Synthesis and evaluation of acridine- and acridone-based anti-herpes agents with topoisomerase activity.


:The discovery of new non-nucleoside antiviral compounds is of significant and growing interest for treating herpes virus infections due to the emergence of nucleoside-resistant strains. Using a whole cell virus-induced cytopathogenic assay, we tested a series of substituted triaryl heterocyclic compounds including acridones, xanthones, and acridines. The compounds which showed activity against Herpes Simplex-1 and/or Herpes Simplex-2 were further assayed for inhibition of topoisomerase activity to gain insight into the mechanism of action. The results indicate that the acridine analogs bearing substituted carboxamides and bulky 9-amino functionalities are able to inhibit herpes infections as well as inhibit topoisomerase II relaxation of supercoiled DNA. Given the mechanism of action of amsacrine (a closely related, well-studied 9-amino substituted acridine), the compounds were further tested in a DNA topoisomerase II cleavage assay to determine if the compounds function as poisons. The results show that the acridines synthesized in this study function through a different mechanism to that of amsacrine, most likely by blocking topoisomerase binding to DNA (akin to that of aclarubicin). This not only suggests a unique mechanism of action in treating herpes virus infections, but also may be of great interest in the development of anticancer agents that target topoisomerase II activity.


Bioorg Med Chem


Goodell JR,Madhok AA,Hiasa H,Ferguson DM




Has Abstract


2006-08-15 00:00:00














  • Identification of topoisomerases as molecular targets of cytosporolide C and its analog.

    abstract::Cytosporolide (Cytos) A-C, isolated from the fungus Cytospora sp., have anti-microbial activity, but their molecular targets in mammalian cells are unknown. We have previously reported the total synthesis of Cytos A by biomimetic hetero-Diels-Alder reaction. In this study, to examine the novel bioactivity of Cytos, we...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Otake K,Yamada K,Miura K,Sasazawa Y,Miyazaki S,Niwa Y,Ogura A,Takao KI,Simizu S

    更新日期:2019-08-01 00:00:00

  • Structure-based design and synthesis of covalent-reversible inhibitors to overcome drug resistance in EGFR.

    abstract::The clinical success of covalent kinase inhibitors in the treatment of EGFR-dependent non-small cell lung cancer (NSCLC) has rejuvenated the appreciation of reactive small molecules. Acquired drug resistance against first-line EGFR inhibitors remains the major bottleneck in NSCLC and is currently addressed by the appl...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Basu D,Richters A,Rauh D

    更新日期:2015-06-15 00:00:00

  • Synthesis and biological evaluation of novel quinazoline-derived human Pin1 inhibitors.

    abstract::A series of novel 2,4-disubstituted quinazoline derivatives were prepared and their inhibitory activities on hPin1 were evaluated. Of all the synthesized compounds, eight compounds displayed inhibitory activities with IC(50) value at the level of 10(-6)mol/L. Preliminary structure-activity relationships were analyzed ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Zhu L,Jin J,Liu C,Zhang C,Sun Y,Guo Y,Fu D,Chen X,Xu B

    更新日期:2011-05-01 00:00:00

  • Electrophilicity index as a possible descriptor of biological activity.

    abstract::The purpose of this study is to probe the suitability of DFT based chemical reactivity parameter, electrophilicity index as a possible biological activity descriptor in the development of QSAR. Testosterone derivatives with activity described in terms of various biological activity parameters and the estrogen derivati...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Parthasarathi R,Subramanian V,Roy DR,Chattaraj PK

    更新日期:2004-11-01 00:00:00

  • Novel imidazo[1,2-c]pyrimidine base-modified nucleosides: synthesis and antiviral evaluation.

