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| 3. |
- Andersson, Hanna, Dr. 1979-, et al.
(author)
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Ligands to the (IRAP)/AT4 receptor encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr2
- 2008
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In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 16:14, s. 6924-6935
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Journal article (peer-reviewed)abstract
- Analogues of the hexapeptide angiotensin IV (Ang IV, Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6)) encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr(2) and a phenylacetic or benzoic acid moiety replacing His(4)-Pro(5)-Phe(6) have been synthesized and evaluated in biological assays. The analogues inhibited the proteolytic activity of cystinyl aminopeptidase (CAP), frequently referred to as the insulin-regulated aminopeptidase (IRAP), and were found less efficient as inhibitors of aminopeptidase N (AP-N). The best Ang IV mimetics in the series were approximately 20 times less potent than Ang IV as IRAP inhibitors. Furthermore, it was found that the ligands at best exhibited a 140 times lower binding affinity to the membrane-bound IRAP/AT4 receptor than Ang IV. Although the best compounds still exert lower activities than Ang IV, it is notable that these compounds comprise only two amino acid residues and are considerably less peptidic in character than the majority of the Ang IV analogues previously reported as IRAP inhibitors in the literature.
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| 4. |
- Andre, Sabine, et al.
(author)
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Glycosyldisulfides from Dynamic Combinatorial Libraries as O-Glycoside Mimetics for Plant and Endogenous Lectins: Their Reactivities in Solid-Phase and Cell Assays and Conformational Analysis by Molecular Dynamics Simulations
- 2006
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In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 14, s. 6314-6326
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Journal article (peer-reviewed)abstract
- Dynamic combinatorial library design exploiting the thiol-disulfide exchange readily affords access to glycosyldisulfides. In order to reveal lectin-binding properties of this type of non-hydrolyzable sugar derivative, libraries originating from a mixture of common building blocks of natural glycans and thiocompounds were tested against three plant agglutinins with specificity to galactose, fucose or N-acetylgalactosamine, respectively, in a solid-phase assay. Extent of lectin binding to matrix-immobilized neoglycoprotein presenting the cognate sugar could be reduced, and evidence for dependence on type of carbohydrate was provided by dynamic deconvolution. Glycosyldisulfides also maintained activity in assays of increased physiological relevance, that is, using native tumor cells and also adding to the test panel an endogenous lectin (galectin-3) involved in tumor spread and cardiac dysfunction. N-Acetylgalactosamine was pinpointed as the most important building block of libraries for the human lectin and the digalactoside as most potent compound acting on the toxic mistletoe agglutinin which is closely related to the biohazard ricin. Because this glycosyldisulfide, which even surpasses lactose in inhibitory capacity, rivals thiodigalactoside as inhibitor, their degrees of intramolecular flexibility were comparatively analyzed by computational calculations. Molecular dynamics runs with explicit consideration of water molecules revealed a conspicuously high degree of potential for shape alterations by the disulfide's three-bond system at the interglycosidic linkage. The presented evidence defines glycosyldisulfides as biologically active ligands for lectins
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| 5. |
- Aujard, Isabelle, et al.
(author)
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Tridemethylisovelleral, a potent cytotoxic agent
- 2005
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In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 13:22, s. 6145-6150
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Journal article (peer-reviewed)abstract
- The synthesis and in vitro cytotoxicity toward various tumor cell lines of (+/-)-tridemethylisovelleral, an analogue of the bioactive fungal sesquiterpene (+)-isovelleral retaining the bicyclo[4,1,0]hept-2-en-1,2-dicarbaidehyde system but lacking the three methyl groups, is reported. The cytotoxicity of tridemethylisovelleral toward several tumor cell lines was found to be comparable with those of established antitumor drugs, and significantly higher than that of isovelleral. (c) 2005 Elsevier Ltd. All rights reserved.
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| 7. |
- Ayesa, Susana, et al.
(author)
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Solid-phase parallel synthesis and SAR of 4-amidofuran-3-one inhibitors of cathepsin S : Effect of sulfonamides P3 substituents on potency and selectivity.
- 2009
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In: Bioorganic & Medicinal Chemistry. - : Elsevier. - 0968-0896 .- 1464-3391. ; 17:3, s. 1307-1324
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Journal article (peer-reviewed)abstract
- Highly potent and selective 4-amidofuran-3-one inhibitors of cathepsin S are described. The synthesis and structure–activity relationship of a series of inhibitors with a sulfonamide moiety in the P3 position is presented. Several members of the series show sub-nanomolar inhibition of the target enzyme as well as an excellent selectivity profile and good cellular potency. Molecular modeling of the most interesting inhibitors describes interactions in the extended S3 pocket and explains the observed selectivity towards cathepsin K.
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| 8. |
- Berggren, Kristina, 1971, et al.
(author)
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Synthesis and biological evaluation of reversible inhibitors of IdeS, a bacterial cysteine protease and virulence determinant
- 2009
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In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 17:9, s. 3463-3470
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Journal article (peer-reviewed)abstract
- Analogues of the irreversible protease inhibitors TPCK and TLCK have been synthesized and tested as inhibitors of the bacterial cysteine protease IdeS excreted by Streptococcus pyogenes. Eight compounds were identified as inhibitors of IdeS in an in vitro assay. The most potent compounds contained an aldehyde function, thus acting as efficient reversible inhibitors, nitrile and azide derivatives showed moderate activity. (C) 2009 Elsevier Ltd. All rights reserved.
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| 9. |
- Berglund, Magnus, et al.
(author)
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SAR studies of capsazepinoid bronchodilators 3: The thiourea part (coupling region) and the 2-(4-chlorophenyl)ethyl moiety (C-region).
- 2008
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In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 16:5, s. 2529-2540
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Journal article (peer-reviewed)abstract
- Certain derivatives and analogues of capsazepine are potent in vitro inhibitors of bronchoconstriction in human small airways. During an investigation of the dependency of the potency on the structural features of the capsazepinoids in the thiourea moiety (coupling region) and the 2-(4-chlorophenyl)ethyl moiety (C-region), it was revealed that capsazepinoids with a thiourea or an amide link between the B-ring and the C-region in general have a good bronchorelaxing activity, while urea is a less attractive choice. Further, it was shown that 1,2,3,4-tetrahydroisoquinolines with a 2-(phenyl)ethyl derivative as the C-region are considerably more potent than those with an octyl group, while 2,3,4,5-tetrahydro-1H-2-benzazepines were found to be more insensitive to the nature of the C-region.
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| 10. |
- Berglund, Magnus, et al.
(author)
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SAR studies of capsazepinoid bronchodilators. Part 2: Chlorination and catechol replacement in the A-ring.
- 2008
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In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 16:5, s. 2513-2528
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Journal article (peer-reviewed)abstract
- Capsazepine as well as its derivatives and analogues are general inhibitors of constriction of human small airways. From a systematic variation of the capsazepine structure, divided into four regions, SARs were established. This paper concerns the chlorination of the A-ring as well as the replacement of the catechol with bioisosteric groups. It is revealed that chlorination of the A-ring has a profound effect on activity. Moreover, di-chlorination of the 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline structure results in a 10-fold increase in potency compared to capsazepine.
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