Design, synthesis and anticancer evaluation of tetrahydro-β-carboline-hydantoin hybrids
A series of new tetrahydro-β-carboline-hydantoin hybrids were synthesized and evaluated for their in vitro cytotoxic potency on selected cancer cell lines and an attempt was made to rationalize their mechanism of action through cell cycle analysis that indicates a G2/M cell cycle arrest. [Display om...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2014-12, Vol.24 (23), p.5413-5417 |
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| creator | Shankaraiah, Nagula Nekkanti, Shalini Chudasama, Karmarajsinh J. Senwar, Kishna Ram Sharma, Pankaj Jeengar, Manish Kumar Naidu, V.G.M. Srinivasulu, Vunnam Srinivasulu, Gannoju Kamal, Ahmed |
| description | A series of new tetrahydro-β-carboline-hydantoin hybrids were synthesized and evaluated for their in vitro cytotoxic potency on selected cancer cell lines and an attempt was made to rationalize their mechanism of action through cell cycle analysis that indicates a G2/M cell cycle arrest. [Display omitted]
A series of new tetrahydro-β-carboline-hydantoin hybrids have been designed and synthesized based on the structure of the known Eg5 inhibitor HR22C16. These compounds have been evaluated for their anticancer activity against lung (A549), cervical (ME180, HeLa), prostate (PC-3) and breast (MCF-7) cancer cell lines by MTT assay. These hybrids have displayed significant in vitro cytotoxicity in comparison to etoposide against PC-3, A549, and MCF-7 cell lines. The hybrids 3a, 3b, 3c, 3e, 3f, 3g, 4b, 4c, 4e and 4f appear to be more effective against the PC-3 cell line, among which compound 4b displayed the highest cytotoxicity (6.08±0.2, IC50 μM). Based on these results, an attempt was made to rationalize their mechanism of action through cell cycle analysis studies. The flow-cytometric analysis of compound 4b in PC-3 cells indicated a G2/M cell cycle arrest. Molecular docking studies substantiate that these compounds indeed bind to the allosteric site of Eg5 formed from Glu116, Gly117, Glu118, Trp127, Ala133, Ile136, Pro137, Tyr211, Leu214, and Glu215 residues with the most potent compound 4b showing the most favorable interaction. |
| doi_str_mv | 10.1016/j.bmcl.2014.10.038 |
| format | Article |
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A series of new tetrahydro-β-carboline-hydantoin hybrids have been designed and synthesized based on the structure of the known Eg5 inhibitor HR22C16. These compounds have been evaluated for their anticancer activity against lung (A549), cervical (ME180, HeLa), prostate (PC-3) and breast (MCF-7) cancer cell lines by MTT assay. These hybrids have displayed significant in vitro cytotoxicity in comparison to etoposide against PC-3, A549, and MCF-7 cell lines. The hybrids 3a, 3b, 3c, 3e, 3f, 3g, 4b, 4c, 4e and 4f appear to be more effective against the PC-3 cell line, among which compound 4b displayed the highest cytotoxicity (6.08±0.2, IC50 μM). Based on these results, an attempt was made to rationalize their mechanism of action through cell cycle analysis studies. The flow-cytometric analysis of compound 4b in PC-3 cells indicated a G2/M cell cycle arrest. Molecular docking studies substantiate that these compounds indeed bind to the allosteric site of Eg5 formed from Glu116, Gly117, Glu118, Trp127, Ala133, Ile136, Pro137, Tyr211, Leu214, and Glu215 residues with the most potent compound 4b showing the most favorable interaction.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2014.10.038</identifier><identifier>PMID: 25453799</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Anticancer ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Carbolines - chemical synthesis ; Carbolines - chemistry ; Carbolines - pharmacology ; Cell Proliferation - drug effects ; Drug Screening Assays, Antitumor ; Eg5 inhibitor ; HR22C16 ; Humans ; Hydantoins - chemical synthesis ; Hydantoins - chemistry ; Hydantoins - pharmacology ; Kinesin spindle protein ; Structure-Activity Relationship ; Tetrahydro-β-carboline ; Tetrahydro-β-carboline-hydantoin hybrids</subject><ispartof>Bioorganic & medicinal chemistry letters, 2014-12, Vol.24 (23), p.5413-5417</ispartof><rights>2014 Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-1d0b38d58e4fe93c4d46f78aac1f6b7d9a0ef4d5d5e2f03570256701e29d11373</citedby><cites>FETCH-LOGICAL-c459t-1d0b38d58e4fe93c4d46f78aac1f6b7d9a0ef4d5d5e2f03570256701e29d11373</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X14010981$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25453799$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shankaraiah, Nagula</creatorcontrib><creatorcontrib>Nekkanti, Shalini</creatorcontrib><creatorcontrib>Chudasama, Karmarajsinh J.