    abstract::The preparation of a series of novel 6-(beta-D-ribofuranosyl)-2-alkyl/aryl-6H-imidazo[1,2-c]pyrimidin-5-one nucleosides and the 2-nitrile nucleosides, 6-(beta-D-ribofuranosyl)-5-oxo-5,6-dihydro-imidazo[1,2-c]pyrimidine-2-carbonitrile and 2R and 2S isomers of 6-(beta-D-ribofuranosyl)-5-oxo-2,3,5,6-tetrahydro-imidazo[1,...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Kifli N,De Clercq E,Balzarini J,Simons C

    更新日期:2004-08-01 00:00:00

  • 1,2,3-Selenadiazole thioacetanilides: synthesis and anti-HIV activity evaluation.

    abstract::The development of new HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) offers the possibility of generating novel structures of increased potency. Based on the bioisosteric principle, novel series of 1,2,3-selenadiazole thioacetanilide derivatives were designed, and synthesized using an original synthet...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Zhan P,Liu X,Fang Z,Pannecouque C,De Clercq E

    更新日期:2009-09-01 00:00:00

  • Downsizing of an HIV-cell fusion inhibitor, T22 ([Tyr5,12, Lys7]-polyphemusin II), with the maintenance of anti-HIV activity and solution structure.

    abstract::T22 ([Tyr5,12,Lys7]-polyphemusin II) has been shown to have strong anti-human immunodeficiency virus (HIV) activity comparable to that of 3'-azido-2',3'-dideoxythymidine (AZT). T22, an 18-residue peptide amide, takes an antiparallel beta-sheet structure that is maintained by two disulfide bridges. Herein we synthesize...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Tamamura H,Waki M,Imai M,Otaka A,Ibuka T,Waki K,Miyamoto K,Matsumoto A,Murakami T,Nakashima H,Yamamoto N,Fujii N

    更新日期:1998-04-01 00:00:00

  • Kinetic controlled affinity labeling of target enzyme with thioester chemistry.

    abstract::High specificity has been an important feature in affinity labeling for target profiling. Especially, to label targets via rapidly progressing reactions with consumption of ligand (probe), high specificity of reaction with common functional groups of target protein should be achieved without reactions with similar gro...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Tomohiro T,Nakabayashi M,Sugita Y,Morimoto S

    更新日期:2016-08-01 00:00:00

  • Amides as bioisosteres of triazole-based geranylgeranyl diphosphate synthase inhibitors.

    abstract::Geranylgeranyl diphosphate synthase (GGDPS) inhibitors are of potential therapeutic interest as a consequence of their activity against the bone marrow cancer multiple myeloma. A series of bisphosphonates linked to an isoprenoid tail through an amide linkage has been prepared and tested for the ability to inhibit GGDP...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Goetz DB,Varney ML,Wiemer DF,Holstein SA

    更新日期:2020-08-15 00:00:00

  • Synthesis and evaluation of imidazole-dioxolane compounds as selective heme oxygenase inhibitors: effect of substituents at the 4-position of the dioxolane ring.

    abstract::Several imidazole-dioxolane compounds were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). These compounds, which include a series of substituted thiophenol and substituted phenol derivatives of (2R,4S)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-[(phenylsulfanyl)methyl]-1,3-dioxol...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Vlahakis JZ,Hum M,Rahman MN,Jia Z,Nakatsu K,Szarek WA

    更新日期:2009-03-15 00:00:00

  • Novel tricyclic Delta(2)-isoxazoline and 3-oxo-2-methyl-isoxazolidine derivatives: synthesis and binding affinity at neuronal nicotinic acetylcholine receptor subtypes.

    abstract::A group of novel tricyclic Delta(2)-isoxazolines (4b, 5b, 7a-b, and 8a-b) and 3-oxo-isoxazolidines (6a-b and 9a-b), structurally related to cytisine or norferruginine, was prepared through 1,3-dipolar cycloadditions involving suitable olefins and bromonitrile oxide. The target compounds were assayed at alpha4beta2 and...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Dallanoce C,Frigerio F,Martelli G,Grazioso G,Matera C,Pomè DY,Pucci L,Clementi F,Gotti C,De Amici M

