-1080, and CCRF-CEM cells after 24 h and 72 incubation, presumably because of higher activity and retention of the compounds in these cells. Furthermore, Dox-SS-[C(WR)4K] showed significantly higher cytotoxic activity in HEK-293, HT-1080, and SKOV-3 cells when compared with Dox after 72 h incubation. Dox-SS-Pyr exhibited higher cellular uptake than Dox-SS-[C(WR)4K] in HT-1080 and HEK-293 cells as shown by flow cytometry. Fluorescence microscopy exhibited that Dox-SS-Pyr, Dox-SH, and Dox-SS-[C(WR)4K] localized in the nucleus as shown in four cell lines, HT-1080, SKOV-3, MDA-MB-468, and MCF-7. Of note, Dox-SS-[C(WR)4K] was significantly less toxic in mouse myoblast cells compared to Dox at the same concentration. Further mechanistic study demonstrated that the level of intracellular reactive oxygen species (ROS) in myoblast cells exposed to Dox-SS-[C(WR)4K] was reduced in comparison of Dox when co-treated with FeCl2. These data indicate that Dox-SH, Dox-SS-Pyr, and Dox-SS-[C(WR)4K] have the potential to be further examined as Dox alternatives and anticancer agents.
Dox-SS-[C(WR)4K] was synthesized and evaluated for antiproliferative activities in different cancer cell lines. [Display omitted]
•Doxorubicin (Dox) thiol analogs, Dox-SH, Dox-SS-Pyr, and Dox-cyclic pepti |
| doi_str_mv | 10.1016/j.ejmech.2018.10.042 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8418874</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0223523418309115</els_id><sourcerecordid>30396106</sourcerecordid><originalsourceid>FETCH-LOGICAL-c430t-a0784a889743c0590ecb0fc43c8ce49be6d85bd462cef2dc1a49f278415327423</originalsourceid><addsrcrecordid>eNp9UMuO00AQHCEQGwJ_gJB_wKHnYWd8QUIrXtJKHALn0binvWnL8VjjSUT-HofAslw4tFrq6qrqLiFeS9hIkPXbfkP9gXC_USDtMtqAUU_ESm5rW2pVmadiBUrpslLa3IgX89wDQFUDPBc3GnRTS6hXYtidx7ynmefCj2GpzFOKA3eUfOYTFR6XxplpLmJXhPgjpmPLyGOR9xyHAuPYH-99pqvAo4VytyvxjANjMdGUOdBL8azzw0yvfve1-P7xw7fbz-Xd109fbt_flWg05NLD1hpvbbM1GqFqgLCFbsHQIpmmpTrYqg2mVkidCii9aTq1cGSl1dYovRbvrrrTsT1QQBpz8oObEh98Orvo2f2LjLx39_HkFglrF9e1MFcBTHGeE3UPXAnukr7r3TV9d0n_MoVfvm8e-z6Q_sT99zBavj8xJTcj04gUOBFmFyL_3-EnWkCcEw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Synthesis and antiproliferative activities of doxorubicin thiol conjugates and doxorubicin-SS-cyclic peptide</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Darwish, Shaban ; Sadeghiani, Neda ; Fong, Shirley ; Mozaffari, Saghar ; Hamidi, Parinaz ; Withana, Thimanthi ; Yang, Sun ; Tiwari, Rakesh Kumar ; Parang, Keykavous</creator><creatorcontrib>Darwish, Shaban ; Sadeghiani, Neda ; Fong, Shirley ; Mozaffari, Saghar ; Hamidi, Parinaz ; Withana, Thimanthi ; Yang, Sun ; Tiwari, Rakesh Kumar ; Parang, Keykavous</creatorcontrib><description>Myocardial toxicity and drug resistance caused by drug efflux are major limitations of doxorubicin (Dox)-based chemotherapy. Dox structure modification could be used to develop conjugates with an improved biological profile, such as antiproliferative activity and higher cellular retention. Thus, Dox thiol conjugates, Dox thiol (Dox-SH), thiol-reactive Dox-SS-pyridine (SS = disulfide), and a Dox-SS-cell-penetrating cyclic peptide, Dox-SS-[C(WR)4K], were synthesized. Dox was reacted with Traut's reagent to generate Dox-SH. The thiol group was activated by the reaction with dithiodipyridine to afford the corresponding Dox-SS-Pyridine (Dox-SS-Pyr). A cyclic cell-penetrating peptide containing a cysteine residue [C(WR)4K] was prepared using Fmoc solid-phase strategy. Dox-SS-Py was reacted with the free sulfhydryl of cysteine in [C(WR)4K] to generate Dox-SS-[C(WR)4K] as a Dox-cyclic peptide conjugate. Cytotoxicity of the compounds was examined in human embryonic kidney (HEK-293), human ovarian cancer (SKOV-3), human fibrosarcoma (HT-1080), and human leukemia (CCRF-CEM) cells. Dox-SH and Dox-SS-pyridine were found to have significantly higher or comparable cytotoxicity when compared to Dox in HEK-293, HT-1080, and CCRF-CEM cells after 24 h and 72 incubation, presumably because of higher activity and retention of the compounds in these cells. Furthermore, Dox-SS-[C(WR)4K] showed