</creatorcontrib><creatorcontrib>Senwar, Kishna Ram</creatorcontrib><creatorcontrib>Sharma, Pankaj</creatorcontrib><creatorcontrib>Jeengar, Manish Kumar</creatorcontrib><creatorcontrib>Naidu, V.G.M.</creatorcontrib><creatorcontrib>Srinivasulu, Vunnam</creatorcontrib><creatorcontrib>Srinivasulu, Gannoju</creatorcontrib><creatorcontrib>Kamal, Ahmed</creatorcontrib><title>Design, synthesis and anticancer evaluation of tetrahydro-β-carboline-hydantoin hybrids</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A series of new tetrahydro-β-carboline-hydantoin hybrids were synthesized and evaluated for their in vitro cytotoxic potency on selected cancer cell lines and an attempt was made to rationalize their mechanism of action through cell cycle analysis that indicates a G2/M cell cycle arrest. [Display omitted]
A series of new tetrahydro-β-carboline-hydantoin hybrids have been designed and synthesized based on the structure of the known Eg5 inhibitor HR22C16. These compounds have been evaluated for their anticancer activity against lung (A549), cervical (ME180, HeLa), prostate (PC-3) and breast (MCF-7) cancer cell lines by MTT assay. These hybrids have displayed significant in vitro cytotoxicity in comparison to etoposide against PC-3, A549, and MCF-7 cell lines. The hybrids 3a, 3b, 3c, 3e, 3f, 3g, 4b, 4c, 4e and 4f appear to be more effective against the PC-3 cell line, among which compound 4b displayed the highest cytotoxicity (6.08±0.2, IC50 μM). Based on these results, an attempt was made to rationalize their mechanism of action through cell cycle analysis studies. The flow-cytometric analysis of compound 4b in PC-3 cells indicated a G2/M cell cycle arrest. Molecular docking studies substantiate that these compounds indeed bind to the allosteric site of Eg5 formed from Glu116, Gly117, Glu118, Trp127, Ala133, Ile136, Pro137, Tyr211, Leu214, and Glu215 residues with the most potent compound 4b showing the most favorable interaction.</description><subject>Anticancer</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Carbolines - chemical synthesis</subject><subject>Carbolines - chemistry</subject><subject>Carbolines - pharmacology</subject><subject>Cell Proliferation - drug effects</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Eg5 inhibitor</subject><subject>HR22C16</subject><subject>Humans</subject><subject>Hydantoins - chemical synthesis</subject><subject>Hydantoins - chemistry</subject><subject>Hydantoins - pharmacology</subject><subject>Kinesin spindle protein</subject><subject>Structure-Activity Relationship</subject><subject>Tetrahydro-β-carboline</subject><subject>Tetrahydro-β-carboline-hydantoin hybrids</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkMtKxDAUhoMoznh5ARfSpQs7njSXtuBGvIPgRsFdSJNTJ0OnGZOOMK_lg_hMZhh1KS7CCT_f_y8-Qo4oTChQeTabNHPTTQqgPAUTYNUWGVMuec44iG0yhlpCXtX8ZUT2YpxBAoHzXTIqBBesrOsxebnC6F770yyu-mGa_jHTvU1vcEb3BkOG77pb6sH5PvNtNuAQ9HRlg88_P3KjQ-M712OeotTxrs-mqyY4Gw_ITqu7iIffd58831w_Xd7lD4-395cXD7nhoh5yaqFhlRUV8hZrZrjlsi0rrQ1tZVPaWgO23AorsGiBiRIKIUugWNSWUlayfXKy2V0E_7bEOKi5iwa7Tvfol1FRKQvOEsr-gfISQMhCJrTYoCb4GAO2ahHcXIeVoqDW8tVMreWrtfx1luSn0vH3_rKZo_2t_NhOwPkGwCTk3WFQ0ThMlq0LaAZlvftr_wv2Tpbn</recordid><startdate>20141201</startdate><enddate>20141201</enddate><creator>Shankaraiah, Nagula</creator><creator>Nekkanti, Shalini</creator><creator>Chudasama, Karmarajsinh J.</creator><creator>Senwar, Kishna Ram</creator><creator>Sharma, Pankaj</creator><creator>Jeengar, Manish Kumar</creator><creator>Naidu, V.G.M.