    更新日期:2010-06-15 00:00:00

  • Synthesis and biological evaluation of 1,1-dichloro-2,3-diarylcyclopropanes as antitubulin and anti-breast cancer agents.

    abstract::Z-1,1-Dichloro-2,3-diphenylcyclopropane (1) is an effective anti-breast cancer agent in rodents and in cell culture. We recently determined that 1 inhibits tubulin assembly in vitro and causes microtubule loss in breast cancer cells, leading to accumulation in the G2/M portion of the cell cycle. Aryl ring-halogenated,...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Jonnalagadda SS,ter Haar E,Hamel E,Lin CM,Magarian RA,Day BW

    更新日期:1997-04-01 00:00:00

  • BRACO19 analog dimers with improved inhibition of telomerase and hPot 1.

    abstract::Human chromosomes terminate with telomeres, which contain double-stranded G-rich, repetitive DNA followed by a single-stranded overhang of the G-rich sequence. Single-stranded oligonucleotides containing G-rich telomeric repeats have been observed in vitro to fold into a variety of G-quadruplex topologies depending on...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Fu YT,Keppler BR,Soares J,Jarstfer MB

    更新日期:2009-03-01 00:00:00

  • Structure-activity relationships of antitubercular salicylanilides consistent with disruption of the proton gradient via proton shuttling.

    abstract::A series of salicylanilides was synthesized based on a high-throughput screening hit against Mycobacterium tuberculosis. A free phenolic hydroxyl on the salicylic acid moeity is required for activity, and the structure-activity relationship of the aniline ring is largely driven by the presence of electron withdrawing ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Lee IY,Gruber TD,Samuels A,Yun M,Nam B,Kang M,Crowley K,Winterroth B,Boshoff HI,Barry CE 3rd

    更新日期:2013-01-01 00:00:00

  • Synthesis and evaluation of N-substituted nipecotic acid derivatives with an unsymmetrical bis-aromatic residue attached to a vinyl ether spacer as potential GABA uptake inhibitors.

    abstract::γ-Amino butyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system (CNS). A malfunction of the GABAergic neurotransmission is connected to several neuronal disorders like epilepsy, Alzheimer's disease, neuropathic pain, and depression. One possibility to enhance GABA levels in...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Quandt G,Höfner G,Wanner KT

    更新日期:2013-06-01 00:00:00

  • Sulfonamide-1,2,4-triazole derivatives as antifungal and antibacterial agents: synthesis, biological evaluation, lipophilicity, and conformational studies.

    abstract::A series of 10 new 5-[2-(substituted sulfamoyl)-4,5-dimethoxy-benzyl]-4aryl-s-triazole-3-thiones were synthesized and evaluated for in vitro antifungal and antibacterial activity. All compounds tested showed significant antifungal activity against all the micromycetes, compared to the commercial fungicide bifonazole. ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ezabadi IR,Camoutsis C,Zoumpoulakis P,Geronikaki A,Soković M,Glamocilija J,Cirić A

    更新日期:2008-02-01 00:00:00

  • A genetically selected cyclic peptide inhibitor of BCL6 homodimerization.

    abstract::We report an inhibitor of the homodimeric protein-protein interaction of the BCL6 oncoprotein, identified from a genetically encoded SICLOPPS library of 3.2 million cyclic hexapeptides in combination with a bacterial reverse two-hybrid system. This cyclic peptide is shown to bind the BTB domain of BCL6, disrupts its h...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Osher EL,Castillo F,Elumalai N,Waring MJ,Pairaudeau G,Tavassoli A

    更新日期:2018-07-15 00:00:00

  • Synthesis and anticancer activity of benzyloxybenzaldehyde derivatives against HL-60 cells.

