227 results match your criteria derivatives distamycin


Specific stabilization of promoter G-Quadruplex DNA by 2,6-disubstituted amidoanthracene-9,10-dione based dimeric distamycin analogues and their selective cancer cell cytotoxicity.

Eur J Med Chem 2020 Jun 16;195:112202. Epub 2020 Mar 16.

Department of Organic Chemistry, Indian Institute of Science, Bangalore, 560012, India; School of Applied & Interdisciplinary Sciences, Indian Association for the Cultivation of Science, Kolkata, 700032, India. Electronic address:

We have designed and synthesized anthraquinone containing compounds which have oligopyrrole side chains of varying lengths. These compounds stabilized the G-quadruplex DNA formed in the promoter regions of c-MYC oncogenes selectively over the duplex DNA. These observations were recorded using UV-vis spectroscopic titrations, fluorescence measurements and circular dichroism (CD) spectral titrations. Read More

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Novel distamycin analogues that block the cell cycle of African trypanosomes with high selectivity and potency.

Eur J Med Chem 2020 Mar 8;189:112043. Epub 2020 Jan 8.

Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Montevideo, Uruguay. Electronic address:

Polyamides-based compounds related to the Streptomycetal distamycin and netropsin are potent cytostatic molecules that bind to AT-rich regions of the minor groove of the DNA, hence interfering with DNA replication and transcription. Recently, derivatives belonging to this scaffold have been reported to halt the proliferation of deadly African trypanosomes by different and unrelated mechanisms. Here we describe the synthesis and preliminary characterization of the anti-trypanosomal mode of action of new potent and selective distamycin analogues. Read More

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Carbocyclic Analogues of Distamycin and Netropsin.

Mini Rev Med Chem 2019 ;19(2):98-113

Department of Organic Chemistry, Medical University, Bialystok 15-222, Mickiewicza Street 2c, Poland.

The DNA as the depository of genetic information is a natural target for chemotherapy. A lot of anticancer and antimicrobial agents derive their biological activity from their selective interaction with DNA in the minor groove and from their ability to interfere with biological processes such as enzyme catalysis, replication and transcription. The discovery of the details of minor groove binding drugs, such as netropsin and distamycin A, oligoamides built of 4-amino-1-methylpyrrole-2-carboxylic acid residues, allowed to develop various DNA sequence-reading molecules, named lexitropsins, capable of interacting with DNA precisely, strongly and with a high specificity, and at the same time exhibiting significant cytotoxic potential. Read More

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January 2019

Targeting DNA Minor Groove by Hybrid Molecules as Anticancer Agents.

Curr Med Chem 2017 ;24(26):2887-2907

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037. India.

Agents which can recognize and bind specific sequences of DNA offer selective therapy through the modulation of specific transcription factors or genes. Recently, there has been renewed interest in the field of anticancer minor groove binders. This may be attributed to the fact that many compounds of this class have demonstrated significant antitumor activity against a wide variety of cancers in recent clinical trials. Read More

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September 2017

An evaluation of Minor Groove Binders as anti-lung cancer therapeutics.

Bioorg Med Chem Lett 2016 08 16;26(15):3478-86. Epub 2016 Jun 16.

WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.

A series of 47 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for anti-lung cancer activity by screening against the melanoma cancer cell line B16-F10. Five compounds have been found to possess significant activity, more so than a standard therapy, Gemcitabine. Moreover, one compound has been found to have an activity around 70-fold that of Gemcitabine and has a favourable selectivity index of greater than 125. Read More

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ANTIPROLIFERATIVE EFFECTS ON BREAST CANCER CELLS AND SOME INTERACTIONS OF NEW DISTAMYCIN ANALOGUES WITH DNA, ENDONUCLEASES AND DNA TOPOISOMERASES.

Acta Pol Pharm 2016 Jan-Feb;73(1):47-53

The evaluation of a new group of distamycin analogues 1-6 as potential minor groove binders for the treatment of cancer were investigated. The activity of the new compounds against several restriction enzymes was examined. The studied compounds did not block GC-rich sequences regions of DNA but inhibited catalytic action of endonucleases in AA, AT, TT and AG restriction sites. Read More

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Conformational changes of the phenyl and naphthyl isocyanate-DNA adducts during DNA replication and by minor groove binding molecules.

Nucleic Acids Res 2013 Oct 19;41(18):8581-90. Epub 2013 Jul 19.