significantly higher cytotoxic activity in HEK-293, HT-1080, and SKOV-3 cells when compared with Dox after 72 h incubation. Dox-SS-Pyr exhibited higher cellular uptake than Dox-SS-[C(WR)4K] in HT-1080 and HEK-293 cells as shown by flow cytometry. Fluorescence microscopy exhibited that Dox-SS-Pyr, Dox-SH, and Dox-SS-[C(WR)4K] localized in the nucleus as shown in four cell lines, HT-1080, SKOV-3, MDA-MB-468, and MCF-7. Of note, Dox-SS-[C(WR)4K] was significantly less toxic in mouse myoblast cells compared to Dox at the same concentration. Further mechanistic study demonstrated that the level of intracellular reactive oxygen species (ROS) in myoblast cells exposed to Dox-SS-[C(WR)4K] was reduced in comparison of Dox when co-treated with FeCl2. These data indicate that Dox-SH, Dox-SS-Pyr, and Dox-SS-[C(WR)4K] have the potential to be further examined as Dox alternatives and anticancer agents.
Dox-SS-[C(WR)4K] was synthesized and evaluated for antiproliferative activities in different cancer cell lines. [Display omitted]
•Doxorubicin (Dox) thiol analogs, Dox-SH, Dox-SS-Pyr, and Dox-cyclic peptide, Dox-SS-[C(WR)4K], were synthesized.•Dox-SS-Pyr demonstrated higher antiproliferative activity when compared to Dox-SH in all the different cancer cell lines.•Dox-SS-[C(WR)4K], showed more cytotoxicity when compared to Dox in HEK-293, HT-1080, and SKOV-3 after 72 h.•Microscopy studies demonstrated high cellular uptake and localization for all these analogs in the nucleus.•New analogs have low cardiotoxicity as compared to Dox and potential to be considered as alternative anticancer agents.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2018.10.042</identifier><identifier>PMID: 30396106</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Animals ; Anticancer ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Cardiotoxicity ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Cells, Cultured ; Cellular uptake ; Cyclic peptide ; Disulfide ; Disulfides - chemistry ; Disulfides - pharmacology ; Dose-Response Relationship, Drug ; Doxorubicin ; Doxorubicin - chemistry ; Doxorubicin - pharmacology ; Drug Screening Assays, Antitumor ; Flow Cytometry ; HEK293 Cells ; Humans ; Mice ; Molecular Conformation ; Peptides, Cyclic - chemistry ; Peptides, Cyclic - pharmacology ; Reactive Oxygen Species - analysis ; Reactive Oxygen Species - metabolism ; Structure-Activity Relationship ; Sulfhydryl Compounds - chemistry ; Sulfhydryl Compounds - pharmacology ; Thiol</subject><ispartof>European journal of medicinal chemistry, 2019-01, Vol.161, p.594-606</ispartof><rights>2018 Elsevier Masson SAS</rights><rights>Copyright © 2018 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c430t-a0784a889743c0590ecb0fc43c8ce49be6d85bd462cef2dc1a49f278415327423</citedby><cites>FETCH-LOGICAL-c430t-a0784a889743c0590ecb0fc43c8ce49be6d85bd462cef2dc1a49f278415327423</cites><orcidid>0000-0001-8600-0893 ; 0000-0002-7676-7959 ; 0000-0003-3701-4548</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0223523418309115$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30396106$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Darwish, Shaban</creatorcontrib><creatorcontrib>Sadeghiani, Neda</creatorcontrib><creatorcontrib>Fong, Shirley</creatorcontrib><creatorcontrib>Mozaffari, Saghar</creatorcontrib><creatorcontrib>Hamidi, Parinaz</creatorcontrib><creatorcontrib>Withana, Thimanthi</creatorcontrib><creatorcontrib>Yang, Sun</creatorcontrib><creatorcontrib>Tiwari, Rakesh Kumar</creatorcontrib><creatorcontrib>Parang, Keykavous</creatorcontrib><title>Synthesis and antiproliferative activities of doxorubicin thiol conjugates and doxorubicin-SS-cyclic peptide</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>Myocardial toxicity and drug resistance caused by drug efflux are major limitations of doxorubicin (Dox)-based chemotherapy. Dox structure modification could be used to develop conjugates with an improved biological profile, such as antiproliferative activity and higher cellular retention. Thus, Dox thiol conjugates, Dox thiol (Dox-SH), thiol-reactive