    abstract::A series of benzyloxybenzaldehyde derivatives were prepared and tested against the HL-60 cell line for anticancer activity. Preliminary structure-activity relationships were established. It was discovered that 2-(benzyloxy)benzaldehyde (17), 2-(benzyloxy)-4-methoxybenzaldehyde (26), 2-(benzyloxy)-5-methoxybenzaldehyde...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Lin CF,Yang JS,Chang CY,Kuo SC,Lee MR,Huang LJ

    更新日期:2005-03-01 00:00:00

  • Design, synthesis, and biological evaluation of novel 4-oxobenzo[d]1,2,3-triazin-benzylpyridinum derivatives as potent anti-Alzheimer agents.

    abstract::Novel 4-oxobenzo[d]1,2,3-triazin derivatives bearing pyridinium moiety 6a-q were synthesized and screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Most of the synthesized compounds showed good inhibitory activity against AChE. Among the synthesized compounds, the compound 6j exhibited the...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Hosseini F,Ramazani A,Mohammadi-Khanaposhtani M,Barazandeh Tehrani M,Nadri H,Larijani B,Mahdavi M

    更新日期:2019-07-01 00:00:00

  • Synthesis and in vitro evaluation of aspartate transcarbamoylase inhibitors.

    abstract::The design, synthesis, and evaluation of a series of novel inhibitors of aspartate transcarbamoylase (ATCase) are reported. Several submicromolar phosphorus-containing inhibitors are described, but all-carboxylate compounds are inactive. Compounds were synthesized to probe the postulated cyclic transition-state of the...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Coudray L,Pennebaker AF,Montchamp JL

    更新日期:2009-11-15 00:00:00

  • Design and optimization of aspartate N-acetyltransferase inhibitors for the potential treatment of Canavan disease.

    abstract::Canavan disease is a fatal neurological disorder caused by defects in the metabolism of N-acetyl-l-aspartate (NAA). Recent work has shown that the devastating symptoms of this disorder are correlated with the elevated levels of NAA observed in these patients, caused as a consequence of the inability of mutated forms o...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Thangavelu B,Mutthamsetty V,Wang Q,Viola RE

    更新日期:2017-02-01 00:00:00

  • Studies on beta-D-Gal(f)-(1-->4)-alpha-L-Rha(p) octyl analogues as substrates for mycobacterial galactosyl transferase activity.

    abstract::The biochemically unique structures of sugar residues in the outer cell wall of Mycobacterium tuberculosis (MTB) make the pathways for their biosynthesis and utilization attractive targets for the development of new and selective anti-tubercular agents. A cell-free assay system for galactosyltransferase activity using...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Pathak AK,Besra GS,Crick D,Maddry JA,Morehouse CB,Suling WJ,Reynolds RC

    更新日期:1999-11-01 00:00:00

  • Synthesis and structure–activity relationships of small molecule inhibitors of the simian virus 40 T antigen oncoprotein, an anti-polyomaviral target.

    abstract::Polyomavirus infections are common and relatively benign in the general human population but can become pathogenic in immunosuppressed patients. Because most treatments for polyomavirusassociated diseases nonspecifically target DNA replication, existing treatments for polyomavirus infection possess undesirable side ef...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ireland AW,Gobillot TA,Gupta T,Seguin SP,Liang M,Resnick L,Goldberg MT,Manos-Turvey A,Pipas JM,Wipf P,Brodsky JL

    更新日期:2014-11-15 00:00:00

  • Chemoenzymatic synthesis and biological evaluation of 2- and 3-hydroxypyridine derivatives against Leishmania mexicana.

    abstract::A series of hydroxyalkyl and acyloxyalkyl derivatives of 2- and 3-hydroxypyridine was synthesized and their biological activity was evaluated as growth inhibitors of protozoan Leishmania mexicana. Thirty novel compounds were obtained through a chemoenzymatic methodology in two reaction steps. The influence of various ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: García Liñares G,Parraud G,Labriola C,Baldessari A

    更新日期:2012-08-01 00:00:00

  • Synthesis and biological evaluation of pyridazine derivatives as novel HIV-1 NNRTIs.

