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>

Novel 5,6-disubstituted pyrrolo[2,3-<i>d</i>]pyrimidine derivatives as broad spectrum antiproliferative agents: Synthesis, cell based assays, kinase profile and molecular docking study

Lee, Ju-Hyeon,El-Damasy, Ashraf K.,Seo, Seon Hee,Gadhe, Changdev G.,Pae, Ae Nim,Jeong, Nakcheol,Hong, Soon-Sun,Keum, Gyochang Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.21

<P><B>Abstract</B></P> <P>Two new series of 5-subtituted and 5,6-disubstituted pyrrolo[2,3-<I>d</I>]pyrimidine octamides (<B>4a</B>–<B>o</B> and <B>6a</B>–<B>g</B>) and their corresponding free amines <B>5a</B>–<B>m</B> and <B>7a</B>–<B>g</B> have been synthesized and biologically evaluated for their antiproliferative activity against three human cancer cell lines. The 5,6-disubstituted octamides <B>6d</B>–<B>g</B> as well as the amine derivative <B>7b</B> have shown the best anticancer activity with single digit micromolar GI<SUB>50</SUB> values over the tested cancer cells, and low cytotoxic effects (GI<SUB>50</SUB> > 10.0 µM) against HFF-1 normal cell. A structure activity relationship (SAR) study has been established and disclosed that terminal octamide moiety at C2 as well as disubstitution with fluorobenzyl piperazines at C5 and C6 of pyrrolo[2,3-<I>d</I>]pyrimidine are the key structural features prerequisite for best antiproliferative activity. Moreover, the most active member <B>6f</B> was tested for its antiproliferative activity over a panel of 60 cancer cell lines at NCI, and exhibited distinct broad spectrum anticancer activity with submicromolar GI<SUB>50</SUB> and TGI values over multiple cancer cells. Kinase profile of compound <B>6f</B> over 53 oncogenic kinases at 10 µM concentration showed its highly selective inhibitory activity towards FGFR4, Tie2 and TrkA kinases. The observed activity of <B>6f</B> against TrkA (IC<SUB>50</SUB> = 2.25 µM), FGFR4 (IC<SUB>50</SUB> = 6.71 µM) and Tie2 (IC<SUB>50</SUB> = 6.84 µM) was explained by molecular docking study, which also proposed that <B>6f</B> may be a type III kinase inhibitor, binding to an allosteric site rather than kinase hinge region. Overall, compound <B>6f</B> may serve as a promising anticancer lead compound that could be further optimized for development of potent anticancer agents.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Synthesis and <I>in vitro</I> antiproliferative activities of new pyrrolo[2,3-<I>d</I>]pyrimidines are reported. </LI> <LI> Compounds <B>6d–g</B> exerted single digit micromolar GI<SUB>50</SUB> values over the tested cancer cell lines. </LI> <LI> Compound <B>6f</B> has selective inhibitory activity towards FGFR4, Tie2 and TrkA kinases. </LI> <LI> Compound <B>6f</B> may be a type III allosteric kinase inhibitor. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Rational design, synthesis, and evaluation of novel 2,4-Chloro- and Hydroxy-Substituted diphenyl Benzofuro[3,2-<i>b</i>]Pyridines: Non-intercalative catalytic topoisomerase I and II dual inhibitor

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>

Antioxidant Activity, Inhibition of Nitric Oxide Overproduction, and In Vitro Antiproliferative Effect of Maple Sap and Syrup from Acer saccharum

Jean Legault,Karl Girard-Lalancette,Carole Grenon,Catherine Dussault,Andre´ Pichette 한국식품영양과학회 2010 Journal of medicinal food Vol.13 No.2

