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Shrestha, Aarajana,Jo, Hyunji,Kwon, Youngjoo,Lee, Eung-Seok Elsevier 2018 Bioorganic & medicinal chemistry letters Vol.28 No.4
<P><B>Abstract</B></P> <P>Human DNA topoisomerases have become attractive targets for developing more effective anticancer drugs. In this study, a series of new benzofuro[3,2-<I>b</I>]pyridin-7-ols were designed and synthesized for the first time and screened for their topoisomerase I and II inhibitory and antiproliferative activity. Structure-activity relationships revealed the position of <I>ortho</I>- and <I>para</I>-hydroxyl group at 2-phenyl ring, and <I>meta</I>-hydroxyl group at 4-phenyl ring of benzofuro[3,2-<I>b</I>]pyridin-7-ol are important for potent and selective topo II inhibitory activity. Compound <B>11</B> showed the most selective and potent topo II inhibition (100% inhibition at 100 µM) and strongest antiproliferative activity (IC<SUB>50</SUB> = 0.86 µM) than all the positive controls in HeLa cell line.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Aarajana Shrestha,,Ritina Shrestha,Sumin Lee,박필훈,Eung-Seok Lee 대한화학회 2021 Bulletin of the Korean Chemical Society Vol.42 No.3
6-Hydroxy-benzofuran-3-(2H)-ones exhibiting LPS stimulated ROS inhibition in RAW 264.7 macrophage
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>
Shrestha, Aarajana,Park, Seojeong,Jang, Hae Jin,Katila, Pramila,Shrestha, Ritina,Kwon, Youngjoo,Lee, Eung-Seok Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.18
<P><B>Abstract</B></P> <P>DNA Topoisomerase IIα (topo IIα) is one of the most effective therapeutic targets to control cancer. In an effort to develop novel and effective topo IIα targeting anti-proliferative agent, a phenolic series of indenopyridinone and indenopyridinol were designed and prepared using efficient multi-component one pot synthetic method. Total twenty-two synthesized compounds were assessed for topo I and IIα inhibition, and anti-proliferation in three different human cancer cell lines. Overall structure-activity relationship study explored the significance of <I>meta-</I>phenolic group at 4-position and <I>para-</I>phenolic group at 2- and/or 4-position of indenopyridinone skeleton for strong topo IIα-selective inhibition and anti-proliferative activity against human cervix (HeLa) and colorectal (HCT15) cell lines. Compound <B>12</B> with excellent topo IIα inhibition (93.7%) was confirmed as a DNA intercalator that could be a new promising lead to develop effective topo IIα-targeted anticancer agents.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Phenolic series of indenopyridinone were synthesized. </LI> <LI> SAR study was performed by comparing topo inhibitory and anti-proliferative activity. </LI> <LI> <I>para-</I>Phenolic group at 2- and/or 4-position of indenopyridinones is important. </LI> <LI> Compound <B>12</B> acted as DNA-intercalative potent topo IIα inhibitor. </LI> <LI> Indenopyridinone as potential scaffold for anticancer activity. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Katila, Pramila,Shrestha, Aastha,Shrestha, Aarajana,Shrestha, Ritina,Park, Pil-Hoon,Lee, Eung-Seok Elsevier 2019 Bioorganic chemistry Vol.87 No.-
<P><B>Abstract</B></P> <P>The design and synthesis of a series of thirty-two halogenated 1-tetralone or 6-amino-1-tetralone chalcone derivatives was achieved by the Claisen-Schmidt condensation reaction and were evaluated for their inhibitory effects against ROS production in LPS-stimulated RAW 264.7 macrophages. It was observed that the introduction of amino moiety into 1-tetralone skeleton greatly increased the inhibitory potency compared to corresponding 1-tetralone chalcones. Among the synthesized compounds, compound <B>18</B> which consists of 6-amino-1-tetralone skeleton together with <I>o</I>-fluorobenzylidene showed the most potent ROS inhibitory effect with IC<SUB>50</SUB> value of 0.25 ± 0.13 µM. SAR analysis revealed that amino moiety at the 6th position of 1-tetralone chalcones have an important role for exerting the greater ROS inhibitory potency in LPS-stimulated RAW 264.7 macrophages than those exhibited by 1-tetralone chalcones alone.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Halogenated 1-tetralone/6-amino-1-tetralone chalcone derivatives were synthesized. </LI> <LI> ROS Inhibitory effect in LPS-stimulated RAW 264.7 macrophages was examined. </LI> <LI> Compounds <B>18</B> showed the most potent ROS inhibition potency. </LI> <LI> Intro duction of amino group at the 6th position was enhanced the ROS inhibition. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
( Kyung-hwa Jeon ),( Aarajana Shrestha ),( Hae Jin Jang ),( Jeong-ahn Kim ),( Naeun Sheen ),( Minjung Seo ),( Eung-seok Lee ),( Youngjoo Kwon ) 한국응용약물학회 2021 Biomolecules & Therapeutics(구 응용약물학회지) Vol.29 No.5
Topoisomerase IIα has been a representative anti-cancer target for decades thanks to its functional necessity in highly proliferative cancer cells. As type of topoisomerase IIα targeting drugs, topoisomerase II poisons are frequently in clinical usage. However, topoisomerase II poisons result in crucial consequences resulted from mechanistically induced DNA toxicity. For this reason, it is needed to develop catalytic inhibitors of topoisomerase IIα through the alternative mechanism of enzymatic regulation. As a catalytic inhibitor of topoisomerase IIα, AK-I-191 was previously reported for its enzyme inhibitory activity. In this study, we clarified the mechanism of AK-I-191 and conducted various types of spectroscopic and biological evaluations for deeper understanding of its mechanism of action. Conclusively, AK-I-191 represented potent topoisomerase IIα inhibitory activity through binding to minor groove of DNA double helix and showed synergistic effects with tamoxifen in antiproliferative activity.
