- Design, synthesis and biological evaluation of estradiol-PEG-linked platinum(II) hybrid molecules: Comparative molecular modeling study of three distinct families of hybrids
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The synthesis of a series of 17β-estradiol-platinum(II) hybrid molecules is reported. The hybrids are made of a PEG linking chain of various length and a 2-(2′-aminoethyl)pyridine ligand. They are prepared from estrone in only 5 chemical steps with an overall yield of 22%. The length of the PEG chain does not influence the solubility of the compounds as it remains relatively constant throughout the series. MTT assays showed that the derivative with the longest PEG chain showed the best activity against two human breast cancer cell lines (MCF-7 and MDA-MB-231). The novel PEG-hybrids are also compared in terms of activities with two other families of 17β-estradiol- platinum(II) hybrids that we reported in previous studies. Molecular modeling study performed on a representative member of each family of hybrids reveals distinct molecular interactions with the estrogen receptor α which further corroborates their notably contrasting cytocidal activities on breast cancer cell lines. This study also shows that lipophilicity and the orientation of the tether chain between the estrogenic portion and the platinum(II) core contribute markedly to the biological activity of the various families of hybrids. The most active hybrids are those possessing an alkyl tether chain at position 16β of the steroid nucleus. For example, derivative 3 (p = 6) is about 16 times more potent on MCF-7 breast cancer cells than the corresponding 16α-PEG-hybrids (2b) made in this study.
- Provencher-Mandeville, Josée,Debnath, Chhanda,Mandal, Sanat K.,Leblanc, Valérie,Parent, Sophie,Asselin, éric,Bérubé, Gervais
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Read Online
- Bifunctional thiosialosides inhibit influenza virus
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We have synthesized a panel of bivalent S-sialoside analogues, with modifications at the 4 position, as inhibitors of influenza virus. These first generation compounds show IC50 values ranging from low micromolar to high nanomolar in enzyme inhibition and plaque reduction assays with two intact viruses, Influenza H1N1 (A/California/07/2009) and H3N2 (A/Hongkong/8/68).
- Yang, Yang,He, Yun,Li, Xingzhe,Dinh, Hieu,Iyer, Suri S.
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Read Online
- Synthesis of 17β-estradiol-platinum(II) hybrid molecules showing cytotoxic activity on breast cancer cell lines
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The synthesis of a series of 17β-estradiol-platinum(II) hybrid molecules is reported. The hybrids are made of a PEG linking chain of various length and a 2-(2′-aminoethyl)pyridine ligand. They are prepared from estrone in five chemical steps with an overall yield of 22%. The length of the PEG chain does not influence the solubility of the compounds as it remains relatively constant throughout the series. MTT assays showed that the derivative with the longest PEG chain showed the best activity against breast cancer cell lines (MCF-7 and MDA-MB-231). Molecular modeling study rationalized the results.
- Provencher-Mandeville, Josée,Desc?teaux, Caroline,Mandal, Sanat K.,Leblanc, Valérie,Asselin, éric,Bérubé, Gervais
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Read Online
- SMALL MOLECULES
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Compounds having the general structure A - L - B are presented wherein A and B are independently an E3 ubiquitin ligase protein binding ligand compound of formula 1A or 1 B. Pharmaceutical compositions comprising these compounds and methods of use are also presented.
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Page/Page column 16; 41
(2018/11/10)
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- Conjugate of dezocine and polyethylene glycol
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The invention relates to the technical field of medicine, in particular to a conjugate of dezocine and polyethylene glycol as well as a pharmaceutical composition thereof. The conjugate of dezocine and polyethylene glycol, which is provided by the invention, has high pharmacokinetic property and high medicine absorbing degree, reduces the side effect of the medicine, and can realize smaller administration dosage and more administration modes such as oral administration in clinical practice; and compared with the dezocine, the conjugate provided by the invention has stronger analgesic effect and longer analgesic duration, can reduce the medicine use times and improve the compliance of a patient, and has the advantages in the aspects of effectiveness, safety, medicine resistance and the likeof the medicine.