Department of Nanobiochemistry, Faculty of Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, 7-1-20, Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan, Frontier Institute for Biomolecular Engineering Research (FIBER), Konan University, 7-1-20, Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan, Department of Chemistry, Faculty of Science and Engineering, Konan University, 8-9-1, Okamoto, Higashinada-ku, Kobe, 658-8501, Japan, Molecular Engineering Institute (MEI), Kinki University, 11-6 Kayanomori, Iizuka, Fukuoka, 820-8555, Japan and Department of Environmental and Biological Chemistry, Kinki University, 11-6 Kayanomori, Iizuka, Fukuoka, 820-8555, Japan.

DNA lesions produced by aromatic isocyanates have an extra bulky group on the nucleotide bases, with the capability of forming stacking interaction within a DNA helix. In this work, we investigated the conformation of the 2'-deoxyadenosine and 2'-deoxycytidine derivatives tethering a phenyl or naphthyl group, introduced in a DNA duplex. The chemical modification experiments using KMnO4 and 1-cyclohexyl-3 -(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate have shown that the 2'-deoxycytidine lesions form the base pair with guanine while the 2'-deoxyadenosine lesions have less ability of forming the base pair with thymine in solution. Read More

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October 2013

Conformational investigation of antibiotic proximicin by X-ray structure analysis and quantum studies suggest a stretched conformation of this type of γ-peptide.

Bioorg Med Chem 2013 Jun 16;21(12):3582-9. Epub 2013 Mar 16.

Institut für Chemie, Technische Universität Berlin, Strasse des 17, Juni 124, 10623 Berlin, Germany.

The proximicins A-C are naturally occurring cytotoxic γ-peptides that contain the unique 4-amino-furan-carboxylic acid. In contrast to the structurally related cytotoxic natural DNA binder netropsin and distamycin, both exhibiting as core building block N-methyl-4-amino-pyrrol-carboxylic acid, no DNA binding was observed for the procimicins. X-ray analysis of crystals of a protected 4-amino-furan-2-carboxylic acid dipeptide revealed a stretched conformation. Read More

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From multiply active natural product to candidate drug? Antibacterial (and other) minor groove binders for DNA.

Authors:
Colin Suckling

Future Med Chem 2012 May;4(8):971-89

WestCHEM, Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK.

Natural products that bind to DNA in the minor groove are valuable templates for drug design. Examples include distamycin, netropsin, duocarmycin and anthramycin. Anticancer and anti-infective drugs feature strongly amongst their derivatives. Read More

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Molecular recognition of T:G mismatched base pairs in DNA as studied by electrospray ionization mass spectrometry.

ChemMedChem 2012 Jun 4;7(6):1112-22. Epub 2012 Apr 4.

Oncology Business Unit, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI), Italy.

Postreplicative mismatch repair (MMR) is a cellular system involved in the recognition and correction of DNA polymerase errors that escape detection in proofreading. Of the various mismatched bases, T:G pairing in DNA is one of the more common mutations leading to the formation of tumors in humans. In addition, the absence of the MMR system can generate resistance to several chemotherapeutic agents, particularly DNA-damaging substances. Read More

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Contribution of AT-, GC-, and methylated cytidine-rich DNA to chromatin composition in Malpighian tubule cell nuclei of Panstrongylus megistus (Hemiptera, Reduviidae).

Acta Histochem 2012 Nov 22;114(7):665-72. Epub 2011 Dec 22.

Structural and Physiological Biology for Anatomy, Cell Biology and Physiology, Institute of Biology, University of Campinas (UNICAMP), 13083-862 Campinas, SP, Brazil.

The Malpighian tubule cell nuclei of male Panstrongylus megistus, a vector of Chagas disease, contain one chromocenter, which is composed solely of the Y chromosome. Considering that different chromosomes contribute to the composition of chromocenters in different triatomini species, the aim of this study was to determine the contribution of AT-, GC-, and methylated cytidine-rich DNA in the chromocenter as well as in euchromatin of Malpighian tubule cell nuclei of P. megistus in comparison with published data for Triatoma infestans. Read More

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November 2012

Synthesis of directly linked diazine isosteres of pyrrole-polyamide that photochemically cleave DNA.

Org Biomol Chem 2012 Feb 7;10(5):1040-6. Epub 2011 Dec 7.

Department of Chemistry, National Sun Yat Sen University, No. 70, Lienhai Rd., Kaohsiung, 804, Taiwan, R.O.C.

