Anticancer and structure-activity relationship evaluation of 3-(naphthalen-2-yl)-N,5-diphenyl-pyrazoline-1-carbothioamide analogs of chalcone

Lee, Y.,Kim, B.S.,Ahn, S.,Koh, D.,Lee, Y.H.,Shin, S.Y.,Lim, Y. Academic Press ; Academic Press 2016 Bioorganic chemistry Vol.68 No.-

<P>To identify new potent chemotherapeutic agents, we synthesized compounds with 3-(naphthalen-2-yl)-N,5-diphenyl-pyrazoline-1-carbothioamide (NDPC) skeletons and evaluated their cytotoxicities using a clonogenic long-term survival assay. Their half-maximal cell growth inhibitory concentrations ranged from a few hundred nanomolars to a few micromolars. Further biological experiments including flow cytometry and western blotting analysis were performed with the derivative showing the best cytotoxicity. To identify a target protein of the selected compound, an in vitro kinase assay was carried out, which revealed that aurora kinases A and B were inhibited by the test compound, and this was confirmed using western blot analysis. The molecular binding mode between the selected compound and the kinases was elucidated using in silico docking. The structural conditions required for good cytotoxicity were identified based on the quantitative relationships between the physicochemical properties of the derivatives and their cytotoxicities. (C) 2016 Elsevier Inc. All rights reserved.</P>

Synthesis and biological evaluation of 2-phenol-4-chlorophenyl-6-aryl pyridines as topoisomerase II inhibitors and cytotoxic agents

Thapa, P.,Kadayat, T.M.,Park, S.,Shin, S.,Thapa Magar, T.B.,Bist, G.,Shrestha, A.,Na, Y.,Kwon, Y.,Lee, E.S. Academic Press ; Academic Press 2016 Bioorganic chemistry Vol.66 No.-

<P>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 mu M 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 compounds possess meta-chlorophenyl. SAR study revealed the importance of ortho-or para-chlorophenyl at 4-position of the central pyridine for selective topo II inhibitory activity. Similarly, all compounds possessing meta-or para-hydroxyphenyl moieties showed moderate to significant cytotoxic effects. Particularly, compounds 27-37, and 39 which showed excellent cytotoxicity (IC50 = 0.68-1.25 mu M) 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. (C) 2016 Elsevier Inc. All rights reserved.</P>

Synthesis and investigation of dihydroxychalcones as calpain and cathepsin inhibitors

Baek, K.H.,Karki, R.,Lee, E.S.,Na, Y.,Kwon, Y. Academic Press ; Academic Press 2013 Bioorganic chemistry Vol.51 No.-

In order to identify potential calpain and cathepsin inhibitors we prepared 12 dihydroxychalcone analogues and tested their ability to inhibit μ-calpain, m-calpain, cathepsins B and L. In the calpain inhibition test, compound 10 exhibited the most active inhibitory activity against m-calpain with an IC<SUB>50</SUB> value of 25.25+/-0.901μM. With respect to inhibition of cathepsins B and L, compound 13 exhibited the most potent inhibitory activity on cathepsin L and moderate inhibitory activity on cathepsin B with IC<SUB>50</SUB> values of 2.80+/-0.100 and 11.47+/-0.087μM, respectively. Our results suggest the possibility of developing dual calpain and cathepsin inhibitors by properly modulating structures and/or combining the essential aspects of the functional group effective for specific calpain and cathepsin inhibition.

Modified 2,4-diaryl-5H-indeno[1,2-b]pyridines with hydroxyl and chlorine moiety: Synthesis, anticancer activity, and structure-activity relationship study

Kadayat, T.M.,Song, C.,Kwon, Y.,Lee, E.S. Academic Press ; Academic Press 2015 Bioorganic chemistry Vol.62 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 chlorine 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 relationship (SAR) study with respect to the non-substituted 2,4-diaryl-5H-indeno[1,2-b]pyridines. Compounds (2, 3, 4, 5, 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 thienyl 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.

