7467-71-2Relevant articles and documents
Small Molecule Inhibitors of Ca2+-S100B Reveal Two Protein Conformations
Cavalier, Michael C.,Ansari, Mohd. Imran,Pierce, Adam D.,Wilder, Paul T.,McKnight, Laura E.,Raman, E. Prabhu,Neau, David B.,Bezawada, Padmavani,Alasady, Milad J.,Charpentier, Thomas H.,Varney, Kristen M.,Toth, Eric A.,MacKerell, Alexander D.,Coop, Andrew,Weber, David J.
, p. 592 - 608 (2016/02/09)
The drug pentamidine inhibits calcium-dependent complex formation with p53 (CaS100B·p53) in malignant melanoma (MM) and restores p53 tumor suppressor activity in vivo. However, off-target effects associated with this drug were problematic in MM patients. Structure-activity relationship (SAR) studies were therefore completed here with 23 pentamidine analogues, and X-ray structures of CaS100B·inhibitor complexes revealed that the C-terminus of S100B adopts two different conformations, with location of Phe87 and Phe88 being the distinguishing feature and termed the "FF-gate". For symmetric pentamidine analogues (CaS100B·5a, CaS100B·6b) a channel between sites 1 and 2 on S100B was occluded by residue Phe88, but for an asymmetric pentamidine analogue (CaS100B·17), this same channel was open. The CaS100B·17 structure illustrates, for the first time, a pentamidine analog capable of binding the "open" form of the "FF-gate" and provides a means to block all three "hot spots" on CaS100B, which will impact next generation CaS100B·p53 inhibitor design.
Biological Efficacy and Toxicity of Diamidines in Myotonic Dystrophy Type 1 Models
Siboni, Ruth B.,Bodner, Micah J.,Khalifa, Muhammad M.,Docter, Aaron G.,Choi, Jessica Y.,Nakamori, Masayuki,Haley, Michael M.,Berglund, J. Andrew
, p. 5770 - 5780 (2015/08/24)
Myotonic dystrophy type 1 (DM1) is a disease characterized by errors in alternative splicing, or "mis-splicing". The causative agent of mis-splicing in DM1 is an inherited CTG repeat expansion located in the 3′ untranslated region of the DM protein kinase gene. When transcribed, CUG repeat expansion RNA sequesters muscleblind-like (MBNL) proteins, which constitute an important family of alternative splicing regulators. Sequestration of MBNL proteins results in the mis-splicing of its regulated transcripts. Previous work has demonstrated that pentamidine, a diamidine which is currently FDA-approved as an antiparasitic agent, was able to partially reverse mis-splicing in multiple DM1 models, albeit at toxic concentrations. In this study, we characterized a series of pentamidine analogues to determine their ability to reverse mis-splicing and their toxicity in vivo. Experiments in cell and mouse models demonstrated that compound 13, also known as furamidine, effectively reversed mis-splicing with equal efficacy and reduced toxicity compared to pentamidine.
ARYL DIAMIDINES AND PRODRUGS THEREOF FOR TREATING MYOTONIC DYSTROPHY
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Paragraph 0115, (2013/11/05)
Disclosed herein are compounds (for example, diamidine derivatives and prodrugs) and methods of use thereof, for example in treating muscular dystrophy (DM) or disease caused by a toxic RNA in a subject. In some embodiments, the methods include administering an effective amount of one of more of the disclosed compounds to a subject to treat or inhibit DM or a disease caused by or associated with toxic RNA, such as DM1, DM2, spinocerebellar ataxia type 8 (SCA8), fragile X tremor ataxia syndrome (FXTAS), or Huntington disease-like 2 (HLD2). In some examples, the methods include selecting a subject for treatment, for example selecting a subject with DM1, DM2, SCA8, FXTAS, or HLD2.
Structure-activity study of pentamidine analogues as antiprotozoal agents
Bakunova, Svetlana M.,Bakunov, Stanislav A.,Patrick, Donald A.,Kumar, E. V. K. Suresh,Ohemeng, Kwasi A.,Bridges, Arlene S.,Wenzler, Tanja,Barszcz, Todd,Jones, Susan Kilgore,Werbovetz, Karl A.,Brun, Reto,Tidwell, Richard R.
scheme or table, p. 2016 - 2035 (2009/12/31)
Diamidine 1 (pentamidine) and 65 analogues (2-66) have been tested for in vitro antiprotozoal activities against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donoVani, and for cytotoxicity against mammalian cells. Dications 32, 64, and 66 exhibited antitrypanosomal potencies equal or greater than melarsoprol (IC50) 4 nM). Nine congeners (2-4, 12, 27, 30, and 64-66) were more active against P. falciparum than artemisinin (IC50) 6 nM). Eight compounds (12, 32, 33, 44, 59, 62, 64, and 66) exhibited equal or better antileishmanial activities than 1 (IC50) 1.8 M). Several congeners were more active than 1 in vivo, curing at least 2/4 infected animals in the acute mouse model of trypanosomiasis. The diimidazoline 66 was the most promising compound in the series, showing excellent in vitro activities and high selectivities against T. b. rhodesiense, P. falciparum, and L. donoVani combined with high antitrypanosomal efficacy in vivo.
