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Bist, Ganesh,Park, Seojeong,Song, Chanju,Thapa Magar, Til Bahadur,Shrestha, Aarajana,Kwon, Youngjoo,Lee, Eung-Seok S.E.C.T. [etc.] 2017 European journal of medicinal chemistry Vol.133 No.-
<P><B>Abstract</B></P> <P>With the aim to develop novel antiproliferative agents, a new series of eighteen dihydroxylated 2,6-diphenyl-4-chlorophenylpyridines were systematically designed, prepared, and investigated for their topoisomerase (topo) I and IIα inhibitory properties and antiproliferative effect in three different human cancer cell lines (HCT15, T47D, and HeLa). Compounds <B>22–30</B> which possess a <I>meta</I>- or <I>para</I>-phenol on 2-, or 6-position of central pyridine ring showed significant dual topo I and topo IIα inhibitory activities with strong antiproliferative activities against all the tested human cancer cell lines. However, compounds <B>13</B>–<B>21</B> which possess an <I>ortho</I>-phenol on 2-, or 6-position of central pyridine ring did not show significant topo I and topo IIα inhibitory activities but displayed moderate antiproliferative activities against all the tested human cancer cell lines. Compound <B>23</B> exhibited the highest antiproliferative potency as much as 348.5 and 105 times compared to etoposide and camptothecin, respectively, in T47D cancer cell line. The structure-activity relationship study revealed that the <I>para</I> position of a hydroxyl group at 2-and 6-phenyl ring and chlorine atom at the <I>para</I> position of 4-phenyl ring of the central pyridine exhibited the most significant topo I and topo IIα inhibition, which might indicate introduction of the chlorine atom at the phenyl ring of 4-pyridine have an important role as dual inhibitors of topo I and topo IIα. Compound <B>30</B> which showed the most potent dual topo I and topo IIα inhibition with strong antiproliferative activity in T47D cell line was selected to perform further study on the mechanism of action, which revealed that compound <B>30</B> functions as a potent DNA non-intercalative catalytic topo I and IIα dual inhibitor.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Dihydroxylated 2,6-diphenyl-4-chlorophenylpyridines were designed and synthesized. </LI> <LI> Introduction of chlorine on 4-phenyl ring of central pyridine showed strong dual topo I and IIα inhibitor. </LI> <LI> Compound <B>30</B> exhibited the most potent dual topo I and IIα inhibition with strong antiproliferative activity. </LI> <LI> Compound <B>30</B> acts as a DNA non-intercalative catalytic topo IIα inhibitor. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Kadayat, Tara Man,Banskota, Suhrid,Bist, Ganesh,Gurung, Pallavi,Magar, Til Bahadur Thapa,Shrestha, Aarajana,Kim, Jung-Ae,Lee, Eung-Seok Elsevier 2018 Bioorganic & medicinal chemistry letters Vol.28 No.14
<P><B>Abstract</B></P> <P>A series of pyridine-linked indanone derivatives were designed and synthesized to discover new small molecules for the treatment of inflammatory bowel disease (IBD). Compounds <B>5b</B> and <B>5d</B> exhibited strongest inhibitory activity against TNF-α-induced monocyte adhesion to colon epithelial cells (an <I>in vitro</I> model of colitis). In TNBS (2,4,6-trinitrobenzenesulfonic acid)-induced rat colitis model, oral administration of the compounds <B>5b</B> and <B>5d</B> ameliorated colitis with significant recovery in altered expressions of E-cadherin, TNF-α and IL-1β expressions, indicating <B>5b</B> and <B>5d</B> as potential agents for therapeutics development against IBD.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Synthesis of pyridine-linked indanone derivatives <B>2</B>, <B>5a–l</B>, <B>8a–c</B> and <B>11a–c</B>. </LI> <LI> Potent anti-inflammatory effect by compounds <B>2</B>, <B>5a</B>, <B>5b</B>, <B>5d</B>, <B>5f</B>, and <B>5h</B>. </LI> <LI> Hydroxyl group substitution is favorable but alkoxy groups at indanone ring is less favored. </LI> <LI> <B>5b</B> and <B>5d</B> as potential agents for inflammatory bowel disease. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Thapa Magar, Til Bahadur,Kadayat, Tara Man,Lee, Hwa-Jong,Park, Seojeong,Bist, Ganesh,Shrestha, Aarajana,Kwon, Youngjoo,Lee, Eung-Seok Elsevier 2017 Bioorganic & medicinal chemistry letters Vol.27 No.15
