Design, Synthesis and Screening of 4,6-Diaryl Pyridine and Pyrimidine Derivatives as Potential Cytotoxic Molecules
A new series of pyridine and pyrimidine derivatives is designed and synthesized as potential antitumor molecules. The tested compounds show promising in vitro cytotoxic activity against HL-60 cell line as eight compounds: 4, 6, 11, 13, 14, 15, 18 and 21 exhibit potent cytotoxic activity in sub-micro...
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| Veröffentlicht in: | Chemical & pharmaceutical bulletin 2018/10/01, Vol.66(10), pp.939-952 |
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| creator | elhameid, Mohammed K. Abd Ryad, Noha MY, Al-Shorbagy mohammed, Manal R. Ismail, Mohammed M. Meligie, Salwa El |
| description | A new series of pyridine and pyrimidine derivatives is designed and synthesized as potential antitumor molecules. The tested compounds show promising in vitro cytotoxic activity against HL-60 cell line as eight compounds: 4, 6, 11, 13, 14, 15, 18 and 21 exhibit potent cytotoxic activity in sub-micromolar concentration higher than the combretastatin A4 (CA-4). Compound 21 shows a cytotoxic activity 5-fold more potent than CA-4 on HL-60 cells. DNA-Flow cytometry cell cycle analysis and annexin-V assay on HL-60 cells show that compounds 4, 18 and 21 exhibit potent cell growth inhibition, cell cycle arrest at G2/M phase and pro-apoptotic inducing activities. The percentage inhibition assay of β-tubulin polymerization on HL-60 cells shows that the antitumor activity of the tested compounds appears to correlate well with its ability to inhibit β-tubulin polymerization. In addition, enzyme-linked immunosorbene assay (ELlSA) measurement for compound 21 shows apoptotic inducing activities through significant up regulation of p53, Bax/Bcl-2 ratio and caspase-3 proteins parallel to down regulation of the level of survivin proteins. |
| doi_str_mv | 10.1248/cpb.c18-00269 |
| format | Article |
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Abd ; Ryad, Noha ; MY, Al-Shorbagy ; mohammed, Manal R. ; Ismail, Mohammed M. ; Meligie, Salwa El</creator><creatorcontrib>elhameid, Mohammed K. Abd ; Ryad, Noha ; MY, Al-Shorbagy ; mohammed, Manal R. ; Ismail, Mohammed M. ; Meligie, Salwa El ; National Center for Radiation Research and Technology ; bPharmaceutical Organic Chemistry Department ; College of Pharmaceutical Sciences and Drug Manufacturing ; aPharmaceutical Organic Chemistry Department ; Cairo University ; eDepartment of Radiation Biology ; cPharmacology and Toxicology Department ; Newgiza University ; Misr University for Science and Technology ; Faculty of Pharmacy ; dSchool of pharmacy</creatorcontrib><description>A new series of pyridine and pyrimidine derivatives is designed and synthesized as potential antitumor molecules. The tested compounds show promising in vitro cytotoxic activity against HL-60 cell line as eight compounds: 4, 6, 11, 13, 14, 15, 18 and 21 exhibit potent cytotoxic activity in sub-micromolar concentration higher than the combretastatin A4 (CA-4). Compound 21 shows a cytotoxic activity 5-fold more potent than CA-4 on HL-60 cells. DNA-Flow cytometry cell cycle analysis and annexin-V assay on HL-60 cells show that compounds 4, 18 and 21 exhibit potent cell growth inhibition, cell cycle arrest at G2/M phase and pro-apoptotic inducing activities. The percentage inhibition assay of β-tubulin polymerization on HL-60 cells shows that the antitumor activity of the tested compounds appears to correlate well with its ability to inhibit β-tubulin polymerization. In addition, enzyme-linked immunosorbene assay (ELlSA) measurement for compound 21 shows apoptotic inducing activities through significant up regulation of p53, Bax/Bcl-2 ratio and caspase-3 proteins parallel to down regulation of the level of survivin proteins.