A distamycin model containing an isosteric diazine linked pyrrole has been designed and synthesized. The key steps of the synthesis involved the successful diazotization of the 4-amino-pyrrole derivatives to give the diazomium salts, which undergo coupling reactions with N-methylpyrrole to yield the directly linked diazine compounds. The amide isosteric-diazine pyrrole I demonstrated photo-induced DNA damage upon iradiation with UV light (365 nm). Read More

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February 2012

DNA as molecular target of analogous palladium and platinum anti-Trypanosoma cruzi compounds: a comparative study.

J Inorg Biochem 2011 Dec 30;105(12):1704-11. Epub 2011 Jul 30.

Cátedra de Química Inorgánica, Facultad de Química, UDELAR, Montevideo, Uruguay.

In the search for drugs with anti-trypanosome activity, we had previously synthesized two series of platinum and palladium analogous compounds of the formula [M(II)Cl(2)(HL)], where HL were bioactive 5-nitrofuryl or 5-nitroacroleine thiosemicarbazone derivatives. In this work, we thoroughly characterized [M(II)Cl(2)(HL)] complexes interaction with DNA by using different techniques: gel electrophoresis, DNA viscosity measurements, circular dichroism (CD) and atomic force microscopy (AFM). Electrophoresis results showed that all complexes induced a withdrawal of DNA superhelicity demonstrated by a decrease in electrophoretic mobility of supercoiled DNA form. Read More

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December 2011

Distamycin A and derivatives as synergic drugs in cisplatin-sensitive and -resistant ovarian cancer cells.

Amino Acids 2012 Feb 4;42(2-3):641-53. Epub 2011 Aug 4.

Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, University of Modena and Reggio Emilia, Via Campi 287, 41100, Modena, Italy.

Acquired resistance to cisplatin (cDDP) is a multifactorial process that represents one of the main problems in ovarian cancer therapy. Distamycin A is a minor groove DNA binder whose toxicity has limited its use and prompted the synthesis of derivatives such as NAX001 and NAX002, which have a carbamoyl moiety and different numbers of pyrrolamidine groups. Their interaction with a B-DNA model and with an extended-TATA box model, [Polyd(AT)], was investigated using isothermal titration calorimetry (ITC) to better understand their mechanism of interaction with DNA and therefore better explain their cellular effects. Read More

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February 2012

Minor groove to major groove, an unusual DNA sequence-dependent change in bend directionality by a distamycin dimer.

Biochemistry 2011 Sep 10;50(35):7674-83. Epub 2011 Aug 10.

Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, United States.

DNA sequence-dependent conformational changes induced by the minor groove binder, distamycin, have been evaluated by polyacrylamide gel electrophoresis. The distamycin binding affinity, cooperativity, and stoichiometry with three target DNA sequences that have different sizes of alternating AT sites, ATAT, ATATA, and ATATAT, have been determined by mass spectrometry and surface plasmon resonance to help explain the conformational changes. The results show that distamycin binds strongly to and bends five or six AT base pair minor groove sites as a dimer with positive cooperativity, while it binds to ATAT as a weak, slightly anticooperative dimer. Read More

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September 2011

[Antiviral properties of the derivatives of netropsin and distamycin against herpes simplex viruses type 1 and variolovaccine].

Vopr Virusol 2010 Nov-Dec;55(6):24-7

The antiherpesvirus activity of newly synthesized DNA-binding compounds for cultured Vero E6 cells was examined. The compounds were found to have selective antiherpesviral activity. Their antiviral activity was shown against the virus strains isolated from clinical specimens. Read More

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Distamycins: strategies for possible enhancement of activity and specificity.

Mini Rev Med Chem 2010 Mar;10(3):217-30

CoReS Techno Group, Department of Pharmaceutical Sciences, University of Ferrara, BioPharmaNet, 44121 Ferrara, Italy.

The present review focused on the strategies aimed to possibly solve toxicity problems of distamycins. Distamycins are compounds characterized by an oligopeptidic pyrrolocarbamoyl frame ending with an amidino moiety. This class of compounds displays antiviral and antibiotic activity and shows interesting antiprotozoal activity related to the ability to reversibly bind to the minor groove of DNA with a high selectivity for TA-rich sequences. Read More

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Liposomes- and ethosomes-associated distamycins: a comparative study.

J Liposome Res 2010 Dec 4;20(4):277-85. Epub 2009 Dec 4.

Department of Pharmaceutical Sciences, University of Ferrara, Italy.

The present article describes a comparative study of the performances of liposomes and ethosomes as specialized delivery systems for distamycin A (DA) and two of its derivatives. Liposomes and ethosomes were prepared by classical methods, extruded through polycarbonate filters, and characterized in terms of dimensions, morphology, and encapsulation efficiency. It was found that DA was associated with vesicles (either liposomes or ethosomes) by around 16. Read More

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December 2010

Copper-1,10-phenanthroline complexes binding to DNA: structural predictions from molecular simulations.