Dox-SS-pyridine (SS = disulfide), and a Dox-SS-cell-penetrating cyclic peptide, Dox-SS-[C(WR)4K], were synthesized. Dox was reacted with Traut's reagent to generate Dox-SH. The thiol group was activated by the reaction with dithiodipyridine to afford the corresponding Dox-SS-Pyridine (Dox-SS-Pyr). A cyclic cell-penetrating peptide containing a cysteine residue [C(WR)4K] was prepared using Fmoc solid-phase strategy. Dox-SS-Py was reacted with the free sulfhydryl of cysteine in [C(WR)4K] to generate Dox-SS-[C(WR)4K] as a Dox-cyclic peptide conjugate. Cytotoxicity of the compounds was examined in human embryonic kidney (HEK-293), human ovarian cancer (SKOV-3), human fibrosarcoma (HT-1080), and human leukemia (CCRF-CEM) cells. Dox-SH and Dox-SS-pyridine were found to have significantly higher or comparable cytotoxicity when compared to Dox in HEK-293, HT-1080, and CCRF-CEM cells after 24 h and 72 incubation, presumably because of higher activity and retention of the compounds in these cells. Furthermore, Dox-SS-[C(WR)4K] showed significantly higher cytotoxic activity in HEK-293, HT-1080, and SKOV-3 cells when compared with Dox after 72 h incubation. Dox-SS-Pyr exhibited higher cellular uptake than Dox-SS-[C(WR)4K] in HT-1080 and HEK-293 cells as shown by flow cytometry. Fluorescence microscopy exhibited that Dox-SS-Pyr, Dox-SH, and Dox-SS-[C(WR)4K] localized in the nucleus as shown in four cell lines, HT-1080, SKOV-3, MDA-MB-468, and MCF-7. Of note, Dox-SS-[C(WR)4K] was significantly less toxic in mouse myoblast cells compared to Dox at the same concentration. Further mechanistic study demonstrated that the level of intracellular reactive oxygen species (ROS) in myoblast cells exposed to Dox-SS-[C(WR)4K] was reduced in comparison of Dox when co-treated with FeCl2. These data indicate that Dox-SH, Dox-SS-Pyr, and Dox-SS-[C(WR)4K] have the potential to be further examined as Dox alternatives and anticancer agents.
Dox-SS-[C(WR)4K] was synthesized and evaluated for antiproliferative activities in different cancer cell lines. [Display omitted]
•Doxorubicin (Dox) thiol analogs, Dox-SH, Dox-SS-Pyr, and Dox-cyclic peptide, Dox-SS-[C(WR)4K], were synthesized.•Dox-SS-Pyr demonstrated higher antiproliferative activity when compared to Dox-SH in all the different cancer cell lines.•Dox-SS-[C(WR)4K], showed more cytotoxicity when compared to Dox in HEK-293, HT-1080, and SKOV-3 after 72 h.•Microscopy studies demonstrated high cellular uptake and localization for all these analogs in the nucleus.•New analogs have low cardiotoxicity as compared to Dox and potential to be considered as alternative anticancer agents.</description><subject>Animals</subject><subject>Anticancer</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cardiotoxicity</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Cells, Cultured</subject><subject>Cellular uptake</subject><subject>Cyclic peptide</subject><subject>Disulfide</subject><subject>Disulfides - chemistry</subject><subject>Disulfides - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Doxorubicin</subject><subject>Doxorubicin - chemistry</subject><subject>Doxorubicin - pharmacology</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Flow Cytometry</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Mice</subject><subject>Molecular Conformation</subject><subject>Peptides, Cyclic - chemistry</subject><subject>Peptides, Cyclic - pharmacology</subject><subject>Reactive Oxygen Species - analysis</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Sulfhydryl Compounds - chemistry</subject><subject>Sulfhydryl Compounds - pharmacology</subject><subject>Thiol</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UMuO00AQHCEQGwJ_gJB_wKHnYWd8QUIrXtJKHALn0binvWnL8VjjSUT-HofAslw4tFrq6qrqLiFeS9hIkPXbfkP9gXC_USDtMtqAUU_ESm5rW2pVmadiBUrpslLa3IgX89wDQFUDPBc3GnRTS6hXYtidx7ynmefCj2GpzFOKA3eUfOYTFR6XxplpLmJXhPgjpmPLyGOR9xyHAuPYH-99pqvAo4VytyvxjANjMdGUOdBL8azzw0yvfve1-P7xw7fbz-Xd109fbt_flWg05NLD1hpvbbM1GqFqgLCFbsHQIpmmpTrYqg2mVkidCii9aTq1cGSl1dYovRbvrrrTsT1QQBpz8oObEh98Orvo2f2LjLx39_HkFglrF9e1MFcBTHGeE3UPXAnukr7r3TV9d0n_MoVfvm8e-z6Q_sT99zBavj8xJTcj04gUOBFmFyL_3-EnWkCcEw</recordid><startdate>20190101</startdate><enddate>20190101</enddate><creator>Darwish, Shaban</creator><creator>Sadeghiani, Neda</creator><creator>Fong, Shirley</creator><creator>Mozaffari, Saghar</creator><creator>Hamidi, Parinaz</creator><creator>Withana, Thimanthi</creator><creator>Yang, Sun</creator><creator>Tiwari, Rakesh