ࡱ> $&#5'` bjbjDD 5&&5%DDDz4RRR8 (zzz$mh4ED":@4y8D,D R0D@zvTDD|zzz44p^zzz R RXlz QSAR analysis and proposal of new heterocyclic compounds with potential antitumor activity Branimir Bertoaa,1 Sanja Tomi,1 Maja Aleksi 2, Grace Karminski-Zamola2 1 Division of Physical Chemisty, Ruer Boakovi Institute, Bijeni ka cesta 54, 10 000 Zagreb, Croatia, bbertosa@irb.hr. 2 Faculty of Chemical Engineering and Technology, Maruliev trg 19, 10 000 Zagreb, Croatia, maleksic@fkit.hr Quantitative Structure Activity Relationship (QSAR) models for predicting antitumor activity of heterocyclic amides and quinolones from benzo[b]thiophene-, thieno[3,2-b]thiophene- and thieno[2,3-b], thiophene series were built. Dataset consisted of 56 compounds with measured antitumor activity. For each compound VolSurf descriptors were derived and correlated with the biological activity using Partial Least Square analysis. Beside standard approaches for building QSAR models, the approach based on a small dataset of 10 compounds selected regarding the results of Principal Component Analysis (PCA), was tested. The latter approach was shown as successful and it seems useful for planning experiments in order to speed up and simplify the search for new drug candidates. Results of PCA and QSAR analysis enabled identification of molecular properties with the highest impact on antitumor activity. Volume, sum of the hydrophobic surface areas and presence of the group that can be easily ionized in the pH range from 4 to 9, were found to be highly important for successful antitumor activity of the investigated compounds.[1] Using this knowledge, new compounds were proposed for synthesis and biological testing. Their activities were predicted using the derived QSAR models and the proposed compounds were shown as promising antitumor candidates.  [1]   & F H J L < >    3 4 > O P  ?Ի®–yqymiyiiyih+"hkhkh8to6 hkh8to h8to6h8to h8toaJ h8toH*aJh8to\aJmHsHh<^WH*\aJmH sH h8toH*\aJmH sH  h<^WH*aJh8to\aJmH sH  h8toH*aJ h8toaJh8to>*\aJmH sH 0h8to5CJOJPJQJ\^JaJmHnHsH(J <   $2d ^2`a$$d a$d  ^`$a$`6TZx\^lprtƶ|php`TjhkOJQJUjhkUhkCJ^JjhkCJU^JhkOJQJ^Jh2jh2U!h8to5CJOJQJaJmHsH!h8to6CJOJQJaJmHsHUh8toCJOJQJaJmHsHhUOJQJh<^WOJQJh8toOJQJ&jhUOJQJUmHnHtH uhUh8to h8toH* B. Bertoaa, M. Aleksi, G. Karminski-Zamola Int. J. Pharm. 2010, 294, 106-114.     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(CH2)3N(CH3)2!% 9aDD!% MEBD!% +ED!N% .E̕D!% ;EvD!% 3ED! DkD '  '  '  '  '  ' "4 (CH2)3N(CH3)26=  N E&XD<0!% &DKD!N% C D!% XAKD!% CD!% uD D!% 6D|C!% :iCDAD!% \DVB!% EC ' (.  '  ' (.  '  ' (.  '  '  '  ' (.  '  '  '   '   '   '   '  (.  '   '  (.  '  '  (.  ' (  '   '  '  '  '  '  '  '  '  % ( % ( FGDIC" ( ( ( ( " % ( " " FGDIC% 666666666666666666666666666666666666 6 66 6  6 66 6  6 66 6  6 66 6  6 66 6 66666666666666666666  ."System-@"Arial Narrow- z2 LJPlenary/Invited lecture / Poster (reserved for editorial purposes; do not                    ,'-2 bchange)  ,'@"Microsoft Sans Serif-,'- 2 |D ,'-,'@"Arial Narrow- 2 D ,'-2 The 5e @"Arial Narrow-2 th-72  Central European Conference       2 &2  Chemistry towards    ;2   Biology, Primoten, September 8       2 2 11, 2010 2 3 ,'--$z|D|Dzz--'--$DD--'@"Arial- h2 >QSAR analysis and proposal of new heterocyclic compounds with               72 \potential antitumor activity          2  @"Helvetica- #2 Branimir Bertoa   - @ !- 2 J,@"Helvetica- 2 Q1- 2 X _@"Helvetica- .2 _ Sanja Tomi    .-  2 ,- 2 1- 2  @"Helvetica- .2  Maja Aleksi    .-  - 2 o - 2 s2- 2 {, Grace  2  Karminski   2 --- 2 Zamola   - 2 2- 2  @"Helvetica- 2 1@"Helvetica- %@"Helvetica-.2 %U Division of Physical Chemisty, Ruer Bokovi Institute, Bijenika cesta 54, 10 000                     .- 2 9Zagrea  72 9b, Croatia, bbertosa@irb.hr.          2 9 - 2 O2- W@"Helvetica-.2 WR Faculty of Chemical Engineering and Technology, Maruliev trg 19, 10 000 Zagreb,               .- 12 lCroatia, maleksic@fkit.hrh         2 lM  2  @"Helvetica-,2 Quantitative Structure       2 Q X2 \3Activity Relationship (QSAR) models for predicting               -J2 *antitumor activity of heterocyclic amides             22 and quinolones from benzo[      @"Helvetica- 2 b -2  ]thiophene  2 C-2 J, -2  thieno[3,2    2 -- 2 b -2  ]thiophene  2 I-"2 O and thieno[2,3     2 -- 2 b -G2 (], thiophene series were built. Dataset         2 Nconsisted of 56 compounds with measured antitumor activity. For each compound                    Y2 4VolSurf descriptors were derived and correlated with               2 Z the a  2 b 2  iological   2   activity   2  using  }2 .LPartial Least Square analysis. Beside standard approaches for building QSAR                 v2 IGmodels, the approach based on a small dataset of 10 compounds selected              [2 d5regarding the results of Principal Component Analysis               2 do ( 2 dPCA  2 d)&2 d, was tested. The      "2 ~latter approach    b2 ~: was shown as successful and it seems useful for planning             2 Rexperiments in order to speed up and simplify the search for new drug candidates.                       2  Results of o    2 P 2 CA 2  and g 2 > QSAR analysis    S2 0 enabled identification of molecular properties             2  with the hii   L2 +ghest impact on antitumor activity. Volume,t            /2 o sum of the hydrophobic      2  surface areas    t2 F and presence of the group that can be easily ionized in the pH range                   2 Tfrom 4 to 9, were found to be highly important for successful antitumor activity of                         -42 the investigated compounds.      @"Helvetica-2 [1]-+2  Using this knowledgei      2 p, 2 v new compounds   2  were   2 9 proposed o  }2 9Lfor synthesis and biological testing. Their activities were predicted using                        |2 TKthe derived QSAR models and the proposed compounds were shown as promising                      +2 oantitumor candidates.i       2 oA  2   2   2   2   2   2   2 )  2 D  2 _ - 2 x[1]  2 x x@"Helvetica-.A2 x$B. Bertoa, M. Aleksi, G. Karminski       .-  2 x-2 xZamola   @"Helvetica-"2 xInt. J. 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