Remarkable enhancement in the DNA-binding ability of C2-fluoro substituted pyrrolo[2,1- c][1,4]benzodiazepines and their anticancer potential
C2-Fluoro substituted DC-81, and its dimers that comprise of two C2-fluoro substituted DC-81 subunits tethered to their C8-position through simple alkane spacers as well as piperazine moiety side-armed with symmetrical alkyloxy spacers have been designed and synthesized. These fluoro substituted pyr...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2009-02, Vol.17 (4), p.1557-1572 |
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| creator | Kamal, Ahmed Rajender Reddy, D. Rajasekhar Reddy, M. Kashi Balakishan, G. Shaik, T. Basha Chourasia, Mukesh Sastry, G. Narahari |
| description | C2-Fluoro substituted DC-81, and its dimers that comprise of two C2-fluoro substituted DC-81 subunits tethered to their C8-position through simple alkane spacers as well as piperazine moiety side-armed with symmetrical alkyloxy spacers have been designed and synthesized. These fluoro substituted pyrrolo[2,1-
c][1,4]benzodiazepines have shown remarkable DNA-binding ability and most of them possess promising anticancer activity, having GI
50 values in micromolar to nanomolar concentration range. DNA thermal denaturation studies show that some of these compounds (
14a–
c and
15) increase the Δ
T
m values in the range of 28.9–38
°C, and this is further confirmed by the restriction endonuclease studies. This study illustrates the importance of introducing fluoro substitution at the C2-position apart from the incorporation of a piperazine ring in between the alkyloxy linker for enhancement of the DNA-binding ability in comparison to DSB-120 and SJG-136 (Δ
T
m
=
10.2 and 25.7
°C). Moreover, the variations in the DNA-binding ability with respect to fluoro substitution in this class of dimers has been investigated by molecular modeling studies. Some representative C2-fluoro substituted dimers (
8a and
14a) have also exhibited significant anticancer activity in the 60 cancer cell line assay of the National Cancer Institute (NCI). |
| doi_str_mv | 10.1016/j.bmc.2008.12.068 |
| format | Article |
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c][1,4]benzodiazepines have shown remarkable DNA-binding ability and most of them possess promising anticancer activity, having GI
50 values in micromolar to nanomolar concentration range. DNA thermal denaturation studies show that some of these compounds (
14a–
c and
15) increase the Δ
T
m values in the range of 28.9–38
°C, and this is further confirmed by the restriction endonuclease studies. This study illustrates the importance of introducing fluoro substitution at the C2-position apart from the incorporation of a piperazine ring in between the alkyloxy linker for enhancement of the DNA-binding ability in comparison to DSB-120 and SJG-136 (Δ
T
m
=
10.2 and 25.7
°C). Moreover, the variations in the DNA-binding ability with respect to fluoro substitution in this class of dimers has been investigated by molecular modeling studies. Some representative C2-fluoro substituted dimers (
8a and
14a) have also exhibited significant anticancer activity in the 60 cancer cell line assay of the National Cancer Institute (NCI).</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2008.12.068</identifier><identifier>PMID: 19168361</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Anticancer activity ; Antineoplastic Agents - metabolism ; Antineoplastic Agents - pharmacology ; Benzodiazepines - metabolism ; Benzodiazepines - pharmacology ; Cell Line, Tumor ; DNA - drug effects ; DNA - metabolism ; DNA Restriction Enzymes - metabolism ; DNA-binding affinity ; Drug Design ; Drug Screening Assays, Antitumor ; Fluoro ; Humans ; Models, Molecular ; Piperazine ; Pyrrolidines - metabolism ; Pyrrolidines - pharmacology ; Pyrrolobenzodiazepine ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry, 2009-02, Vol.17 (4), p.1557-1572</ispartof><rights>2009 Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c382t-1eaa91a41127539da5327e86a5d23d6ee2e3273f6f767d6ae609f839c7a860793</citedby><cites>FETCH-LOGICAL-c382t-1eaa91a41127539da5327e86a5d23d6ee2e3273f6f767d6ae609f839c7a860793</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089609000042$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19168361$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kamal, Ahmed</creatorcontrib><creatorcontrib>Rajender</creatorcontrib><creatorcontrib>Reddy, D. Rajasekhar</creatorcontrib><creatorcontrib>Reddy, M. Kashi</creatorcontrib><creatorcontrib>Balakishan, G.