Synthesis of novel and diverse mollugin analogues and their antibacterial and antioxidant activities

Idhayadhulla, A.,Xia, L.,Lee, Y.R.,Kim, S.H.,Wee, Y.J.,Lee, C.S. Academic Press ; Academic Press 2014 Bioorganic chemistry Vol.52 No.-

Novel and diverse mollugin analogues (1-12) were synthesized using PhB(OH)<SUB>2</SUB>/AcOH-mediated electrocyclization reaction as a key step. The newly synthesized compounds were screened for antioxidant and antibacterial activities. Compounds 1, 2, 5, 6, 8, and 10-12 showed high antioxidant activities in DPPH inhibition (IC<SUB>50</SUB>=0.52-1.11μM) compared with BHT (IC<SUB>50</SUB>=9.67μM). Compounds 3 exhibited potent antibacterial activity against Staphylococcus aureus (KCTC-1916) bacterial strain at 100μg/mL. Structures of newly synthesized compounds were confirmed by IR, <SUP>1</SUP>H NMR, <SUP>13</SUP>C NMR data and high-resolution mass spectrometry.

Discovery of novel purine-based heterocyclic P2X₇ receptor antagonists

Kwak, S.H.,Lee, W.G.,Lee, Y.J.,Lee, S.D.,Kim, Y.C.,Ko, H. Academic Press ; Academic Press 2015 Bioorganic chemistry Vol.61 No.-

The pyridine core skeleton of the previously reported dichloropyridine-based potent hP2X<SUB>7</SUB> receptor antagonist 5 (IC<SUB>50</SUB>=13nM in hP2X<SUB>7</SUB>-expressing HEK293 cells) was modified with various heterocyclic scaffolds. Among the derivatives with quinoline, quinazoline, acridine, and purine scaffolds, the chloropurine-based analog 9o exhibited the most potent antagonistic activity, with an IC<SUB>50</SUB> value of 176+/-37nM in an ethidium bromide uptake assay. In addition, 9o significantly inhibited IL-1β release in THP-1 cells stimulated with LPS/IFN-γ/BzATP (IC<SUB>50</SUB>=120+/-15nM). Although 9o was less active than the previous antagonist 5, 9o exhibited greatly improved metabolic stability in the in vitro evaluation (71.4% in human, 72.3% in mouse).

Design, synthesis and biological evaluation of novel hydroxamic acids bearing artemisinin skeleton

Ha, V.T.,Kien, V.T.,Binh, L.H.,Tien, V.D.,My, N.T.T.,Nam, N.H.,Baltas, M.,Hahn, H.,Han, B.W.,Thao, D.T.,Vu, T.K. Academic Press ; Academic Press 2016 Bioorganic chemistry Vol.66 No.-

<P>A series of novel hydroxamic acids bearing artemisinin skeleton was designed and synthesized. Some compounds in this series exhibited moderate inhibition against the whole cell HDAC enzymes. Especially, compound 6g displayed potent cytotoxicity against three human cancer cell lines, including HepG2 (liver cancer), MCF-7 ( breast cancer) and HL-60 (leukemia cancer), with IC50 values of 2.50, 2.62 and 1.28 mu g/mL, respectively. Docking studies performed with two potent compounds 6a and 6g using Autodock Vina showed that both compounds bound to HDAC2 with relatively high binding affinities from -7.1 to 7.0 kcal/mol compared to SAHA (-7.4 kcal/mol). It was found in this research that most of the target compounds seemed to be more cytotoxic toward blood cancer cells (HL-60) than liver (HepG2), and breast (MCF-7) cancer cells. (C) 2016 Elsevier Inc. All rights reserved.</P>

Bioactivity-guided isolation of antioxidant triterpenoids from Betula platyphylla var. japonica bark

Eom, H.J.,Kang, H.R.,Kim, H.K.,Jung, E.B.,Park, H.B.,Kang, K.S.,Kim, K.H. Academic Press ; Academic Press 2016 Bioorganic chemistry Vol.66 No.-