Kumar</creator><creator>Parang, Keykavous</creator><general>Elsevier Masson SAS</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8600-0893</orcidid><orcidid>https://orcid.org/0000-0002-7676-7959</orcidid><orcidid>https://orcid.org/0000-0003-3701-4548</orcidid></search><sort><creationdate>20190101</creationdate><title>Synthesis and antiproliferative activities of doxorubicin thiol conjugates and doxorubicin-SS-cyclic peptide</title><author>Darwish, Shaban ; Sadeghiani, Neda ; Fong, Shirley ; Mozaffari, Saghar ; Hamidi, Parinaz ; Withana, Thimanthi ; Yang, Sun ; Tiwari, Rakesh Kumar ; Parang, Keykavous</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c430t-a0784a889743c0590ecb0fc43c8ce49be6d85bd462cef2dc1a49f278415327423</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Anticancer</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cardiotoxicity</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Cells, Cultured</topic><topic>Cellular uptake</topic><topic>Cyclic peptide</topic><topic>Disulfide</topic><topic>Disulfides - chemistry</topic><topic>Disulfides - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Doxorubicin</topic><topic>Doxorubicin - chemistry</topic><topic>Doxorubicin - pharmacology</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Flow Cytometry</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Mice</topic><topic>Molecular Conformation</topic><topic>Peptides, Cyclic - chemistry</topic><topic>Peptides, Cyclic - pharmacology</topic><topic>Reactive Oxygen Species - analysis</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Sulfhydryl Compounds - chemistry</topic><topic>Sulfhydryl Compounds - pharmacology</topic><topic>Thiol</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Darwish, Shaban</creatorcontrib><creatorcontrib>Sadeghiani, Neda</creatorcontrib><creatorcontrib>Fong, Shirley</creatorcontrib><creatorcontrib>Mozaffari, Saghar</creatorcontrib><creatorcontrib>Hamidi, Parinaz</creatorcontrib><creatorcontrib>Withana, Thimanthi</creatorcontrib><creatorcontrib>Yang, Sun</creatorcontrib><creatorcontrib>Tiwari, Rakesh Kumar</creatorcontrib><creatorcontrib>Parang, Keykavous</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Darwish, Shaban</au><au>Sadeghiani, Neda</au><au>Fong, Shirley</au><au>Mozaffari, Saghar</au><au>Hamidi, Parinaz</au><au>Withana, Thimanthi</au><au>Yang, Sun</au><au>Tiwari, Rakesh Kumar</au><au>Parang, Keykavous</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and antiproliferative activities of doxorubicin thiol conjugates and doxorubicin-SS-cyclic peptide</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2019-01-01</date><risdate>2019</risdate><volume>161</volume><spage>594</spage><epage>606</epage><pages>594-606</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>Myocardial toxicity and drug resistance caused by drug efflux are major limitations of doxorubicin (Dox)-based chemotherapy. Dox structure modification could be used to develop conjugates with an improved biological profile, such as antiproliferative activity and higher cellular retention. Thus, Dox thiol conjugates, Dox thiol (Dox-SH), thiol-reactive Dox-SS-pyridine (SS = disulfide), and a Dox-SS-cell-penetrating cyclic peptide, Dox-SS-[C(WR)4K], were synthesized. Dox was reacted with Traut's reagent to generate Dox-SH. The thiol group was activated by the reaction with dithiodipyridine to afford the corresponding Dox-SS-Pyridine (Dox-SS-Pyr). A cyclic cell-penetrating peptide containing a cysteine residue [C(WR)4K] was prepared using Fmoc solid-phase strategy. Dox-SS-Py was reacted with the free sulfhydryl of cysteine in [C(WR)4K] to generate Dox-SS-[C(WR)4K] as a Dox-cyclic peptide conjugate. Cytotoxicity of the