3D QSAR/CoMFA and CoMSIA Studies on Antileukemic Steroidal Esters Coupled with Conformationally Flexible Nitrogen Mustards
Thirty-eight antileukemic steroidal esters possessing conformationally flexible nitrogen mustards were studied, and the 3D QSAR/CoMFA and CoMSIA methodologies were applied in order to derive the correlation between their structure and the in vivo antileukemic activity. These compounds show significa...
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| Veröffentlicht in: | Journal of Chemical Information and Modeling 2008-11, Vol.48 (11), p.2254-2264 |
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| container_title | Journal of Chemical Information and Modeling |
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| creator | Kapou, Agnes Benetis, Nikolas-P Durdagi, Serdar Nikolaropoulos, Sotiris Mavromoustakos, Thomas |
| description | Thirty-eight antileukemic steroidal esters possessing conformationally flexible nitrogen mustards were studied, and the 3D QSAR/CoMFA and CoMSIA methodologies were applied in order to derive the correlation between their structure and the in vivo antileukemic activity. These compounds show significantly reduced toxicity and possibly increased bioavailability compared to free nitrogen mustards and therefore constitute potent antileukemic drugs. Both the CoMFA and CoMSIA studies gave similar results indicating that the steric effect and the hydrophobic/hydrophilic balance especially in the steroidal part of the molecules probably determined their bioactivity. Of paramount interest is the observation that the orientation of the alkylating part of the SMEs toward the surface of ring B of the steroidal skeleton was related with increased activity. Concerning the steroidal part, the presence of hydrophobic groups in rings B and D was found to be important for enhanced activity. Enhancement of antileukemic potency is further observed if hydrophilic/H-bond acceptor groups are present at the positions 7 and 17 of the steroidal skeleton. Leapfrog simulations provided novel compounds which lead our future synthetic endeavor for obtaining SMEs with optimum bioactivity. |
| doi_str_mv | 10.1021/ci800240m |
| format | Article |
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These compounds show significantly reduced toxicity and possibly increased bioavailability compared to free nitrogen mustards and therefore constitute potent antileukemic drugs. Both the CoMFA and CoMSIA studies gave similar results indicating that the steric effect and the hydrophobic/hydrophilic balance especially in the steroidal part of the molecules probably determined their bioactivity. Of paramount interest is the observation that the orientation of the alkylating part of the SMEs toward the surface of ring B of the steroidal skeleton was related with increased activity. Concerning the steroidal part, the presence of hydrophobic groups in rings B and D was found to be important for enhanced activity. Enhancement of antileukemic potency is further observed if hydrophilic/H-bond acceptor groups are present at the positions 7 and 17 of the steroidal skeleton. Leapfrog simulations provided novel compounds which lead our future synthetic endeavor for obtaining SMEs with optimum bioactivity.</description><identifier>ISSN: 1549-9596</identifier><identifier>EISSN: 1520-5142</identifier><identifier>EISSN: 1549-960X</identifier><identifier>DOI: 10.1021/ci800240m</identifier><identifier>PMID: 18954137</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Analytical chemistry ; Animals ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - toxicity ; Chemical compounds ; Drug Design ; Female ; Humans ; Hydrophobic and Hydrophilic Interactions ; Informatics ; Leukemia ; Leukemia - drug therapy ; Male ; Mice ; Mice, Inbred BALB C ; Models, Molecular ; Molecular Conformation ; Molecular Structure ; Nitrogen ; Nitrogen Mustard Compounds - chemistry ; Nitrogen Mustard Compounds - pharmacology ; Nitrogen Mustard Compounds - toxicity ; Pharmaceutical Modeling ; Quantitative Structure-Activity Relationship ; Rats ; Static Electricity ; Steroids ; Steroids - chemical synthesis ; Steroids - pharmacology ; Steroids - toxicity ; Thermodynamics ; Toxicity</subject><ispartof>Journal of Chemical Information and Modeling, 2008-11, Vol.48 (11), p.2254-2264</ispartof><rights>Copyright © 2008 American Chemical Society</rights><rights>Copyright American Chemical Society Nov 24, 