</creator><creator>Srinivasulu, Vunnam</creator><creator>Srinivasulu, Gannoju</creator><creator>Kamal, Ahmed</creator><general>Elsevier Ltd</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20141201</creationdate><title>Design, synthesis and anticancer evaluation of tetrahydro-β-carboline-hydantoin hybrids</title><author>Shankaraiah, Nagula ; Nekkanti, Shalini ; Chudasama, Karmarajsinh J. ; Senwar, Kishna Ram ; Sharma, Pankaj ; Jeengar, Manish Kumar ; Naidu, V.G.M. ; Srinivasulu, Vunnam ; Srinivasulu, Gannoju ; Kamal, Ahmed</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-1d0b38d58e4fe93c4d46f78aac1f6b7d9a0ef4d5d5e2f03570256701e29d11373</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Anticancer</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Carbolines - chemical synthesis</topic><topic>Carbolines - chemistry</topic><topic>Carbolines - pharmacology</topic><topic>Cell Proliferation - drug effects</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Eg5 inhibitor</topic><topic>HR22C16</topic><topic>Humans</topic><topic>Hydantoins - chemical synthesis</topic><topic>Hydantoins - chemistry</topic><topic>Hydantoins - pharmacology</topic><topic>Kinesin spindle protein</topic><topic>Structure-Activity Relationship</topic><topic>Tetrahydro-β-carboline</topic><topic>Tetrahydro-β-carboline-hydantoin hybrids</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shankaraiah, Nagula</creatorcontrib><creatorcontrib>Nekkanti, Shalini</creatorcontrib><creatorcontrib>Chudasama, Karmarajsinh J.</creatorcontrib><creatorcontrib>Senwar, Kishna Ram</creatorcontrib><creatorcontrib>Sharma, Pankaj</creatorcontrib><creatorcontrib>Jeengar, Manish Kumar</creatorcontrib><creatorcontrib>Naidu, V.G.M.</creatorcontrib><creatorcontrib>Srinivasulu, Vunnam</creatorcontrib><creatorcontrib>Srinivasulu, Gannoju</creatorcontrib><creatorcontrib>Kamal, Ahmed</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shankaraiah, Nagula</au><au>Nekkanti, Shalini</au><au>Chudasama, Karmarajsinh J.</au><au>Senwar, Kishna Ram</au><au>Sharma, Pankaj</au><au>Jeengar, Manish Kumar</au><au>Naidu, V.G.M.</au><au>Srinivasulu, Vunnam</au><au>Srinivasulu, Gannoju</au><au>Kamal, Ahmed</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis and anticancer evaluation of tetrahydro-β-carboline-hydantoin hybrids</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2014-12-01</date><risdate>2014</risdate><volume>24</volume><issue>23</issue><spage>5413</spage><epage>5417</epage><pages>5413-5417</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A series of new tetrahydro-β-carboline-hydantoin hybrids were synthesized and evaluated for their in vitro cytotoxic potency on selected cancer cell lines and an attempt was made to rationalize their mechanism of action through cell cycle analysis that indicates a G2/M cell cycle arrest. [Display omitted]
A series of new tetrahydro-β-carboline-hydantoin hybrids have been designed and synthesized based on the structure of the known Eg5 inhibitor HR22C16. These compounds have been evaluated for their anticancer activity against lung (A549), cervical (ME180, HeLa), prostate (PC-3) and breast (MCF-7) cancer cell lines by MTT assay. These hybrids have displayed significant in vitro cytotoxicity in comparison to etoposide against PC-3, A549, and MCF-7 cell lines. The hybrids 3a, 3b, 3c, 3e, 3f, 3g, 4b, 4c, 4e and 4f appear to be more effective against the PC-3 cell line, among which compound 4b displayed the highest cytotoxicity (6.08±0.2, IC50 μM). Based on these results, an attempt was made to rationalize their mechanism of action through cell cycle analysis studies. The flow-cytometric analysis of compound 4b in PC-3 cells indicated a G2/M cell cycle arrest. Molecular docking studies substantiate that these compounds indeed bind to the allosteric site of Eg5 formed from Glu116, Gly117, Glu118, Trp127, Ala133, Ile136, Pro137, Tyr211, Leu214, and Glu215 residues with the most potent compound 4b showing the most favorable interaction.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>25453799</pmid><doi>10.1016/j.bmcl.2014.10.038</doi><tpages>5</tpages></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2014-12, Vol.24 (23), p.5413-5417 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Anticancer Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Carbolines - chemical synthesis Carbolines - chemistry Carbolines - pharmacology Cell Proliferation - drug effects Drug Screening Assays, Antitumor Eg5 inhibitor HR22C16 Humans Hydantoins - chemical synthesis Hydantoins - chemistry Hydantoins - pharmacology Kinesin spindle protein Structure-Activity Relationship Tetrahydro-β-carboline Tetrahydro-β-carboline-hydantoin hybrids |
| title | Design, synthesis and anticancer evaluation of tetrahydro-β-carboline-hydantoin hybrids |
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