</description><identifier>ISSN: 0009-2363</identifier><identifier>EISSN: 1347-5223</identifier><identifier>DOI: 10.1248/cpb.c18-00269</identifier><identifier>PMID: 30111667</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Cell Cycle Checkpoints - drug effects ; Cell Proliferation - drug effects ; combretastatin A4 ; Dose-Response Relationship, Drug ; Drug Design ; Drug Evaluation, Preclinical ; Drug Screening Assays, Antitumor ; Enzyme-Linked Immunosorbent Assay ; HCT116 Cells ; HL-60 Cells ; Humans ; leukemia ; MCF-7 Cells ; Molecular Structure ; Oxidative Stress - drug effects ; Polymerization - drug effects ; pyridine ; Pyridines - chemical synthesis ; Pyridines - chemistry ; Pyridines - pharmacology ; pyrimidine ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Structure-Activity Relationship ; survivin ; tubulin ; Tubulin - biosynthesis</subject><ispartof>Chemical and Pharmaceutical Bulletin, 2018/10/01, Vol.66(10), pp.939-952</ispartof><rights>2018 The Pharmaceutical Society of Japan</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c675t-ca02ab2ae8f9148968dbcbae2968fd9ec962ac6773d5822cfa1a8fdfbd42bc383</citedby><cites>FETCH-LOGICAL-c675t-ca02ab2ae8f9148968dbcbae2968fd9ec962ac6773d5822cfa1a8fdfbd42bc383</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,1877,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30111667$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>elhameid, Mohammed K. Abd</creatorcontrib><creatorcontrib>Ryad, Noha</creatorcontrib><creatorcontrib>MY, Al-Shorbagy</creatorcontrib><creatorcontrib>mohammed, Manal R.</creatorcontrib><creatorcontrib>Ismail, Mohammed M.</creatorcontrib><creatorcontrib>Meligie, Salwa El</creatorcontrib><creatorcontrib>National Center for Radiation Research and Technology</creatorcontrib><creatorcontrib>bPharmaceutical Organic Chemistry Department</creatorcontrib><creatorcontrib>College of Pharmaceutical Sciences and Drug Manufacturing</creatorcontrib><creatorcontrib>aPharmaceutical Organic Chemistry Department</creatorcontrib><creatorcontrib>Cairo University</creatorcontrib><creatorcontrib>eDepartment of Radiation Biology</creatorcontrib><creatorcontrib>cPharmacology and Toxicology Department</creatorcontrib><creatorcontrib>Newgiza University</creatorcontrib><creatorcontrib>Misr University for Science and Technology</creatorcontrib><creatorcontrib>Faculty of Pharmacy</creatorcontrib><creatorcontrib>dSchool of pharmacy</creatorcontrib><title>Design, Synthesis and Screening of 4,6-Diaryl Pyridine and Pyrimidine Derivatives as Potential Cytotoxic Molecules</title><title>Chemical & pharmaceutical bulletin</title><addtitle>Chem. Pharm. Bull.</addtitle><description>A new series of pyridine and pyrimidine derivatives is designed and synthesized as potential antitumor molecules. The tested compounds show promising in vitro cytotoxic activity against HL-60 cell line as eight compounds: 4, 6, 11, 13, 14, 15, 18 and 21 exhibit potent cytotoxic activity in sub-micromolar concentration higher than the combretastatin A4 (CA-4). Compound 21 shows a cytotoxic activity 5-fold more potent than CA-4 on HL-60 cells. DNA-Flow cytometry cell cycle analysis and annexin-V assay on HL-60 cells show that compounds 4, 18 and 21 exhibit potent cell growth inhibition, cell cycle arrest at G2/M phase and pro-apoptotic inducing activities. The percentage inhibition assay of β-tubulin polymerization on HL-60 cells shows that the antitumor activity of the tested compounds appears to correlate well with its ability to inhibit β-tubulin polymerization. In addition, enzyme-linked immunosorbene assay (ELlSA) measurement for compound 21 shows apoptotic inducing activities through significant up regulation of p53, Bax/Bcl-2 ratio and caspase-3 proteins parallel to down regulation of the level of survivin proteins.