2008</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a378t-ee359aa5a37c4cd97cba0b593a0bfb10bb7e0ce15657e302bd0ef6082838400f3</citedby><cites>FETCH-LOGICAL-a378t-ee359aa5a37c4cd97cba0b593a0bfb10bb7e0ce15657e302bd0ef6082838400f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/ci800240m$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/ci800240m$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18954137$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kapou, Agnes</creatorcontrib><creatorcontrib>Benetis, Nikolas-P</creatorcontrib><creatorcontrib>Durdagi, Serdar</creatorcontrib><creatorcontrib>Nikolaropoulos, Sotiris</creatorcontrib><creatorcontrib>Mavromoustakos, Thomas</creatorcontrib><title>3D QSAR/CoMFA and CoMSIA Studies on Antileukemic Steroidal Esters Coupled with Conformationally Flexible Nitrogen Mustards</title><title>Journal of Chemical Information and Modeling</title><addtitle>J. Chem. Inf. Model</addtitle><description>Thirty-eight antileukemic steroidal esters possessing conformationally flexible nitrogen mustards were studied, and the 3D QSAR/CoMFA and CoMSIA methodologies were applied in order to derive the correlation between their structure and the in vivo antileukemic activity. These compounds show significantly reduced toxicity and possibly increased bioavailability compared to free nitrogen mustards and therefore constitute potent antileukemic drugs. Both the CoMFA and CoMSIA studies gave similar results indicating that the steric effect and the hydrophobic/hydrophilic balance especially in the steroidal part of the molecules probably determined their bioactivity. Of paramount interest is the observation that the orientation of the alkylating part of the SMEs toward the surface of ring B of the steroidal skeleton was related with increased activity. Concerning the steroidal part, the presence of hydrophobic groups in rings B and D was found to be important for enhanced activity. Enhancement of antileukemic potency is further observed if hydrophilic/H-bond acceptor groups are present at the positions 7 and 17 of the steroidal skeleton. Leapfrog simulations provided novel compounds which lead our future synthetic endeavor for obtaining SMEs with optimum bioactivity.</description><subject>Analytical chemistry</subject><subject>Animals</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - toxicity</subject><subject>Chemical compounds</subject><subject>Drug Design</subject><subject>Female</subject><subject>Humans</subject><subject>Hydrophobic and Hydrophilic Interactions</subject><subject>Informatics</subject><subject>Leukemia</subject><subject>Leukemia - drug therapy</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Molecular Structure</subject><subject>Nitrogen</subject><subject>Nitrogen Mustard Compounds - chemistry</subject><subject>Nitrogen Mustard Compounds - pharmacology</subject><subject>Nitrogen Mustard Compounds - toxicity</subject><subject>Pharmaceutical Modeling</subject><subject>Quantitative Structure-Activity Relationship</subject><subject>Rats</subject><subject>Static Electricity</subject><subject>Steroids</subject><subject>Steroids - chemical synthesis</subject><subject>Steroids - pharmacology</subject><subject>Steroids - toxicity</subject><subject>Thermodynamics</subject><subject>Toxicity</subject><issn>1549-9596</issn><issn>1520-5142</issn><issn>1549-960X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNplkE1P3DAQhq2qVaHQQ_8AspB64JAytmMnOUZb0iLxVRY49GI5yQQMSbzYiQr99TXaFRx6mXln5tHM6CXkC4NvDDg7bGwOwFMY3pFtJjkkkqX8_YtOi6SQhdoin0K4BxCiUPwj2WJ5IVMmsm3yV3ynv5bl5eHCnVYlNWNLo1oel3Q5za3FQN1Iy3GyPc4PONgm9tE725qeHoUoQ-TnVY8t_WOnu1iMnfODmawbTd8_06rHJ1v3SM_s5N0tjvR0DpPxbdglHzrTB_y8yTvkujq6WvxMTs5_HC_Kk8SILJ8SRCELY2SsmrRpi6ypDdSyEDF2NYO6zhAaZFLJDAXwugXsFOQ8F3kK0Ikdsr_eu_LuccYw6Xs3-_hd0JwprjjLRIQO1lDjXQgeO73ydjD-WTPQLybrV5Mju7dZONcDtm_kxtUIJGvARoeeXufGP2iViUzqq4ulrtTN78tUMV1F_uuaN014e-7_w_8A4M2SHw</recordid><startdate>20081124</startdate><enddate>20081124</enddate><creator>Kapou, Agnes</creator><creator>Benetis, Nikolas-P</creator><creator>Durdagi, Serdar</creator><creator>Nikolaropoulos, Sotiris</creator><creator>Mavromoustakos, Thomas</creator><general>American Chemical Society</general><scope>BSCLL</scope><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>7SC</scope><scope>7SR</scope><scope>7U5</scope><scope>8BQ</scope><scope>8FD</scope><scope>JG9</scope><scope>JQ2</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope></search><sort><creationdate>20081124</creationdate><title>3D QSAR/CoMFA and CoMSIA Studies on Antileukemic Steroidal Esters Coupled with Conformationally Flexible Nitrogen Mustards</title><author>Kapou, Agnes ; Benetis, Nikolas-P ; Durdagi, Serdar ; Nikolaropoulos, Sotiris ; Mavromoustakos, Thomas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a378t-ee359aa5a37c4cd97cba0b593a0bfb10bb7e0ce15657e302bd0ef6082838400f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Analytical