</creatorcontrib><creatorcontrib>Shaik, T. Basha</creatorcontrib><creatorcontrib>Chourasia, Mukesh</creatorcontrib><creatorcontrib>Sastry, G. Narahari</creatorcontrib><title>Remarkable enhancement in the DNA-binding ability of C2-fluoro substituted pyrrolo[2,1- c][1,4]benzodiazepines and their anticancer potential</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>C2-Fluoro substituted DC-81, and its dimers that comprise of two C2-fluoro substituted DC-81 subunits tethered to their C8-position through simple alkane spacers as well as piperazine moiety side-armed with symmetrical alkyloxy spacers have been designed and synthesized. These fluoro substituted pyrrolo[2,1-
c][1,4]benzodiazepines have shown remarkable DNA-binding ability and most of them possess promising anticancer activity, having GI
50 values in micromolar to nanomolar concentration range. DNA thermal denaturation studies show that some of these compounds (
14a–
c and
15) increase the Δ
T
m values in the range of 28.9–38
°C, and this is further confirmed by the restriction endonuclease studies. This study illustrates the importance of introducing fluoro substitution at the C2-position apart from the incorporation of a piperazine ring in between the alkyloxy linker for enhancement of the DNA-binding ability in comparison to DSB-120 and SJG-136 (Δ
T
m
=
10.2 and 25.7
°C). Moreover, the variations in the DNA-binding ability with respect to fluoro substitution in this class of dimers has been investigated by molecular modeling studies. Some representative C2-fluoro substituted dimers (
8a and
14a) have also exhibited significant anticancer activity in the 60 cancer cell line assay of the National Cancer Institute (NCI).</description><subject>Anticancer activity</subject><subject>Antineoplastic Agents - metabolism</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Benzodiazepines - metabolism</subject><subject>Benzodiazepines - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>DNA - drug effects</subject><subject>DNA - metabolism</subject><subject>DNA Restriction Enzymes - metabolism</subject><subject>DNA-binding affinity</subject><subject>Drug Design</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Fluoro</subject><subject>Humans</subject><subject>Models, Molecular</subject><subject>Piperazine</subject><subject>Pyrrolidines - metabolism</subject><subject>Pyrrolidines - pharmacology</subject><subject>Pyrrolobenzodiazepine</subject><subject>Structure-Activity Relationship</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc2KFDEURoMoTs_oA7iRrFxNlfmpSiW4GlodhUFBdDUMIVW55aStSsokJfS8g-9smm5wp6tcwrnfhe8g9IKSmhIqXu_qfh5qRoisKauJkI_QhjaiqThX9DHaECVkRaQSZ-g8pR0hhDWKPkVnVFEhuaAb9PsLzCb-MP0EGPy98QPM4DN2Hud7wG8_XVW989b579j0bnJ5j8OIt6wapzXEgNPap-zymsHiZR9jmMItu6QVHu5u6WVz14N_CNaZB1ich4SNt4dgF8uU3XC4F_EScrnpzPQMPRnNlOD56b1A396_-7r9UN18vv64vbqpBi5ZrigYo6hpKGVdy5U1LWcdSGFay7gVAAzKBx_F2InOCgOCqFFyNXRGCtIpfoFeHXOXGH6ukLKeXRpgmoyHsCYthGopaZr_goxw2baCFJAewSGGlCKMeomuNLvXlOiDLL3TRZY-yNKU6SKr7Lw8ha_9DPbvxslOAd4cAShd_HIQdRoclMqsizBkbYP7R_wfNf6luQ</recordid><startdate>20090215</startdate><enddate>20090215</enddate><creator>Kamal, Ahmed</creator><creator>Rajender</creator><creator>Reddy, D. Rajasekhar</creator><creator>Reddy, M. Kashi</creator><creator>Balakishan, G.</creator><creator>Shaik, T. Basha</creator><creator>Chourasia, Mukesh</creator><creator>Sastry, G. Narahari</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>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20090215</creationdate><title>Remarkable enhancement in the DNA-binding ability of C2-fluoro substituted pyrrolo[2,1- c][1,4]benzodiazepines and their anticancer potential</title><author>Kamal, Ahmed ; Rajender ; Reddy, D. Rajasekhar ; Reddy, M. Kashi ; Balakishan, G. ; Shaik, T. Basha ; Chourasia, Mukesh ; Sastry, G. Narahari</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c382t-1eaa91a41127539da5327e86a5d23d6ee2e3273f6f767d6ae609f839c7a860793</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Anticancer