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Cell Cycle Checkpoints - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>combretastatin A4</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Design</subject><subject>Drug Evaluation, Preclinical</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>HCT116 Cells</subject><subject>HL-60 Cells</subject><subject>Humans</subject><subject>leukemia</subject><subject>MCF-7 Cells</subject><subject>Molecular Structure</subject><subject>Oxidative Stress - drug effects</subject><subject>Polymerization - drug effects</subject><subject>pyridine</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>pyrimidine</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>survivin</subject><subject>tubulin</subject><subject>Tubulin - biosynthesis</subject><issn>0009-2363</issn><issn>1347-5223</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE1v1DAQhi0EokvhyBXlyKEp_kic-Ih2oVQqolLhbDnOZNcrr7PY3qr775lsyvYyntE8fmfmJeQjo9eMV-0Xu--uLWtLSrlUr8iCiaopa87Fa7KglKqSCykuyLuUtojUtBFvyYWgjDEpmwWJK0huHa6Kh2PIG8xTYUJfPNgIEFxYF-NQVFeyXDkTj764P0bXuwAnaCp2c7mC6B5Ndo-A_1NxP2YI2RlfLI95zOOTs8XP0YM9eEjvyZvB-AQfnt9L8uf7t9_LH-Xdr5vb5de70sqmzqU1lJuOG2gHxapWybbvbGeAYzb0CqyS3CDaiL5uObeDYQYbQ9dXvLOiFZfk86y7j-PfA6Ssdy5Z8N4EGA9Jc9oqrtC2CS1n1MYxpQiD3uNpeLFmVE82a7RZo836ZDPyn56lD90O-jP931cEbmYAu84aPwaPNunteIgBb9Y2NXYDO4dLnESlxEGU1poqoTDUXLBaNXwatZqVtimbNZxHmZid9XBaTMppT4znDV_aGxM1BPEPe0qpHQ</recordid><startdate>20181001</startdate><enddate>20181001</enddate><creator>elhameid, Mohammed K. Abd</creator><creator>Ryad, Noha</creator><creator>MY, Al-Shorbagy</creator><creator>mohammed, Manal R.</creator><creator>Ismail, Mohammed M.</creator><creator>Meligie, Salwa El</creator><general>The Pharmaceutical Society of Japan</general><general>Pharmaceutical Society of Japan</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>7X8</scope></search><sort><creationdate>20181001</creationdate><title>Design, Synthesis and Screening of 4,6-Diaryl Pyridine and Pyrimidine Derivatives as Potential Cytotoxic Molecules</title><author>elhameid, Mohammed K. Abd ; Ryad, Noha ; MY, Al-Shorbagy ; mohammed, Manal R. ; Ismail, Mohammed M. ; Meligie, Salwa El</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c675t-ca02ab2ae8f9148968dbcbae2968fd9ec962ac6773d5822cfa1a8fdfbd42bc383</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Cell Cycle Checkpoints - drug effects</topic><topic>Cell Proliferation - drug effects</topic><topic>combretastatin A4</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Design</topic><topic>Drug Evaluation, Preclinical</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>HCT116 Cells</topic><topic>HL-60 Cells</topic><topic>Humans</topic><topic>leukemia</topic><topic>MCF-7 Cells</topic><topic>Molecular Structure</topic><topic>Oxidative Stress - drug effects</topic><topic>Polymerization - drug effects</topic><topic>pyridine</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacology</topic><topic>pyrimidine</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>survivin</topic><topic>tubulin</topic><topic>Tubulin - biosynthesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>elhameid, Mohammed K. Abd</creatorcontrib><creatorcontrib>Ryad, Noha</creatorcontrib><creatorcontrib>MY, Al-Shorbagy</creatorcontrib><creatorcontrib>mohammed, Manal R.</creatorcontrib><creatorcontrib>Ismail, Mohammed M.