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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>
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>
( 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.
Therapeutic Properties and Biological Benefits of Marine-Derived Anticancer Peptides
Kang, Hee Kyoung,Choi, Moon-Chang,Seo, Chang Ho,Park, Yoonkyung MDPI 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.3
<P>Various organisms exist in the oceanic environment. These marine organisms provide an abundant source of potential medicines. Many marine peptides possess anticancer properties, some of which have been evaluated for treatment of human cancer in clinical trials. Marine anticancer peptides kill cancer cells through different mechanisms, such as apoptosis, disruption of the tubulin-microtubule balance, and inhibition of angiogenesis. Traditional chemotherapeutic agents have side effects and depress immune responses. Thus, the research and development of novel anticancer peptides with low toxicity to normal human cells and mechanisms of action capable of avoiding multi-drug resistance may provide a new method for anticancer treatment. This review provides useful information on the potential of marine anticancer peptides for human therapy.</P>