activity</topic><topic>Antineoplastic Agents - metabolism</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Benzodiazepines - metabolism</topic><topic>Benzodiazepines - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>DNA - drug effects</topic><topic>DNA - metabolism</topic><topic>DNA Restriction Enzymes - metabolism</topic><topic>DNA-binding affinity</topic><topic>Drug Design</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Fluoro</topic><topic>Humans</topic><topic>Models, Molecular</topic><topic>Piperazine</topic><topic>Pyrrolidines - metabolism</topic><topic>Pyrrolidines - pharmacology</topic><topic>Pyrrolobenzodiazepine</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kamal, Ahmed</creatorcontrib><creatorcontrib>Rajender</creatorcontrib><creatorcontrib>Reddy, D. Rajasekhar</creatorcontrib><creatorcontrib>Reddy, M. Kashi</creatorcontrib><creatorcontrib>Balakishan, G.</creatorcontrib><creatorcontrib>Shaik, T. Basha</creatorcontrib><creatorcontrib>Chourasia, Mukesh</creatorcontrib><creatorcontrib>Sastry, G. Narahari</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>Nucleic Acids 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</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kamal, Ahmed</au><au>Rajender</au><au>Reddy, D. Rajasekhar</au><au>Reddy, M. Kashi</au><au>Balakishan, G.</au><au>Shaik, T. Basha</au><au>Chourasia, Mukesh</au><au>Sastry, G. Narahari</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Remarkable enhancement in the DNA-binding ability of C2-fluoro substituted pyrrolo[2,1- c][1,4]benzodiazepines and their anticancer potential</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2009-02-15</date><risdate>2009</risdate><volume>17</volume><issue>4</issue><spage>1557</spage><epage>1572</epage><pages>1557-1572</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>C2-Fluoro substituted DC-81, and its dimers that comprise of two C2-fluoro substituted DC-81 subunits tethered to their C8-position through simple alkane spacers as well as piperazine moiety side-armed with symmetrical alkyloxy spacers have been designed and synthesized. These fluoro substituted pyrrolo[2,1-
c][1,4]benzodiazepines have shown remarkable DNA-binding ability and most of them possess promising anticancer activity, having GI
50 values in micromolar to nanomolar concentration range. DNA thermal denaturation studies show that some of these compounds (
14a–
c and
15) increase the Δ
T
m values in the range of 28.9–38
°C, and this is further confirmed by the restriction endonuclease studies. This study illustrates the importance of introducing fluoro substitution at the C2-position apart from the incorporation of a piperazine ring in between the alkyloxy linker for enhancement of the DNA-binding ability in comparison to DSB-120 and SJG-136 (Δ
T
m
=
10.2 and 25.7
°C). Moreover, the variations in the DNA-binding ability with respect to fluoro substitution in this class of dimers has been investigated by molecular modeling studies. Some representative C2-fluoro substituted dimers (
8a and
14a) have also exhibited significant anticancer activity in the 60 cancer cell line assay of the National Cancer Institute (NCI).</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>19168361</pmid><doi>10.1016/j.bmc.2008.12.068</doi><tpages>16</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0968-0896 |
| ispartof | Bioorganic & medicinal chemistry, 2009-02, Vol.17 (4), p.1557-1572 |
| issn | 0968-0896 1464-3391 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_66951044 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Anticancer activity Antineoplastic Agents - metabolism Antineoplastic Agents - pharmacology Benzodiazepines - metabolism Benzodiazepines - pharmacology Cell Line, Tumor DNA - drug effects DNA - metabolism DNA Restriction Enzymes - metabolism DNA-binding affinity Drug Design Drug Screening Assays, Antitumor Fluoro Humans Models, Molecular Piperazine Pyrrolidines - metabolism Pyrrolidines - pharmacology Pyrrolobenzodiazepine Structure-Activity Relationship |
| title | Remarkable enhancement in the DNA-binding ability of C2-fluoro substituted pyrrolo[2,1- c][1,4]benzodiazepines and their anticancer potential |
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