</creatorcontrib><creatorcontrib>Meligie, Salwa El</creatorcontrib><creatorcontrib>National Center for Radiation Research and Technology</creatorcontrib><creatorcontrib>bPharmaceutical Organic Chemistry Department</creatorcontrib><creatorcontrib>College of Pharmaceutical Sciences and Drug Manufacturing</creatorcontrib><creatorcontrib>aPharmaceutical Organic Chemistry Department</creatorcontrib><creatorcontrib>Cairo University</creatorcontrib><creatorcontrib>eDepartment of Radiation Biology</creatorcontrib><creatorcontrib>cPharmacology and Toxicology Department</creatorcontrib><creatorcontrib>Newgiza University</creatorcontrib><creatorcontrib>Misr University for Science and Technology</creatorcontrib><creatorcontrib>Faculty of Pharmacy</creatorcontrib><creatorcontrib>dSchool of pharmacy</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Chemical & pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>elhameid, Mohammed K. Abd</au><au>Ryad, Noha</au><au>MY, Al-Shorbagy</au><au>mohammed, Manal R.</au><au>Ismail, Mohammed M.</au><au>Meligie, Salwa El</au><aucorp>National Center for Radiation Research and Technology</aucorp><aucorp>bPharmaceutical Organic Chemistry Department</aucorp><aucorp>College of Pharmaceutical Sciences and Drug Manufacturing</aucorp><aucorp>aPharmaceutical Organic Chemistry Department</aucorp><aucorp>Cairo University</aucorp><aucorp>eDepartment of Radiation Biology</aucorp><aucorp>cPharmacology and Toxicology Department</aucorp><aucorp>Newgiza University</aucorp><aucorp>Misr University for Science and Technology</aucorp><aucorp>Faculty of Pharmacy</aucorp><aucorp>dSchool of pharmacy</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, Synthesis and Screening of 4,6-Diaryl Pyridine and Pyrimidine Derivatives as Potential Cytotoxic Molecules</atitle><jtitle>Chemical & pharmaceutical bulletin</jtitle><addtitle>Chem. Pharm. Bull.</addtitle><date>2018-10-01</date><risdate>2018</risdate><volume>66</volume><issue>10</issue><spage>939</spage><epage>952</epage><pages>939-952</pages><issn>0009-2363</issn><eissn>1347-5223</eissn><abstract>A new series of pyridine and pyrimidine derivatives is designed and synthesized as potential antitumor molecules. The tested compounds show promising in vitro cytotoxic activity against HL-60 cell line as eight compounds: 4, 6, 11, 13, 14, 15, 18 and 21 exhibit potent cytotoxic activity in sub-micromolar concentration higher than the combretastatin A4 (CA-4). Compound 21 shows a cytotoxic activity 5-fold more potent than CA-4 on HL-60 cells. DNA-Flow cytometry cell cycle analysis and annexin-V assay on HL-60 cells show that compounds 4, 18 and 21 exhibit potent cell growth inhibition, cell cycle arrest at G2/M phase and pro-apoptotic inducing activities. The percentage inhibition assay of β-tubulin polymerization on HL-60 cells shows that the antitumor activity of the tested compounds appears to correlate well with its ability to inhibit β-tubulin polymerization. In addition, enzyme-linked immunosorbene assay (ELlSA) measurement for compound 21 shows apoptotic inducing activities through significant up regulation of p53, Bax/Bcl-2 ratio and caspase-3 proteins parallel to down regulation of the level of survivin proteins.</abstract><cop>Japan</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>30111667</pmid><doi>10.1248/cpb.c18-00269</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis - drug effects Cell Cycle Checkpoints - drug effects Cell Proliferation - drug effects combretastatin A4 Dose-Response Relationship, Drug Drug Design Drug Evaluation, Preclinical Drug Screening Assays, Antitumor Enzyme-Linked Immunosorbent Assay HCT116 Cells HL-60 Cells Humans leukemia MCF-7 Cells Molecular Structure Oxidative Stress - drug effects Polymerization - drug effects pyridine Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacology pyrimidine Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Structure-Activity Relationship survivin tubulin Tubulin - biosynthesis |
| title | Design, Synthesis and Screening of 4,6-Diaryl Pyridine and Pyrimidine Derivatives as Potential Cytotoxic Molecules |
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