    abstract::In continuation of our efforts toward identification and optimization of novel non-nucleoside reverse transcriptase inhibitors (NNRTIs), we have employed a structure-based bioisosterism strategy, with which a new series of diarylpyridazine (DAPD) derivatives were synthesized and evaluated for their anti-HIV-1 (human i...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Li D,Zhan P,Liu H,Pannecouque C,Balzarini J,De Clercq E,Liu X

    更新日期:2013-04-01 00:00:00

  • Synthesis and in vitro activity of some epimeric 20 alpha-hydroxy, 20-oxime and aziridine pregnene derivatives as inhibitors of human 17 alpha-hydroxylase/C17,20-lyase and 5 alpha-reductase.

    abstract::Some epimeric 20-hydroxy, 20-oxime, 16 alpha, 17 alpha-, 17,20- and 20,21-aziridine derivatives of progesterone were synthesized and evaluated as inhibitors of human 17 alpha-hydroxylase/C17,20-lyase (P450(17) alpha) and 5 alpha-reductase (5 alpha-R). The reduction of 16-dehydropregenolone acetate (3a) was reinvestiga...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ling YZ,Li JS,Kato K,Liu Y,Wang X,Klus GT,Marat K,Nnane IP,Brodie AM

    更新日期:1998-10-01 00:00:00

  • Acidic biphenyl derivatives: synthesis and biological activity of a new series of potent 5-HT(4) receptor antagonists.

    abstract::Serotonin (5-hydroxytryptamine, 5-HT) is an important signaling molecule in the central nervous system (CNS) and in non-neuronal tissues and organs. Serotonin mediates a positive chronotropic and inotropic response through 5-HT4 receptors in the atrium and ventricle of the heart. Recent investigations have revealed in...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Brudeli B,Andressen KW,Moltzau LR,Nilsen NO,Levy FO,Klaveness J

    更新日期:2013-11-15 00:00:00

  • Synthesis of phenserine analogues and evaluation of their cholinesterase inhibitory activities.

    abstract::Phenserine is a potentially attractive drug for Alzheimer's disease. In order to further expand SAR study for inhibitions of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), the methyl group at the 3a-position of phenserine was replaced with an alkyl or alkenyl group, and its phenylcarbamoyl moiety was s...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Shinada M,Narumi F,Osada Y,Matsumoto K,Yoshida T,Higuchi K,Kawasaki T,Tanaka H,Satoh M

    更新日期:2012-08-15 00:00:00

  • Pharmacophore identification of a chemokine receptor (CXCR4) antagonist, T22 ([Tyr(5,12),Lys7]-polyphemusin II), which specifically blocks T cell-line-tropic HIV-1 infection.

    abstract::We have previously found that T22 ([Tyr(5,12), Lys7]-polyphemusin II) has strong anti-human immunodeficiency virus (HIV) activity, and that T22 inhibits T cell-line-tropic HIV-1 infection mediated by CXCR4/fusin. T22 is an 18-residue peptide amide, which takes an antiparallel beta-sheet structure that is maintained by...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Tamamura H,Imai M,Ishihara T,Masuda M,Funakoshi H,Oyake H,Murakami T,Arakaki R,Nakashima H,Otaka A,Ibuka T,Waki M,Matsumoto A,Yamamoto N,Fujii N

    更新日期:1998-07-01 00:00:00

  • Inhibition of human beta-tryptase by Bowman-Birk inhibitor derived peptides: creation of a new tri-functional inhibitor.

    abstract::Bowman-Birk inhibitor proteins (BBIs), which are potent inhibitors of chymotrypsin-like proteases, do not inhibit human beta-tryptase despite this protein having a chymotrypsin-like fold. We have reported previously that, in contrast, BBI-derived peptides (whose sequences incorporate the solvent exposed reactive site ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Scarpi D,McBride JD,Leatherbarrow RJ

    更新日期:2004-12-01 00:00:00