Antioxidant activity, inhibition of nitric oxide (NO) overproduction, and antiproliferative effect of ethyl acetate extracts of maple sap and syrup from 30 producers were evaluated in regard to the period of harvest in three different regions of Québec, Canada. Oxygen radical absorbance capacity (ORAC) values of maple sap and syrup extracts are, respectively, 12±6 and 15±5μmol of Trolox equivalents (TE)/mg. The antioxidant activity was also confirmed by a cell-based assay. The period of harvest has no statistically significant incidence on the antioxidant activity of both extracts. The antioxidant activity of pure maple syrup was also determined using the ORAC assay. Results indicate that the ORAC value of pure maple syrup (8±2μmol of TE/mL) is lower than the ORAC value of blueberry juice (24±1μmol of TE/mL) but comparable to the ORAC values of strawberry (10.7±0.4μmol of TE/mL) and orange (10.8±0.5μmol of TE/mL) juices. Maple sap and syrup extracts showed to significantly inhibit lipopolysaccharide-induced NO overproduction in RAW264.7 murine macrophages. Maple syrup extract was significantly more active than maple sap extract, suggesting that the transformation of maple sap into syrup increases NO inhibition activity. The highest NO inhibition induced by the maple syrup extracts was observed at the end of the season. Moreover, darker maple syrup was found to be more active than clear maple syrup, suggesting that some colored oxidized compounds could be responsible in part for the activity. Finally, maple syrup extracts (50% inhibitory concentration=42±6μg/mL) and pure maple syrup possess a selective in vitro antiproliferative activity against cancer cells.

만가닥 버섯의 일부 생리활성

최용민,이준수,장후봉,최재선,송인규,노재관,최성렬,민경범 경상대학교 농업생명과학연구원 2008 농업생명과학연구 Vol.42 No.1

Among various naturally occurring food resources, mushrooms have been used in traditional medicines and foods in many Asia. Numerous studies have been shown its medicinal attributes such as anti-tumor, liver function improving and cholesterol lowering activity. The objectives of this study were to determine antioxidant compounds and to evaluate biological activities of Lyopyllum ulmarium. The concentrations of total polypenolics and flavonoids in extracts were investigated by colorimetric methods. Electron donating activity, chelating effect, inhibitory effects of tyrosinase and angiotensin converting enzyme and antiproliferative activitis on the different cancer cell lines have been used to compare the relative biological activities of the mushroom. In this study, the hot water extracts prepared from Lyopyllum ulmarium exhibited significantly high amounts of total polyphenolic compounds (506.71 mg/100g) and biological activities including chelating activity (67.57%), inhibitory effect of angiotensin converting enzyme (84.08%) and antiproliferative activity on the breast cancer cell line (MCF7, 69.87%). The results of this study show that Lyopyllum ulmarium have notable biological activities for potential use in nutraceuticals or functional food formulations. 본 연구에서는 만가닥 버섯의 항산화 효과 및 생리활성 효과를 입증하여 농가 소득 증대에 기여 할 뿐만 아니라 신 기능성 식품개발에 대한 기초 자료를 제시하고자 하였다. 본 연구에서는 만가닥 버섯의 생리활성을 평가하기위해 항산화 성분 함량, 전자공여능, 금속이온 제거능, tyrosinase 및 angiotensin converting enzyme의 저해 활성, 그리고 항암 활성을 각각 측정하였다. 만가닥 버섯 열수 추출물의 총 폴리페놀 함량과 총 플라보노이드 함량은 각각 506.71, 69.62 mg/100g으로 나타났다. 만가닥 버섯 열수 추출물의 경우 전자 공여능 (34.61%)은 우수하지 않았지만 체내 주요 물질의 산화에 촉매로 작용하는 전이금속은 효과적으로 제거 (61.57%)하는 것을 알 수 있었다. 또한 tyrosinase에 대한 저해 효과를 측정한 결과, 만가닥 버섯은 16.56%의 저해율을 나타내었는데 이것은 버섯 자체의 tyrosinase 효소 활성이 높거나 tyrosinase의 기질이 될 수 있는 물질의 함유량이 높을 경우 혹은 tyrosinase activator가 존재하기 때문인 것으로 생각된다. Angiotensin converting enzyme에 대한 저해 효과를 측정한 결과 만가닥 버섯은 84.08%의 높은 저해율을 나타내어 고혈압 예방에 우수한 식품이 될 것으로 생각된다. 마지막으로 만가닥 버섯은 유방암세포에 (MCF7) 대해서 약 70%의 암세포 증식 억제 효과를 나타내었다.