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Paragraph 0092; 0093; 0094
(2018/07/30)
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- LOW MOLECULAR WEIGHT POLYETHYLENE GLYCOL DRUG CONJUGATES HAVING IMPROVED DRUG BIOLOGICAL ACTIVITY
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Provided are polyethylene glycol drug conjugates of general formula (I), (II) or (III) and pharmaceutical compositions and a use thereof. The conjugates are formed by combining low molecular weight polyethylene glycol with 2-4 drug molecules. The conjugates can interact with receptor dimers or polymers, thereby improving the in vivo distribution of the drug, changing the oil and water distribution coefficient, enhancing the pharmacological activity, reducing the blood-brain barrier permeability of the drug, and improving the bioavailability of the drug.
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Paragraph 0045
(2016/04/19)
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- Polyacrylamide pseudo crown ethers via hydrogen bond-assisted cyclopolymerization
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Polyacrylamide pseudo crown ethers with large in-chain rings (15–24 membered) were synthesized by hydrogen bond-mediated cyclopolymerization of bisacrylamides comprising poly(ethylene oxide) spacers (PEGnDAAm, ethylene oxide units: n = 3–6). The monomers undergo the intramolecular hydrogen bonding of the bisacrylamide units in halogenated solvents to dynamically place the two olefins adjacently. As a result, the bisacrylamides homogeneously allowed controlled radical cyclopolymerization without any macroscopic gelation in 1,2-dichloroethane, even at relatively high concentration of monomers (200 mM), to directly provide precision cyclopolyacrylamides and the related copolymers with high cyclization efficiency (84–98%). Owing to the in-chain ring pendants, a cyclopolyacrylamide had glass transition temperature higher than a corresponding polyacrylamide with linear pendants.
- Kimura, Yoshihiko,Miyabara, Yuichiro,Terashima, Takaya,Sawamoto, Mitsuo
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p. 3294 - 3302
(2016/09/09)
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- BIVALENT BROMODOMAIN LIGANDS, AND METHODS OF USING SAME
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Described herein are compounds capable of modulating one or more biomolecules substantially simultaneously, e.g., modulating two or more binding domains (e.g., bromodomains) on a protein or on different proteins. For example, in one aspect, a bivalent compound or a pharmaceutically acceptable salt, stereoisomer, metabolite, or hydrate thereof is provided. In another aspect, a method of treating a disease associated with a protein having tandem bromodomains in a patient in need thereof is provided. The method comprises administering to the patient the bivalent compound as described.
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Paragraph 00357-00361; 00370; 00371
(2015/06/11)
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- Optimization of the Sensitization Process and Stability of Octadentate Eu(III) 1,2-HOPO Complexes
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The synthesis of a series of octadentate ligands containing the 1-hydroxypyridin-2-one (1,2-HOPO) group in complex with europium(III) is reported. Within this series, the central bridge connecting two diethylenetriamine units linked to two 1,2-HOPO chromophores at the extremities (5-LIN-1,2-HOPO) is varied from a short ethylene chain (H(2,2)-1,2-HOPO) to a long pentaethylene oxide chain (H(17O5,2)-1,2-HOPO). The thermodynamic stability of the europium complexes has been studied and reveals these complexes may be effective for biological measurements. Extension of the central bridge results in exclusion of the inner-sphere water molecule observed for [Eu(H(2,2)-1,2-HOPO)]- going from a nonacoordinated to an octacoordinated Eu(III) ion. With the longer chain length ligands, the complexes display increased luminescence properties in aqueous medium with an optimum of 20% luminescence quantum yield for the [Eu(H(17O5,2)-1,2-HOPO)]- complex. The luminescence properties for [Eu(H(14O4,2)-1,2-HOPO)]- and [Eu(H(17O5,2)-1,2-HOPO)]- are better than that of the model bis-tetradentate [Eu(5LINMe-1,2-HOPO)2]- complex, suggesting a different geometry around the metal center despite the geometric freedom allowed by the longer central chain in the H(mOn,2) scaffold. These differences are also evidenced by examining the luminescence spectra at room temperature and at 77 K and by calculating the luminescence kinetic parameters of the europium complexes. (Graph Presented).
- D'Aléo, Anthony,Moore, Evan G.,Xu, Jide,Daumann, Lena J.,Raymond, Kenneth N.