chemistry</topic><topic>Animals</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - toxicity</topic><topic>Chemical compounds</topic><topic>Drug Design</topic><topic>Female</topic><topic>Humans</topic><topic>Hydrophobic and Hydrophilic Interactions</topic><topic>Informatics</topic><topic>Leukemia</topic><topic>Leukemia - drug therapy</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Molecular Structure</topic><topic>Nitrogen</topic><topic>Nitrogen Mustard Compounds - chemistry</topic><topic>Nitrogen Mustard Compounds - pharmacology</topic><topic>Nitrogen Mustard Compounds - toxicity</topic><topic>Pharmaceutical Modeling</topic><topic>Quantitative Structure-Activity Relationship</topic><topic>Rats</topic><topic>Static Electricity</topic><topic>Steroids</topic><topic>Steroids - chemical synthesis</topic><topic>Steroids - pharmacology</topic><topic>Steroids - toxicity</topic><topic>Thermodynamics</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kapou, Agnes</creatorcontrib><creatorcontrib>Benetis, Nikolas-P</creatorcontrib><creatorcontrib>Durdagi, Serdar</creatorcontrib><creatorcontrib>Nikolaropoulos, Sotiris</creatorcontrib><creatorcontrib>Mavromoustakos, Thomas</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Computer and Information Systems Abstracts</collection><collection>Engineered Materials Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>Computer and Information Systems Abstracts Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><jtitle>Journal of Chemical Information and Modeling</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kapou, Agnes</au><au>Benetis, Nikolas-P</au><au>Durdagi, Serdar</au><au>Nikolaropoulos, Sotiris</au><au>Mavromoustakos, Thomas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>3D QSAR/CoMFA and CoMSIA Studies on Antileukemic Steroidal Esters Coupled with Conformationally Flexible Nitrogen Mustards</atitle><jtitle>Journal of Chemical Information and Modeling</jtitle><addtitle>J. Chem. Inf. Model</addtitle><date>2008-11-24</date><risdate>2008</risdate><volume>48</volume><issue>11</issue><spage>2254</spage><epage>2264</epage><pages>2254-2264</pages><issn>1549-9596</issn><eissn>1520-5142</eissn><eissn>1549-960X</eissn><abstract>Thirty-eight antileukemic steroidal esters possessing conformationally flexible nitrogen mustards were studied, and the 3D QSAR/CoMFA and CoMSIA methodologies were applied in order to derive the correlation between their structure and the in vivo antileukemic activity. These compounds show significantly reduced toxicity and possibly increased bioavailability compared to free nitrogen mustards and therefore constitute potent antileukemic drugs. Both the CoMFA and CoMSIA studies gave similar results indicating that the steric effect and the hydrophobic/hydrophilic balance especially in the steroidal part of the molecules probably determined their bioactivity. Of paramount interest is the observation that the orientation of the alkylating part of the SMEs toward the surface of ring B of the steroidal skeleton was related with increased activity. Concerning the steroidal part, the presence of hydrophobic groups in rings B and D was found to be important for enhanced activity. Enhancement of antileukemic potency is further observed if hydrophilic/H-bond acceptor groups are present at the positions 7 and 17 of the steroidal skeleton. Leapfrog simulations provided novel compounds which lead our future synthetic endeavor for obtaining SMEs with optimum bioactivity.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>18954137</pmid><doi>10.1021/ci800240m</doi><tpages>11</tpages></addata></record> |
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| subjects | Analytical chemistry Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antineoplastic Agents - toxicity Chemical compounds Drug Design Female Humans Hydrophobic and Hydrophilic Interactions Informatics Leukemia Leukemia - drug therapy Male Mice Mice, Inbred BALB C Models, Molecular Molecular Conformation Molecular Structure Nitrogen Nitrogen Mustard Compounds - chemistry Nitrogen Mustard Compounds - pharmacology Nitrogen Mustard Compounds - toxicity Pharmaceutical Modeling Quantitative Structure-Activity Relationship Rats Static Electricity Steroids Steroids - chemical synthesis Steroids - pharmacology Steroids - toxicity Thermodynamics Toxicity |
| title | 3D QSAR/CoMFA and CoMSIA Studies on Antileukemic Steroidal Esters Coupled with Conformationally Flexible Nitrogen Mustards |
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