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( 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.
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>
Man Kadayat, Tara,Lee, Geumwoo,Jung, Kyungjin,Hwang, Hee-Jong,Joo, Jeongmin,Hahn, Dongyup,Hwang, Hayoung,Park, Keun-Gyu,Cho, Sung Jin,Kim, Kyung-Hee,Chin, Jungwook Elsevier 2018 Tetrahedron letters: the international organ for t Vol.59 No.50
<P><B>Abstract</B></P> <P>Peroxisome proliferator-activated receptor delta (PPARδ) is considered as a promising biological target for the development of new drugs to treat metabolic syndrome including hyperlipidemia. In this study, a simple and efficient method for the preparation of a unique dimethyl thiazoline containing intermediate (<B>13</B>) of new PPARδ agonists as GW501516 analogue is described. The intermediate <B>13</B> was readily obtained by coupling reaction of 4-(chloromethyl)-5,5-dimethyl-2-(4-(trifluoromethyl)phenyl)-4,5-dihydrothiazole (<B>11</B>) with 4-mercapto-2-methylphenol (<B>12</B>) in the presence of tetrabutylammonium hydrogensulfate (TBAHS) and Cs<SUB>2</SUB>CO<SUB>3</SUB> in DMF at 80 °C for 1 h. This unique intermediate could be useful for the synthesis of various novel PPARδ agonists to understand the structural and biological significance of PPARδ.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Method for unique dimethyl thiazoline containing intermediate of PPARδ agonists. </LI> <LI> <I>TBAHS</I> as catalyst for efficient coupling of <B>11</B> with <B>12</B>. </LI> <LI> Potential use of intermediate <B>13</B> for synthesis of novel PPARδ-selective agonists. </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>
( Tara Man Kadayat ),( Mi Jin Kim ),( Tae Gyu Nam ),( Pil Hoon Park ),( Eung Seok Lee ) 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0
Twelve thienyl/furanyl-hydroxyphenylpropenones were systematically designed and synthesized, and evaluated for their inhibitory effect on LPS-induced ROS and NO production in RAW 264.7 macrophages. Compound 11 displayed the most significant inhibitory activity of LPS-induced ROS and NO production in RAW 264.7 macrophages. Structure-activity relationship study indicated that para-hydroxyphenyl moiety plays an important role for inhibitory activities on both LPS-induced ROS and NO production as well as 3-thienyl moiety on molecule.
( 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.
Kadayat, Tara Man,Kim, Mi Jin,Nam, Tae-Gyu,Park, Pil-Hoon,Lee, Eung-Seok Korean Chemical Society 2014 Bulletin of the Korean Chemical Society Vol.35 No.8
Twelve thienyl/furanyl-hydroxyphenylpropenones were systematically designed and synthesized, and evaluated for their inhibitory effect on LPS-induced ROS and NO production in RAW 264.7 macrophages. Compound 11 displayed the most significant inhibitory activity of LPS-induced ROS and NO production in RAW 264.7 macrophages. Structure-activity relationship study indicated that para-hydroxyphenyl moiety plays an important role for inhibitory activities on both LPS-induced ROS and NO production as well as 3-thienyl moiety on molecule.
( Tara Man Kadayat ),( Chanju Song ),( Youngjoo Kwon ),( Eung Seok Lee ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-
As a part of ongoing studies in developing novel anticancer agents, a series of modified 2,4-diaryl-5H-indeno[1.2-b )pyridines were designed. and synthesized by introducing hydroxyl and chlo-rine moieties. They were evaluated for topoisomerase inhibitory activity and cytotoxicity against HCT15. T47D. and HeLa cancer cell lines. This modification allowed us to demonstrate structure-activity relation-ship (SAR) study with respect to the non-substituted 2,4-diaryl-5H-indenoI1.2-b]pyridines. Compounds (2, 3, 4, S, 8, and 9) with meta or para hydroxyl group on 2 or 4-phenyl ring have enhanced topo I and II inhibitory activity and cytotoxicity. However. additional substitution of chlorine group on furyl or thie-nyl ring (11.12.14.16-18) generally reduced topo I and II inhibitory activity but improved cytotoxicity. The observation of cytotoxic properties and SAR study according to the position of hydroxyl and chlorine group will provide valuable insight for further study of development of novel anticancer agents with related scaffolds.
( 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.
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>