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p. 6807 - 6820
(2015/08/03)
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- Fast and efficient MCR-based synthesis of clickable rhodamine tags for protein profiling
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Protein profiling probes are important tools for studying the composition of the proteome and as such have contributed greatly to the understanding of various complex biological processes in higher organisms. For this purpose the application of fluorescently labeled activity or affinity probes is highly desirable. Especially for in vivo detection of low abundant target proteins, otherwise difficult to analyse by standard blotting techniques, fluorescently labeled profiling probes are of high value. Here, a one-pot protocol for the synthesis of activated fluorescent labels (i.e. azide, alkynyl or NHS), based on the Ugi-4-component reaction (Ugi-4CR), is presented. As a result of the peptoidic structure formed, the fluorescent properties of the products are pH insensitive. Moreover, the applicability of these probes, as exemplified by the labeling of model protein BSA, will be discussed.
- Brauch, Sebastian,Henze, Michael,Osswald, Bianca,Naumann, Kai,Wessjohann, Ludger A.,Van Berkel, Sander S.,Westermann, Bernhard
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supporting information; experimental part
p. 958 - 965
(2012/04/10)
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- OLIGOMER CONJUGATES OF LIDOCAINE AND ITS DERIVATIVES
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The invention provides small molecule drugs that are chemically modified by covalent attachment of a water-soluble oligomer.
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Page/Page column 49
(2009/05/30)
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- Synthesis of unique 17β-estradiol homo-dimers, estrogen receptors binding affinity evaluation and cytocidal activity on breast, intestinal and skin cancer cell lines
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A rapid and efficient synthesis of a series of C2-symmetric 17β-estradiol homo-dimers is described. The new molecules are linked at position 17α of the steroid nucleus with either an alkyl chain or a polyethylene glycol chain. They are made from estrone in only five chemical steps with an overall yield exceeding 30%. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent (ER+ and ER-) human breast tumor cell lines: MCF-7 and MDA-MB-231. Some of the dimers present selective cytotoxic activity against the ER+ cell line. However, they are not very cytotoxic when compared to the antiestrogen tamoxifen. Unfortunately, they show only weak affinity for the estrogen receptor alpha (ERα) and no affinity for the estrogen receptor beta (ERβ). The new compounds were also tested on human intestinal (HT-29) cancer and on murine skin cancer (B16-F10) cell lines for further biological assessment. Interestingly, the dimers were found to be cytotoxic to the murine skin cancer cell line but were inactive towards the intestinal cancer cell line.
- Bérubé, Gervais,Rabouin, Daniel,Perron, Valérie,N'Zemba, Blaise,Gaudreault, René-C.,Parent, Sophie,Asselin, éric
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p. 911 - 921
(2007/10/03)
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- A facile synthesis of C2-symmetric 17β-estradiol dimers
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A rapid and efficient synthesis of a series of C2-symmetric 17β-estradiol dimers is described. The new molecules are linked at position 17α of the steroid nucleus with either an alkyl chain or a polyethylene glycol chain. They are made from estrone in five chemical steps with an overall yield exceeding 30%. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent (ER+ and ER-) human breast tumor cell lines: MCF-7 and MDA-MB-231. Some of the dimers present selective cytotoxic activity against the ER+ cell line.
- Rabouin, Daniel,Perron, Valerie,N'Zemba, Blaise,C.-Gaudreault, Rene,Berube, Gervais
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p. 557 - 560
(2007/10/03)
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- Syntheses and Reactions of Crown Ether-Bridged Stilbenes
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A high yield synthesis of o,o' crown ether-bridged stilbenes 3b-e by reductive McMurry condensation of (2-formylphenyl)oligoethylene glycols 2b-e with facile (E/Z) diastereomer separation by selective cation complexation is described.Derivatization of the stilbene double bonds of (E)- or (Z)-3b-e affords dihydroxy crown ethers 4c, d and 5c, d diastereo- and enantioselectively.Likewise, trans- and cis-epoxides 11b-d and 12b-d are stereospecifically obtained.A crown ether-bridged diphenylacetaldehyde 13 is formed by rearrangement of 11c or 12c.Photocyclization of 3e yields large-ring 1,8-phenanthrene crown ether 18.The crystal structures of racemic 5c and of 12d are presented.A high caesium selectivity compared to the other alkali metal and alkaline earth cations is found for ion exchange membranes with incorporated crown ether (Z)-3c. - Key Words: McMurry reaction / Crown ethers / Hydroxylation, enantioselective / Ion exchange membranes
- Merz, Andreas,Karl, Andreas,Futterer, Thomas,Stacherdinger, Natascha,Schneider, Oliver,et al.
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p. 1199 - 1210
(2007/10/02)
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