compounds was examined in human embryonic kidney (HEK-293), human ovarian cancer (SKOV-3), human fibrosarcoma (HT-1080), and human leukemia (CCRF-CEM) cells. Dox-SH and Dox-SS-pyridine were found to have significantly higher or comparable cytotoxicity when compared to Dox in HEK-293, HT-1080, and CCRF-CEM cells after 24 h and 72 incubation, presumably because of higher activity and retention of the compounds in these cells. Furthermore, Dox-SS-[C(WR)4K] showed significantly higher cytotoxic activity in HEK-293, HT-1080, and SKOV-3 cells when compared with Dox after 72 h incubation. Dox-SS-Pyr exhibited higher cellular uptake than Dox-SS-[C(WR)4K] in HT-1080 and HEK-293 cells as shown by flow cytometry. Fluorescence microscopy exhibited that Dox-SS-Pyr, Dox-SH, and Dox-SS-[C(WR)4K] localized in the nucleus as shown in four cell lines, HT-1080, SKOV-3, MDA-MB-468, and MCF-7. Of note, Dox-SS-[C(WR)4K] was significantly less toxic in mouse myoblast cells compared to Dox at the same concentration. Further mechanistic study demonstrated that the level of intracellular reactive oxygen species (ROS) in myoblast cells exposed to Dox-SS-[C(WR)4K] was reduced in comparison of Dox when co-treated with FeCl2. These data indicate that Dox-SH, Dox-SS-Pyr, and Dox-SS-[C(WR)4K] have the potential to be further examined as Dox alternatives and anticancer agents.
Dox-SS-[C(WR)4K] was synthesized and evaluated for antiproliferative activities in different cancer cell lines. [Display omitted]
•Doxorubicin (Dox) thiol analogs, Dox-SH, Dox-SS-Pyr, and Dox-cyclic peptide, Dox-SS-[C(WR)4K], were synthesized.•Dox-SS-Pyr demonstrated higher antiproliferative activity when compared to Dox-SH in all the different cancer cell lines.•Dox-SS-[C(WR)4K], showed more cytotoxicity when compared to Dox in HEK-293, HT-1080, and SKOV-3 after 72 h.•Microscopy studies demonstrated high cellular uptake and localization for all these analogs in the nucleus.•New analogs have low cardiotoxicity as compared to Dox and potential to be considered as alternative anticancer agents.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>30396106</pmid><doi>10.1016/j.ejmech.2018.10.042</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0001-8600-0893</orcidid><orcidid>https://orcid.org/0000-0002-7676-7959</orcidid><orcidid>https://orcid.org/0000-0003-3701-4548</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0223-5234 |
| ispartof | European journal of medicinal chemistry, 2019-01, Vol.161, p.594-606 |
| issn | 0223-5234 1768-3254 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8418874 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Anticancer Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cardiotoxicity Cell Proliferation - drug effects Cell Survival - drug effects Cells, Cultured Cellular uptake Cyclic peptide Disulfide Disulfides - chemistry Disulfides - pharmacology Dose-Response Relationship, Drug Doxorubicin Doxorubicin - chemistry Doxorubicin - pharmacology Drug Screening Assays, Antitumor Flow Cytometry HEK293 Cells Humans Mice Molecular Conformation Peptides, Cyclic - chemistry Peptides, Cyclic - pharmacology Reactive Oxygen Species - analysis Reactive Oxygen Species - metabolism Structure-Activity Relationship Sulfhydryl Compounds - chemistry Sulfhydryl Compounds - pharmacology Thiol |
| title | Synthesis and antiproliferative activities of doxorubicin thiol conjugates and doxorubicin-SS-cyclic peptide |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T16%3A22%3A41IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Synthesis%20and%20antiproliferative%20activities%20of%20doxorubicin%20thiol%20conjugates%20and%20doxorubicin-SS-cyclic%20peptide&rft.jtitle=European%20journal%20of%20medicinal%20chemistry&rft.au=Darwish,%20Shaban&rft.date=2019-01-01&rft.volume=161&rft.spage=594&rft.epage=606&rft.pages=594-606&rft.issn=0223-5234&rft.eissn=1768-3254&rft_id=info:doi/10.1016/j.ejmech.2018.10.042&rft_dat=%3Cpubmed_cross%3E30396106%3C/pubmed_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/30396106&rft_els_id=S0223523418309115&rfr_iscdi=true |