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( Daulat Bikram Khadka ),( Giap Huu Tran ),( Somin Shin ),( Hang Thi Minh Nguyen ),( Hue Thi Cao ),( Chao Zhao ),( Yifeng Jin ),( Hue Thi My Van ),( Minh Van Chau ),( Youngjoo Kwon ),( Thanh Nguyen Le 전남대학교 약품개발연구소 2015 약품개발연구지 Vol.24 No.-
A series of 2-arylquinazolinones with structural homology to known 3-arylisoquinolines were designed and synthesized in order to develop safe. effective, and selective cytotoxic agents targeting topoisomerases (topos). 2-Arylquinzolinones with various substitutions on the aromatic rings were obtained by thermal cyclodehydration/dehydrogenation on reacting anthranilamides and benzaldehydes. The compounds had superior topo l-inhibitory activities but were generally inactive against topo IIα, Among the 6-methyl-, 6-amino-, and 7-methylquinazolinones, 6-amino-substituted derivatives displayed potent cytotoxicity at submicromolar to nanomolar concentrations against human colorectal adenocarcinoma cells (HCT-15), human ductal breast epithelial tumor cells (T47D), and cervical cancer cells (HeLa). There was a good correlation between topo I inhibition and the cytotoxic effects of 6-aminoquinazolinones. Docking models demonstrated that topo I inhibition by these compounds is owing to intercalation and H-bond interactions with the DNA bases and amino acid residues at the enzymatic site.
( Daulat Bikram Khadka ),( Hyunjung Woo ),( Su Hui Yang ),( Chao Zhao ),( Yifeng Jin ),( Thanh Nguyen ),( Youngjoo Kwon ),( Won-jea Cho ) 전남대학교 약품개발연구소 2015 약품개발연구지 Vol.24 No.-
Inspired by the initial success of the monoarylisoquinolines and the quest to identify more potent and selective anticancer agents with topoisomerase (topo) inhibitory activity, series of diarylisoquinolines (3,4-diarylisoquinolones and 3,4-diarylisoquinolinamines) were designed and synthesized. Synthesis of these compounds primarily involved Iithiated toluamide-benzonitrile cycloaddition, Suzuki coupling, and nucleophilic aromatic substitution reactions. Eight of the derivatives were selectively toxic against human ductal breast epithelial tumor cells (T47D), human prostate cancer cells (DU145), and human colorectal adenocarcinoma cells (HCT-15), but had no effect on normal human breast epithelial cells (MCF10A)T. he topo inhibitory activities of the diarylisoquinoline compounds were relatively dependent upon their chemical structure. 3,4-Diarylisoquinolones generally did not inhibit topo I and only showed moderate inhibition of topo II. In contrast, several 3,4-diarylisoquinolinamines showed superior topo I inhibitory activity. Isoquinolinamine derivatives had greater affinity for topo I than for topo II. Topo inhibition by 3,4-diarylisoquinolines was further supported by docking models showing intercalative and/or H-bond interactions between these compounds and the DNA/topo(s). An analysis of the correlation between the cytotoxicity and topo inhibition of these compounds indicated that the primary biological target of derivatives with potent cytotoxicity was topo, which in turn establishes diarylsubstituted isoquinolines as a novel class of potential anticancer drugs.
Khadka, Daulat Bikram,Park, Seojeong,Jin, Yifeng,Han, Jinhe,Kwon, Youngjoo,Cho, Won-Jea Elsevier 2018 European journal of medicinal chemistry Vol.143 No.-
<P><B>Abstract</B></P> <P>With a goal of identifying potent topoisomerase (topo) inhibitor, the C4-aromatic ring of the anticancer agent, 3,4-diarylisoquinolone, was strategically shifted to design 1,3-diarylisoquinoline. Twenty-two target compounds were synthesized in three simple and efficient steps. The 1,3-diarylisoquinolines exhibited potent anti-proliferative effects on cancer cells but few compounds spared non-cancerous cells. Inhibition of topo I/IIα-mediated DNA relaxation by several derivatives was greater than that by camptothecin (CPT)/etoposide even at low concentration (20 μM). In addition, these compounds had little or no effect on polymerization of tubulin. A series of biological evaluations performed with the most potent derivative <B>4cc</B> revealed that the compound is a non-intercalative topo I catalytic inhibitor interacting with free topo I. Collectively, the potent cytotoxic effect on cancer cells including the drug resistance ones, absence of lethal effect on normal cells, and different mechanism of action than topo I poisons suggest that the 1,3-diarylisoquinolines might be a promising class of anticancer agents worthy of further pursuit.</P> <P><B>Highlights</B></P> <P> <UL> <LI> 1,3-Diarylisoquinoline was designed based on structure of 3,4-diarylisoquinoline. </LI> <LI> 1,3-Diarylisoquinolines were cytotoxic against cancer cells. </LI> <LI> Several derivatives inhibited topo I/IIα activity even at low concentration. </LI> <LI> 1,3-Diarylisoquinolines had weak or no antitubulin activity. </LI> <LI> 1,3-Diarylisoquinoline <B>4 cc</B> is a non-intercalative topo I catalytic inhibitor. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
ELSEVIER : Synthesis of novel 5-oxaprotoberberines as bioisosteres of protoberberines
( Yi Feng Jin ),( Daulat Bikram Khadka ),( Su Hui Yang ),( Chao Zhao ),( Won Jea Cho ) 전남대학교 약품개발연구소 2014 약품개발연구지 Vol.23 No.-
5-0xaprotoberberinones and 5-oxaprotoberberinium were synthesized as bioisosteres of protoberberines. 5-0xaprotoberberinones were prepared by linking phenol with the isoquinolone ring of 3-phenoIisoquinoIones by methyleneoxy bridge, while the quaternary 5-oxaprotoberberinium salt was synthesized by reduction and oxidation of the lactam moiety of 5-oxaprotoberberinone. ⓒ 2014 Elsevier Ltd. All rights reserved.
( Yifeng Jin ),( Younho Han ),( Daulat Bikram Khadka ),( Chao Zhao ),( Kwang Youl Lee ),( Won-jea Cho ) 전남대학교 약품개발연구소 2016 약품개발연구지 Vol.25 No.-
Conformational change in helix 12 can alter ligand-in duced PPARγ activity; based on this reason, isoquinolinoquinazolinones, structural homologs of berberine, were designed and synthesized as PPARγ antagonists. Computational docking and mutational study indicated that isoquinolinoquinazolinones form hydrogen bonds with the Cys285 and Arg288 residues of PPARγ. Furthermore, SPR results demonstrated strong binding affinity of isoquinolinoquinazolinones towards PPARγ. Additionally, biological assays showed that this new series of PPARγ antagonists more strongly inhibit adipocyte differentiation and PPARγ2-induced transcriptional activity than GW9662.
Paudel, Suresh,Sun, Ningning,Khadka, Daulat Bikram,Yoon, Goon,Kim, Kyeong-Man,Cheon, Seung Hoon Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.14
<P><B>Abstract</B></P> <P>Rational drug design method has been used to generate 4-arylpiperazine carboxamides in an effort to develop safer, more potent and effective monoamine neurotransmitters reuptake inhibitors. Out of twenty-seven synthesized compounds, compound <B>9</B> displayed potent monoamine neurotransmitter reuptake inhibitory activity against HEK cells transfected with hSERT or hNET. A Surflex-Dock docking model of <B>9</B> was also studied.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>