J Phys Chem B 2009 Aug;113(31):10881-90

SISSA, via Beirut 4, I-0 I-34014 Trieste, Italy.

Copper-1,10-phenanthroline (phen) complexes Cu(phen)(2)(), Cu(2-Clip-phen), and Cu(3-Clip-phen) (Clip = a serinol bridge between the phen parts) are typically employed as DNA-cleaving agents and are now becoming increasingly important for building multifunctional drugs with improved cytotoxic properties. For instance, Cu(3-Clip-phen) has been combined with distamycin-like minor-groove binders and cisplatin-derivatives, leading to promising results. Density Functional Theory (DFT) and docking calculations as well as molecular dynamics (MD) simulations were performed to describe the mode of binding to DNA of these complexes. Read More

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Total synthesis of proximicin A-C and synthesis of new furan-based DNA binding agents.

Org Lett 2009 Jul;11(13):2804-7

Institut für Chemie, TU Berlin, Strasse des 17. Juni 124, 10623 Berlin, Germany.

The total synthesis of the natural occurring polyamides proximicin A-C (3-5) has been accomplished. A short and efficient synthesis of a thus far unknown 4-amino-2-furan carboxylic acid was developed. Furthermore, this unique heterocyclic gamma-amino-acid was used for the synthesis of a new class of AT-selective DNA-binding agents derived from the natural products combining structural features of the proximicins with those from the known DNA-binding natural products netropsin (1) and distamycin (2). Read More

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Efficient solid-phase synthesis of a library of distamycin analogs containing novel biaryl motifs on SynPhase Lanterns.

J Comb Chem 2009 Jul-Aug;11(4):576-86

Gene Targeted Drug Design Research Group, Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, University of London, 29-39 Brunswick Square, London, UK.

Distamycin is a naturally occurring antibiotic that binds to AT-rich sequences in the minor groove of DNA in a noncovalent manner. It continues to be of interest as a "building block" for more-complex small-molecule ligands capable of targeting specific DNA sequences for gene regulation purposes (i.e. Read More

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October 2010

alpha-halogenoacrylic derivatives of antitumor agents.

Mini Rev Med Chem 2009 Jan;9(1):81-94

Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-19, 44100-Ferrara, Italy.

In this review article we have reported a series of hybrid compounds characterized by the presence of a alpha-halogenocryloyl alkylating moiety of low chemical reactivity, linked to known antitumor agents or their active moieties. Among them, brostallicin (PNU-166196), was selected for clinical development and is now undergoing Phase II studies in patients with advanced or metastatic soft tissue sarcoma. Read More

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January 2009

Bis-epoxyethyl derivatives of distamycin A modified on the amidino moiety: induction of production of fetal hemoglobin in human erythroid precursor cells.

Int J Mol Med 2009 Jan;23(1):105-11

BioPharmaNet, Dipartimento di Biochimica e Biologia Molecolare, Università di Ferrara, Ferrara, Italy.

Derivatives of distamycin A modified at the C-terminal amidine moiety and tethered to bis-epoxyethyl moieties at the N-terminal position were tested for their ability to induce erythroid differentiation in the human erythroleukemic cell line K562. None of the compounds without bis-epoxyethyl moiety were active. A comparison of the biological activity of diepoxy compounds containing different non-basic amidine-modified moieties, showed low activity of amidoxime, carbamoyl and N-methyl carbamoyl derivatives as differentiation agents. Read More

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January 2009

Efficient DNA binding and nuclear uptake by distamycin derivatives conjugated to octa-arginine sequences.

Chembiochem 2008 Nov;9(17):2822-9

Departamento de Química Orgánica, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.

Efficient targeting of DNA by designed molecules requires not only careful fine-tuning of their DNA-recognition properties, but also appropriate cell internalization of the compounds so that they can reach the cell nucleus in a short period of time. Previous observations in our group on the relatively high affinity displayed by conjugates between distamycin derivatives and bZIP basic regions for A-rich DNA sites, led us to investigate whether the covalent attachment of a positively charged cell-penetrating peptide to a distamycin-like tripyrrole might yield high affinity DNA binders with improved cell internalization properties. Our work has led to the discovery of synthetic tripyrrole-octa-arginine conjugates that are capable of targeting specific DNA sites that contain A-rich tracts with low nanomolar affinity; they simultaneously exhibit excellent membrane and nuclear translocation properties in living HeLa cells. Read More

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November 2008

Ligand binding to tetra-end-linked (TGGGGT)4 G-quadruplexes: an electrospray mass spectroscopy study.