<P><B>Abstract</B></P> <P>A new series of 2-chloropheny-substituted benzofuro[3,2-<I>b</I>]pyridines were designed, synthesized, and evaluated for topoisomerase I and II inhibition and antiproliferative activity. Compounds <B>17</B>–<B>19, 23, 24, 26,</B> and <B>27</B> exhibited excellent topo II inhibitory activity. A systematic structure-activity relationship study revealed the important role of chlorine substitution in the strong topoisomerase inhibitory activity.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Park, Seojeong,Thapa Magar, Til Bahadur,Kadayat, Tara Man,Lee, Hwa Jong,Bist, Ganesh,Shrestha, Aarajana,Lee, Eung-Seok,Kwon, Youngjoo S.E.C.T. [etc.] 2017 European journal of medicinal chemistry Vol.127 No.-
<P><B>Abstract</B></P> <P>Novel series of conformationally constrained 2,4-chloro- and hydroxy-substituted diphenyl benzofuro[3,2-<I>b</I>]pyridines were rationally designed and synthesized. Their biological activities were evaluated for topoisomerase I and II inhibitory activity, and antiproliferative activity against several human cancer cell lines for the development of novel anticancer agents. Most of the compounds with phenol moiety at 4-position of central pyridine exhibited significant dual topoisomerase I and II inhibitory activities, and strong antiproliferative activity in low micromolar range. Structure activity relationship study suggested that phenol moiety at 4-position of the central pyridine regardless of chlorophenyl moiety at 2-position of the central pyridine has an important role in dual topoisomerase inhibitory activity as well as antiproliferative activity. For investigation of mode of action for compound <B>14</B> which displayed the most strong dual topoisomerase I and II inhibitory activity and antiproliferative activity against HCT15 cell, we performed cleavable complex assay, band depletion assay, comet assay, and competitive EtBr displacement assay. Compound <B>14</B> functioned as non-intercalative catalytic topo I and II dual inhibitor. In addition, compound <B>14</B> induced apoptosis in HCT15 cells through increase of Bax, decrease of Bcl-2 and increase of PARP cleavage.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A new class of dual topo inhibitors, 2,4-substituted diphenyl benzofuro[3,2-<I>b</I>]pyridines were prepared. </LI> <LI> Observed positive correlation with dual topo inhibition and antiproliferative activity. </LI> <LI> Benzofuran moiety and phenol on 4-position of central pyridine is crucial for both activity. </LI> <LI> Compound <B>14</B> acts as a non-intercalative catalytic dual topo I and II inhibitor. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
( Tara Man Kadayat ),( Seojeong Park ),( Kyu Yeon Jun ),( Til Bahadur Thapa Magar ),( Ganesh Bist ),( Aarajana Shrestha ),( Younghwa Na ),( Youngjoo Kwon ),( Eung Seok Lee ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-
In continuation of our previous work, six hydroxylated 2,4-diphenyl-5H-indenoll ,2-b ]pyridine analogs were modified by introducing one chlorine functionality at ortho, meta or para position of the 2- or 4-phe-nyl ring. Eighteen new chlorinated compounds were thus prepared and assessed for topoisomerase inhi-bitory activity and cytotoxicity against HG15, T470, and HeLa cancer cell lines. All of the chlorinated compounds displayed significant cytotoxic effect, revealing potent anticancer activity against T470 breast cancer cells. This functional group modification allowed us to explore the importance of chlorine group substitution for the cytotoxic properties. The information reported here provides valuable insight for further study to develop new anticancer agents using related scaffolds.