DNA sequence-specific ligands: XII. Synthesis and cytological studies of dimeric hoechst 33258 molecules
Gromyko,Popov,Mosoleva,Streltsov,Grokhovsky,Oleinikov,Zhuze
, p. 344 - 351 (2008/02/03)
We synthesized dimeric Hoechst dye molecules composed of two moieties of Hoechst 33258 fluorescent dye with the phenolic hydroxy groups tethered via pentamethylene, heptamethylene, or triethylene oxide linkers. A characteristic pattern of differential staining of chromosome preparations from human HL60 premonocytic leukemia cells was observed for all the three fluorescent dyes. The most contrasting pattern was obtained for the bisHoechst analogue with the heptamethylene linker; its quality was comparable with the picture obtained in the case of chromosome staining with 4′,6-diamidino-2-phenylindole. The ability to penetrate into live human fibroblasts was studied for the three bisHoechst compounds. The fluorescence intensity of nuclei of live and fixed cells stained with the penta- and heptamethylene-linked bisHoechst analogues was found to differ only slightly, whereas the fluorescence of the nuclei of live cells stained with triethylene oxide-linked bisHoechst was considerably weaker than that of the fixed cells. The bisHoechst molecules are new promising fluorescent dyes that can both differentially stain chromosome preparations and penetrate through cell and nuclear membranes and effectively stain cell nuclei.
Derivatives of pentamidine designed to target the Leishmania lipophosphoglycan
Kramp, Kari L.,DeWitt, Kristin,Flora, Jason W.,Muddiman, David C.,Slunt, Kelli M.,Houston, Todd A.
, p. 695 - 698 (2007/10/03)
Compound 7, based on pentamidine, was designed to increase the parent compound's affinity for the Leishmania cell surface. The leishmanicidal activity of 7 is similar to that of the nonboronated diamine 4 and appears to be more effective at lower concentrations. The Leishmania lipophosphoglycan (LPG) is the most abundant cell surface glycoconjugate of a family of infectious protozoa. Pentamidine, a common drug used in the treatment of Leishmania infections, has been modified with boronic acids so that it might bind more selectively to the phosphodisaccharide repeating unit of the LPG. This could serve to target the drug to the protozoan surface and increase its efficacy in vivo.
Dendrimers with anthyridine-based hydrogen-bonding units at their cores: Synthesis, complexation and self-assembly studies
Wang, Yue,Zeng, Fanwen,Zimmerman, Steven C.
, p. 5459 - 5462 (2007/10/03)
Generation 1-4 Frechet-type dendritic bromides were covalently linked to anthyridine (6) to give 'sticky' dendrons 7a-7d. The binding constants of 1:1 complexes between 7 and benzamidinium salt 8 were measured to assess their ability to act as building blocks for self-assembly A 2:1 complex of 7 and pentamidine 9 formed in 1% CD3CN/CDCl3 indicating the utility of these compounds for constructing larger dendritic assemblies.
Synthesis, Spectroscopic Properties and Antileishmanial Screening of some Pentamidine Analogues
Nandi, Gopa,Mukherjee, S.,Basu, M. K.,Mahato, Shashi B.
, p. 527 - 532 (2007/10/02)
Pentamidine, the diamidine drug of choice is used for the treatment of antimony resistant leishmanial infection.A modified method for preparation of the water-soluble isethionate salt of pentamidine has been developed using p-hydroxybenzaldehyde as starting material.Beside the synthesis of the dimethoxy analogues of pentamidine hydrochloride and pentamidine isethionate, two compounds have been prepared by substitution of amidino groups of pentamidine and its dimethoxy analogue by imidazoline moieties.Cmr spectral data of the compounds have been assigned and the in vitro antileishmanial activity of the analogues were compared with pentamidine isethionate using Leishmania donovani UR-6 strain.
Analogues of 1,5-bis(4-amidinophenoxy)pentane (pentamidine) in the treatment of experimental Pneumocystis carinii pneumonia
Tidwell,Jones,Geratz,Ohemeng,Cory,Hall
, p. 1252 - 1257 (2007/10/02)
A series of 33 analogues of the anti-Pneumocystis carinii drug 1,5-bis(4-amidinophenoxy)pentane (pentamidine) was synthesized for screening against a rat model of P. carinii pneumonia (PCP). Twenty-five of the compounds showed efficacy against PCP when compared to a saline-treated control group. Two compounds, 1,4-bis(4-amidinophenoxy)butane (butamidine, 6) and 1,3-bis(4-amidino-2-methoxyphenoxy)propane (DAMP, 16), were statistically more effective than the parent drug in treating PCP in the rat model of infection. In addition to their activity against PCP, the compounds were also evaluated for antitrypsin activity, ability to inhibit thymidylate synthetase, affinity for DNA, and toxicity. No correlation was observed between the tested molecular interactions of the diamidines and their effectiveness against PCP.