Nucleic Acids Symp Ser (Oxf) 2008 (52):165-6

Dipartimento di Chimica delle Sostanze Naturali, Università degli Studi di Napoli Federico II, Via D. Montesano 49, I-80131 Napoli, Italy.

The binding properties of a series of known G-quadruplex ligands have been studied by ESI-MS experiments. The tetramolecular (TG(4)T)(4) quadruplex and its analogues I and II blocked, respectively, at the 3' or 5'-end by a tetra-end-linker (TEL) unit were chosen as the ligands targets. The stoichiometries of the obtained complexes as well as the ligand affinity and selectivity to the different quadruplexes were determined to deduce the ligand binding site. Read More

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November 2010

Targeting DNA quadruplexes with distamycin A and its derivatives: an ITC and NMR study.

Biochimie 2008 Aug 28;90(8):1224-32. Epub 2008 Mar 28.

Dipartimento di Scienze Farmaceutiche, Università di Salerno, via Ponte Don Melillo, 84084 Fisciano (SA), Italy.

The use of small molecules that bind and stabilize G-quadruplex structures is emerging as a promising way to inhibit telomerase activity in tumor cells. In this paper, isothermal titration calorimetry (ITC) and 1H NMR studies have been conducted to examine the binding of distamycin A and its two carbamoyl derivatives (compounds 1 and 2) to the target [d(TGGGGT)]4 and d[AG3(T2AG3)3] quadruplexes from the Tetrahymena and human telomeres, respectively. The interactions were examined using two different buffered solutions containing either K+ or Na+ at a fixed ionic strength, to evaluate any influence of the ions present in solution on the binding behaviour. Read More

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Small molecules anti-HIV therapeutics targeting CXCR4.

Curr Pharm Des 2008 ;14(4):385-404

Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.

HIV cellular entry is a multistep process that requires the interaction of a viral envelope glycoprotein (gp120) and a host receptor (CD4) followed by binding to a co-receptor. The CC-chemokine receptor 5 (CCR5) and CXC-chemokine receptor 4 (CXCR4) have been identified as the major HIV co-receptors and therefore are promising targets for the development of new anti-HIV drugs. CXCR4 is also involved in several diseases such as angiogenesis, metabolic and neurological disorders, rheumatoid arthritis and in different forms of metastatic cancer. Read More

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Small-molecule based delivery systems for alkylating antineoplastic compounds.

ChemMedChem 2008 Apr;3(4):536-42

Department of Medicinal Chemistry and Drug Technology, Medical University of Białystok, Kilińskiego 1, 15-089 Białystok, Poland.

Alkylating agents are a major class of anticancer drugs for the treatment of various cancers including hematological malignancies. Targeting alkylating moieties to DNA by attachment of a DNA minor groove binding carrier such as distamycin, netropsin, or Hoechst 33252 reduces the loss of active drug due to reaction with other cell components and makes it possible to direct the alkylation both sequence specifically and regiospecifically. We reported the synthesis and structure-activity studies of amidine analogues of alkylating antineoplastic compounds, which appeared to be a new class of cytotoxic minor groove binders and topoisomerase II inhibitors. Read More

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Synthesis and evaluation of 2-pyrrolepolyamide-2'-deoxyguanosine 5'-phosphate.

Nucleic Acids Symp Ser (Oxf) 2007 (51):263-4

School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji,Tokyo 192-0392, Japan.

2-Pyrrolepolyamide-2'-deoxyguanosine 5'-phosphate (hybrid 4) was synthesized and evaluated in terms of the inhibition of mouse mammary carcinoma FM3A cell growth. Hybrid 4 exhibited the highest activity compared with the other hybrids (1, 2, and 3) and distamycin A. Read More

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Antimicrobial lexitropsins containing amide, amidine, and alkene linking groups.

J Med Chem 2007 Nov 26;50(24):6116-25. Epub 2007 Oct 26.

WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, Scotland, U.K.

The synthesis and properties of 80 short minor groove binders related to distamycin and the thiazotropsins are described. The design of the compounds was principally predicated upon increased affinity arising from hydrophobic interactions between minor groove binders and DNA. The introduction of hydrophobic aromatic head groups, including quinolyl and benzoyl derivatives, and of alkenes as linkers led to several strongly active antibacterial compounds with MIC for Staphylococcus aureus, both methicillin-sensitive and -resistant strains, in the range of 0. Read More

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November 2007