( Tara Man Kadayat ),( Chan Mi Park ),( Kyu Yeon Jun ),( Til Bahadur Thapa Magar ),( Ganesh Bist ),( Han Young Yoo ),( Young Joo Kwon ),( Eung Seok Lee ) 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-
For the development of potential anticancer agents, We designed and synthesized 30 new 2,4-diaryl-5H-indeno[1,2-ь]pyridine derivatives containing aryl moiery such as furyl, thienyl, Pyridyl, and phenyl at 2-and 4-position of 5H-indeno[1,2-ь]pyridine. They were avaluated for topoisomerase I and ll inhibitory activity, and cytotoxicity against several human cancer cell lines. Among prepared 30 compounds, 7,8,9,10,12,14,16,19,20,22, and 23 with 2-or 3-thienyl either at 2-or 4-position of central pyridine showed the significant or moderate topoisomerase ll inhibitory activity. Compoumds 7,8,11,12,13, and 22 with 2-furyl, 2-thienyl or 3-thienyl at 2-position of central pyridine showed the significant or moderate topoisomerase I inhibitory activity. Especially. compound 12 with strong topoisomerase ll inhibitory activity at 100 um and 20 um. and moderate topoisomerase I inhibitory activity displayed strong cytotoxicity against several human cancer cell lines. ⓒ 2014 Elsevier Ltd. All rights reserved.
( Pritam Thapa ),( Tara Man Kadayat ),( Seojeong Park ),( Somin Shin ),( Til Bahadur Thapa Magar ),( Ganesh Bist ),( Aarajana Shrestha ),( Younghwa Na ),( Youngjoo Kwon ),( Eung Seok Lee ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-
A new series of 2-phenol-4-chlorophenyl-6-aryl pyridines were designed, synthesized, and evaluated for topoisomerase (topo) I and II inhibitory activities as well as cytotoxic activity against four different human cancer cell lines such as HCT15, T47D, DU145, and Hela. Most of the tested compounds exhibited stronger topo II inhibitory activity at 100 μM as compared to etoposide. All the compounds, except 39, did not show topo I inhibitory activity. Interestingly, compounds that showed better topo II inhibition than etoposide have ortho- or para-chlorophenyl at 4-position of central pyridine, and none of the com-pounds possess meta-chlorophenyl. SAR study revealed the importance of ortha- or para-chlorophenyl at 4-position of the central pyridine for selective tapa II inhibitory activity. Similarly, all compounds possessing mere- or para-hydroxyphenyl moieties shawed moderate to significant cytotoxic effects. Particularly, compounds 27-37, and 39 which showed excellent cytotoxicity (IC<sub>50</sub> = 0.68-1.25 μM) against T47D breast cancer cells suggest the importance of meta- or para-hydroxyphenyl moiety at 2-position of the central pyridine for the design of anticancer agents with related scaffolds.
( Radha Karki ),( Kyu Yeon Jun ),( Tara Man Kadayat ),( Somin Shin ),( Til Bahadur Thapa Magar ),( Ganesh Bist ),( Aarajana Shrestha ),( Younghwa Na ),( Youngjoo Kwon ),( Eung Seok Lee ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-
As a continuous effort to develop novel antitumor agents, a new series of forty-five-2phenol-4-aryl-6-chlorophenyl pyridine compounds were synthesized and evaluated for cytotoxicity against four different human cancer cell lines(DU145, HCT15, T47D, and HeLa), and topoisomerase I and II inhibitory activity, Several compounds(10-15, 20, 22, 24, 28, 42, and 49) displayed strong to moderate dual topoisomerase I and II inhibitory activity at 100 μM. It was observed that hydroxyl and chlorine moiety at meta or para position of phenyl ring is favorable for dual topoisomerase inhibitory activity and cytotoxicity. Most of the compounds displayed stronger cytotoxicities than those of all positive controls against the HCT15 and T47D cell lines. For investigation of the structure-activity relationships, a 3D-QSAR analysis using the method of comparative molecular field analysis (CoMFA) was performed. The generated 3D contour maps can be used for further rational design of novel terpyridine derivatives as highly selective and potent cytotoxic agents.