Kadayat, Tara Man,Park, Seojeong,Shrestha, Aarajana,Jo, Hyunji,Hwang, Soo-Yeon,Katila, Pramila,Shrestha, Ritina,Nepal, Mahesh Raj,Noh, Keumhan,Kim, Sang Kyoon,Koh, Woo-Suk,Kim, Kil Soo,Jeon, Yong Hyun American Chemical Society 2019 Journal of medicinal chemistry Vol.62 No.17
<P>With the aim of developing new effective topoisomerase IIα-targeted anticancer agents, we synthesized a series of hydroxy- and halogenated 2,4-diphenyl indeno[1,2-<I>b</I>]pyridinols using a microwave-assisted single step synthetic method and investigated structure-activity relationships. The majority of compounds with chlorophenyl group at 2-position and phenol group at the 4-position of indeno[1,2-<I>b</I>]pyridinols exhibited potent antiproliferative activity and topoisomerase IIα-selective inhibition. Of the 172 compounds tested, <B>89</B> showed highly potent and selective topoisomerase IIα inhibition and antiproliferative activity in the nanomolar range against human T47D breast (2.6 nM) cancer cell lines. In addition, mechanistic studies revealed compound <B>89</B> is a nonintercalative topoisomerase II poison, and in vitro studies showed it had promising cytotoxic effects in diverse breast cancer cell lines and was particularly effective at inducing apoptosis in T47D cells. Furthermore, in vivo administration of compound <B>89</B> had significant antitumor effects in orthotopic mouse model of breast cancer.</P> [FIG OMISSION]</BR>
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>
Magar, Til Bahadur Thapa,Seo, Seung Hee,Kadayat, Tara Man,Jo, Hyunji,Shrestha, Aarajana,Bist, Ganesh,Katila, Pramila,Kwon, Youngjoo,Lee, Eung-Seok Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.8
<P><B>Abstract</B></P> <P>As part of our effort to develop potential topoisomerase IIα (topo IIα) targeting anticancer agents, we systematically designed a new series of hydroxy and chloro-substituted 2,4-diphenyl 5<I>H</I>-chromeno[4,3-<I>b</I>]pyridines. Total eighteen compounds were synthesized and tested for their ability to inhibit the function of topo I and IIα, and proliferation of human breast (T47D), colorectal (HCT15), and cervix (HeLa) cancer cells. Except compound <B>11</B>, all of the tested compounds displayed selective topo IIα inhibitory activity. Compounds <B>8</B>–<B>18</B>, <B>22</B>, <B>24</B>, and <B>25</B> showed excellent topo IIα inhibitory activity than a positive control, etoposide. Most of the compounds appeared to be superior to reference compounds in their antiproliferative activity. Structure-activity relationship (SAR) study has shown that it is better to place the hydroxyphenyl group at the 4-position of the central pyridine for superior topo IIα inhibition and antiproliferative activity. Similarly, the 3′-, or 4′-hydroxyphenyl substitution at the 2- and 4-positon of pyridine ring is important for better activity than 2′-substitution.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A new series of hydroxy and chloro-substituted 2,4-diphenyl 5<I>H</I>-chromeno[4,3-<I>b</I>]pyridines were synthesized. </LI> <LI> Evaluated for topo I and IIα inhibitory activity, and antiproliferative activity. </LI> <LI> Compounds showed selective topo IIα inhibitory activity. </LI> <LI> SAR study indicated the importance of hydroxyphenyl-substitution at 4-position. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>