Original article : Discovery of dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridine as a non-intercalative DNA-binding topoismerase ll-specific catalytic inhibitor

( Kyu Yeon Jun ),( Hanbyeol Kwon ),( So Eun Park ),( Eunyoung Lee ),( Radha Karki ),( Pritam Thapa ),( Jun Ho Lee ),( Eung Seok Lee ),( Youngjoo Kwon ) 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0

We describe our rationale for designing specific catalytic inhibitors of topoisomerase II (topo II) over topoisomerase I (topo I). Based on 3D-QSAR studies of previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives, 9 novel dihydroxylated 2,4-diphenyl-6-thiophen-2-yl pyridine compounds were designed, synthesized, and their biological activities were evaluated. These compounds have 2-thienyl ring substituted on the R(3) group on the pyridine ring and they all showed excellent specificity toward topo II compared to topo I. In vitro experiments were performed for compound 13 to determine the mechanism of action for this series of compounds. Compound 13 inhibited topoisomerase II specifically by non-intercalative binding to DNA and did not stabilize enzyme-cleavable DNA complex. Compound 13 efficiently inhibited cell viability, cell migration, and induced G1 arrest. Also from 3D-QSAR studies, the results were compared with other previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives to explain the structure-activity relationships.ⓒ2014 Elsevier Masson SAS. All rights reserved.

Medicinal Chemistry : ELSEVIER ; Qriginal article : Synthesis, and biological activity of 2,4-di-p-phenolyl-6-2-furanyl-pyridine as a potent topoisomerase 2 poison

( Radha Karki ),( Chan Mi Park ),( Kyu Yeon Jun ),( Tara Man Kadayat ),( Eung Seok Lee ),( Young Joo Kwon ) 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-

Dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives were simply achieved using Claisen-Schmidt condensation reaction and mdifiled Krohnke pyridine synthetic method. Total forty-five compounds were designed and synthesized which contain hydroxyl groups at ortho, meta or para position of 2- and 4-phrnyl rings attached to the central pyridine. They were evaluated for topoisomerase I and II inhibitory activity, and cytotoxicity against several human cancer cell lines for the development of novel antitumor agents. Most of the prepared compounds exhibited dignificant antiproliferative activity on human cancer cell lines, HCT15 and K562, as well as potent topo II inhibitory activity comparable to or stronger than etoposide. The structure-activity relationship demonstrated that compounds with hydroxyl group at meta or para position of 2-phenyl ring in combination with htdroxyl at ottho, meta or para position of 4-phenyl ring displayed the most potent topoisomerase II inhibitory activity and cytotoxicity. Posirice correlation between topoisomerase II inhibition and cytotoxicity was obtained for several compounds (30, 35, 36, 40-45, 49, 54, 56). Compound 56 showed the most potent topoisomerase II inhibitory activity at low concentrartion and functioned as a topoisomerase poison like the mode of action of etoposide. ⓒ2014 Elsevier Masson SAS. All rights reserved.

Dihydroxylated 2,6-diphenyl-4-chlorophenylpyridines: Topoisomerase I and IIα dual inhibitors with DNA non-intercalative catalytic activity

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>

(2S,3R)-3-하이드록시호모세린락톤의 입체선택적 합성 : 바이닐글라이신 OBO Ester 유도체의 입체선택적인 이중알콜화 반응

고무현 ( Moo-hyun Koh ),전종호 ( Jongho Jeon ),김영규 ( Young Gyu Kim ) 한국공업화학회 2020 공업화학 Vol.31 No.2

(2S,3R)-3-hydroxyhomoserine lactone (HSL)은 생리학적 활성을 가지는 다양한 종류의 화합물을 합성하기 위한 중간체로 활용되어 왔다. 본 논문에서는 OBO ester로 보호된 바이닐글라이신 유도체에 이중알콜화 반응을 수행하여 효율적인 HSL 합성 결과를 보고하고자 한다. 바이닐글라이신의 비고리 conformation은 크기가 큰 OBO ester에 의해 조절되었으며 N-inside conformation을 통해 이중알콜화 반응이 진행됨으로써 높은 anti 선택성(> 10 : 1)을 얻을 수 있었다. 이러한 결과를 바탕으로 N-Cbz-L-serine을 출발물질로 사용하여 총 7단계 34%의 수율로 HSL을 합성할 수 있었다. 본 연구의 결과는 amino diol 구조를 가지는 다양한 생리활성 천연물들의 입체선택적인 합성에 유용하게 활용될 수 있을 것으로 기대된다. (2S,3R)-3-hydroxyhomoserine lactone (HSL) has been used as a key intermediate for the synthesis of various biologically active compounds. In this study, we demonstrated an efficient synthesis of HSL via anti selective dihydroxylation of a protected vinyl glycine analog with an oxabicyclo[2.2.2]octyl orthoester (OBO) ester group. Because the acyclic conformation of the substrate was efficiently controlled by the bulky OBO ester group, a diastereoselectivity of > 10 : 1 was obtained in the dihydroxylation reaction without the use of a chiral reagent. By using this result, the target compound 1 can be obtained from commercially available N-Cbz-L-serine 2 in seven steps with an overall yeid of 34%. This result could be applied to the stereoselective synthesis of biologically active molecules containing a vicinal amino diol moiety.

(2S,3S,4S)-3,4-다이하이드록시글루타믹산의 효율적인 입체선택적 합성

전종호 ( Jong Ho Jeon ),신나라 ( Na Ra Shin ),이종협 ( Jong Hyup Lee ),김영규 ( Young Gyu Kim ) 한국공업화학회 2014 공업화학 Vol.25 No.4

(2S,3S,4S)-3,4-Dihydroxyglutamic acid (DHGA), a biologically active α,β-dihydroxy-γ-amino acid, was efficiently synthesizedfrom a readily available D-serine derivative in 30% overall yield over 11 steps. The key stereoselective OsO4-catalyzeddihydroxylation reaction controlled by an N-diphenylmethylene group on the amino group of γ-amino-α,β-unsaturated(Z)-ester successfully introduced the diol moiety of the intermediate 5a in 86% with more than 10 : 1 diastereomeric ration. Then it was in turn successfully converted to the desired target compound, (2S,3S,4S)-3,4-DHGA, via simple oxidation andhydrolysis in a highly stereoselective manner and a higher yield than the previous syntheses. This result strongly supportsthat our synthetic methodology of stereoselective OsO4-catalyzed dihydroxylation should be useful in stereoselctive synthesisof various bioactive compounds with an amino diol moiety.

Regioselective β -Functionalizations of syn-2,3-Dihydroxy Esters

Park, Jung-Nam,Ko, Soo-Y. Korean Chemical Society 2002 Bulletin of the Korean Chemical Society Vol.23 No.3