( Pritam Thapa ),( Kyu Yeon Jun ),( Tara Man Kadayat ),( Chanmi Park ),( Zhi Zheng ),( Til Bahadur Thapa Magar ),( Ganesh Bist ),( Aarajana Shrestha ),( Younghwa Na ),( Youngjoo Kwon ),( Eung Seok Lee 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-
To develop novel selective topoisomerase II inhibitors, we designed and synthesized a series of conforma-tionally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines and evaluated their to poi so-merase inhibitory activity and cytotoxicity against three human cancer cell lines (DU145, HCn5, and T47D) and a normal cell line (MCF10A). All of the prepared compounds displayed stronger or similar topoisomerase II inhibitory activity as well as cytotoxicity against three human cancer cell lines com-pared to etoposide. Compounds 10., 109, 11., 11f, 11g, 12., 12f, and 12g especially showed stronger topoisornerase II inhibitory activity as compared to etoposide at both 100 μM and 20 μM. A structure-ac-tivity relationship study revealed that hydroxyphenyl moiety at 4-position of pyridine and ortho-hydrox-yphenyl or thienyl moiety at 2-position of pyridine has an important role in displaying selective topoisomerase II inhibition. The compound 12b with para-hydroxyphenyl and meta-hydroxyphenyl at 4- and 2-position of pyridine. respectively, showed the most significant cytotoxicity against all three can-cer cell lines, whereas less cytotoxicity to a normal cell line as compared to adriamycin.
Shrestha, Aarajana,Jin Oh, Hye,Kim, Mi Jin,Pun, Nirmala Tilija,Magar, Til Bahadur Thapa,Bist, Ganesh,Choi, Hongseok,Park, Pil-Hoon,Lee, Eung-Seok Elsevier 2017 European journal of medicinal chemistry Vol.133 No.-
<P><B>Abstract</B></P> <P>As a continuous effort to discover new potential anti-inflammatory agents, we systematically designed and synthesized sixty-one 2-benzylidene-1-indanone derivatives with structural modification of chalcone, and evaluated their inhibitory activity on LPS-stimulated ROS production in RAW 264.7 macrophages. Systematic structure-activity relationship study revealed that hydroxyl group in C-5, C-6, or C-7 position of indanone moiety, and <I>ortho</I>-, <I>meta</I>-, or <I>para</I>-fluorine, trifluoromethyl, trifluoromethoxy, and bromine functionalities in phenyl ring are important for inhibition of ROS production in LPS-stimulated RAW 264.7 macrophages. Among all the tested compounds, 6-hydroxy-2-(2-(trifluoromethoxy) benzylidene)-2,3-dihydro-1<I>H</I>-inden-1-one (compound <B>44</B>) showed the strongest inhibitory activity of ROS production. Further studies on the mode of action revealed that compound <B>44</B> potently suppressed LPS-stimulated ROS production via modulation of NADPH oxidase. The findings of this work could be useful to design 2-benzylidene-indanone based lead compounds as novel anti-inflammatory agents.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A series of halogen containing 2-benzylidene-indanone derivatives were synthesized. </LI> <LI> Evaluated for inhibition of ROS production in LPS-stimulated RAW 264.7 macrophages. </LI> <LI> Structure-activity relationship study was performed. </LI> <LI> C-5, C-6, and C-7 hydroxy-indanone analogues showed better inhibition than malvidin. </LI> <LI> Compound <B>44</B> suppressed LPS-stimulated NADPH oxidase activity. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>