Antioxidant and Antiproliferative Activities of Grape Seeds from Different Cultivars

Sung, Jee-Hye,Lee, Jun-Soo 한국식품과학회 2010 Food Science and Biotechnology Vol.19 No.2

Grape seeds contain high levels of phytochemicals, which have been correlated with a decreased risk of chronic diseases. In this study, grape seeds from 10 different cultivars ('SV 18315', 'Naples', 'Agawam', 'Aligote', 'V.50151', 'Cabernet Sauvignon', 'Urbana', 'Baco22A', 'Clinton', and 'Campbell Early') were evaluated for their antioxidant and antiproliferative activities. The antioxidant activity of the grape seeds was evaluated by radical scavenging activities and reducing power. The antiproliferative activity was assessed by the inhibition of MCF7, NCI-H460, HCT116, and MKN45 cancer cell proliferation. The total polyphenol and flavonoid contents were determined by spectrophotometric methods. 'Cabernet Sauvignon' and 'Baco22A' had high polyphenol (4,369.2 and 3,747.0 mg/100 g seeds) and flavonoid contents (3,072.7 and 2,032.9 mg/100 g seeds). 'Cabernet Sauvignon' and 'Baco22A' also possessed the highest radical scavenging activity. In addition, these were showed generally higher antiproliferative activity than other cultivars. Both the polyphenol and flavonoid contents were positively correlated with radical scavenging activity ($R^2$>0.9). These results may provide basic information about health-beneficial effects of grape seeds.

Design, synthesis, and biological evaluation of novel aminopyrimidinylisoindolines as AXL kinase inhibitors

Choi, Min Jung,Roh, Eun Joo,Hur, Wooyoung,Lee, So Ha,Sim, Taebo,Oh, Chang-Hyun,Lee, Sun-Hwa,Kim, Jong Seung,Yoo, Kyung Ho Elsevier 2018 Bioorganic & medicinal chemistry letters Vol.28 No.23

<P><B>Abstract</B></P> <P>A novel series of aminopyrimidinylisoindoline derivatives <B>1a-w</B> having an aminopyrimidine scaffold as a hinge region binding motif were designed and synthesized. Among them, six compounds showed potent inhibitory activities against AXL kinase with IC<SUB>50</SUB> values of submicromolar range. Especially, compound <B>1u</B> possessing (4-acetylpiperazin-1-yl)phenyl moiety exhibited extremely excellent efficacy (IC<SUB>50</SUB> = <0.00050 μM). Their <I>in vitro</I> antiproliferative activities were tested over five cancer cell lines. Most compounds showed good antiproliferative activities against HeLa cell line. The kinase panel profiling of 50 different kinases and the selected inhibitory activities for the representative compound <B>1u</B> were carried out. The compound <B>1u</B> exhibited excellent inhibitory activities (IC<SUB>50</SUB> = <0.00050, 0.025, and 0.050 μM for AXL, MER, and TYRO3, respectively) against TAM family, together with potent antiproliferative activity against MV4-11 cell line (GI<SUB>50</SUB> = 0.10 μM) related to acute myeloid leukemia (AML).</P> <P><B>Highlights</B></P> <P> <UL> <LI> Six compounds showed potent inhibitory activities against AXL kinase. </LI> <LI> Most compounds showed good antiproliferative activities against HeLa cell line. </LI> <LI> <B>1u</B> exhibited extremely excellent efficacy (IC<SUB>50</SUB> = <0.00050 μM) against AXL kinase. </LI> <LI> <B>1u</B> showed the best combination of enzyme inhibitory and antiproliferative activities. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Antiproliferative and antibacterial activity of extracts of Ganoderma strains grown in vitro