<P>The bark of Betula platyphylla var. japonica (Betulaceae) has been used to treat pneumonia, choloplania, nephritis, and chronic bronchitis. This study aimed to investigate the bioactive chemical constituents of the bark of B. platyphylla var. japonica. A bioassay-guided fractionation and chemical investigation of the bark of B. platyphylla var. japonica resulted in the isolation and identification of a new lupane-type triterpene, 27-hydroxybetunolic acid (1), along with 18 known triterpenoids (2-19). The structure of the new compound (1) was elucidated on the basis of 1D and 2D NMR spectroscopic data analysis as well as HR-ESIMS. Among the known compounds, chilianthin B (17), chilianthin C (18), and chilianthin A (19) were triterpene-lignan esters, which are rarely found in nature. Compounds 4, 6, 7, 17, 18, and 19 showed significant antioxidant activities with IC50 values in the range 4.48-43.02 mu M in a DPPH radical-scavenging assay. However, no compound showed significant inhibition of acetylcholine esterase (AChE). Unfortunately, the new compound (1) exhibited no significance in both biological activities. This study strongly suggests that B. platyphylla var. japonica bark is a potential source of natural antioxidants for use in pharmaceuticals and functional foods. (C) 2016 Elsevier Inc. All rights reserved.</P>

Synthesis and antitumor activity of (-)-bassianolide in MDA-MB 231 breast cancer cells through cell cycle arrest

Mun, B.,Park, Y.J.,Sung, G.H.,Lee, Y.,Kim, K.H. Academic Press ; Academic Press 2016 Bioorganic chemistry Vol.69 No.-

<P>The high level of interest in the cyclodepsipeptides family in the natural products stems from their diverse range of biological activities. One of the cyclodepsipeptides, (-)-bassianolide, represents rich pharmacophores with diverse biological activities including potential cytotoxicity to various cancer cells. Efficient total synthesis of (-)-bassianolide was designed and achieved in nine steps, with significant improvements in the overall yield of 46.8% (vs. 7.2% yield in previous synthesis) using Ghosez's chloroenamine reagent under mild conditions. The cytotoxicity of the (-)-bassianolide was evaluated against five human tumor cells, and the results showed that the (-)-bassianolide displayed significant cytotoxicity against A549, SK-OV-3, HepG2, HCT-15, MCF-7 and MDA-MB 231 cell lines with IC50 values of 7.24, 8.44, 15.39, 6.40, 11.42 and 3.98 mu g/mL respectively. Specifically, (-)-bassianolide induced G0/G1 arrest associated with a decrease of cyclin A, D1 and an increase of p53, MDM2, and p21 expression in MDA-MB 231 cells. These results demonstrate that (-)-bassianolide possesses antitumor activities via arresting of the cell cycle and the synthetic approach features an efficient and mild method for the formation of amide bonds through three inter-and intramolecular coupling reactions. (C) 2016 Elsevier Inc. All rights reserved.</P>

Applicability of a continuous-flow system inner-coated with S-doped titania for the photocatalysis of dimethyl sulfide at low concentrations

Jo, W.K.,Shin, M.H. Academic Press 2010 Journal of environmental management Vol.91 No.10

The present study investigated the photocatalytic activity of an S-doped TiO<SUB>2</SUB> photocatalyst with regards to dimethyl sulfide degradation under visible-light irradiation, along with its deactivation and reactivation. The dimethyl sulfide conversion was between 85% and 93% for the lowest relative humidity range (10-20%) and close to 100% for the two higher relative humidity ranges (45-55% and 80-90%). The conversion was also close to 100% for the two lowest input concentrations (0.039 and 0.195 ppm), while it was between 91% and 96% at 3.9 ppm and between 85% and 90% at 7.9 ppm. In contrast to the input concentration dependences on conversion, the calculated degradation rates increased as input concentrations increased. The dimethyl sulfide conversion at low concentrations (@?0.39 ppm), which are associated with non-occupational inn occurring. However, catalyst deactivations were observed during the photocatalytic process whdoor air quality issues, was up to nearly 100% for long time periods (at least 603 h), without any significant catalyst deactivatioen higher concentrations (3.9 and 7.8 ppm) were used. The photocatalyst, reactivated by using two types of air (dried and humidified) under visible-light irradiation, did not regain all of its initial activities. Sulfate groups were qualitatively identified as the reaction products on the photocatalyst surface. In addition, gaseous byproducts, quantitatively determined, included dimethyl disulfide, methanol, and SO<SUB>2</SUB>. It is noteworthy that the peak concentration of dimethyl disulfide (0.79 ppm = 790 ppb), generated over the photocatalytic process with the highest dimethyl sulfide input concentration, exceeded the odor threshold value of 0.1-3.6 ppb for dimethyl disulfide.