Leonardo Serrano-Marquez,Angel Trigos,Alan Couttolenc,Jose M. Padron,Alla V. Shnyreva,Guillermo Mendoza 한국식품과학회 2021 Food Science and Biotechnology Vol.30 No.5

In this bioprospecting study the biologicalactivities of extracts of the in vitro culture of GanodermaMexican strains were evaluated. The extracts were testedby the Sulforhodamine B staining method for antiproliferativeactivity and the plate microdilution method forantibacterial activity. Extracts that proved bioactive inthese two activities, the antioxidant activity (Galvinoxyl,ABTS, and DPPH) and total phenolic contents (Folin-Ciocalteu) were additionally determined, as well as acutetoxicity (Artemia franciscana). In the antiproliferativeactivity Ganoderma curtisii strain (GH-16-015) obtained aremarkable value of GI50 B 50 lg/mL against tumorlines: A549, HBL-100, HeLa, and T-47D. G. curtisiistrains (GH-16-012 and GH-16-015) showed MIC values= 500 lg/mL against Staphylococcus aureus. G. curtisiistrain (GH-16-012) almost reduced by 50% theradical Galvinoxyl. Finally, G. curtisii strain (GH-16-023)presented the lowest level of toxicity with a LC50 of490.881 lg/mL against A. franciscana. These resultssupport the potential medicinal effects of Mexican strainsof G. curtisii.

Cultivar Differences in Phenolic Contents/Biological Activities of Color-fleshed Potatoes and Their Relationships

장혜림,윤경영 한국원예학회 2012 Horticulture, Environment, and Biotechnology Vol.53 No.2

The current study was performed to evaluate colored potatoes (Solamum tuberosum L.) as a potential source of functional food material. We compared the total phenolic content (TPC) in potato tubers of a white-fleshed potato variety with six color-fleshed potato cultivars. We also examined their antioxidant and antiproliferative activities. The TPC of the analyzed cultivars varied between 113.3 mg・100 g-1 powder (‘Superior’) and 153.3 mg・100 g-1 powder (‘Blue’). The colored potato extracts showed higher radical scavenging activities than the white fleshed potato extract (‘Superior’), and all colored potato extracts, except for ‘Rose’ and ‘Haryoung’, induced significant antiproliferative activities against THP-1 cells at the tested concentrations. In particular, ‘Jaseo’ and ‘Jasim’ showed 35% and 31% cell viability, respectively, at the concentration of 100 μg・mL-1. The greatest positive correlation was found between TPC and hydroxyl radical scavenging activity (r = 0.912, p <0.01), and TPC also showed a strong positive correlation with nitrite scavenging ability (r = 0.808, p < 0.01). Our results indicate that color-fleshed potatoes have higher antioxidant and stronger antiproliferative activities than white-fleshed potatoes.

Synthesis and Antiproliferative Activity of 1,4-Bis(dimethylamino)- 9,10-anthraquinone Derivatives against P388 Mouse Leukemic Tumor Cells

Guang-Zhu Jin,Hai-Shan Jin,Li-Li Jin 대한약학회 2011 Archives of Pharmacal Research Vol.34 No.7

A series of 2-substituted-1,4-bis(dimethylamino)-9,10-anthraquinone derivatives were synthesized and their in vitro antiproliferative activities against p388 mouse leukemic tumor cells were evaluated. In addition, the effect of substituents on the phenyl ring was investigated. Among the derivatives tested, seven showed a high antiproliferative effect and three showed a moderate effect. In addition, introduction of a series of substituted phenyl groups into 1,4-bis(dimethylamino)-9,10-anthraquinone at 2-position were shown to enhance its antiproliferative activity. The antiproliferative activity also increased upon substitution of the benzene ring by an electron donating group such as an amine or methoxyl group.