Mapping pilicide anti-virulence effect in Escherichia coli, a comprehensive structure–activity study

August 7, 2014, 10:22 pm

≫ Next: Synthesis and cytotoxic activity evaluation of dihydrocucurbitacin B and cucurbitacin B derivatives

≪ Previous: Free radical scavenging and antiproliferative properties of Biginelli adducts

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Publication date: 1 May 2012
Source:Bioorganic & Medicinal Chemistry, Volume 20, Issue 9
Author(s): Erik Chorell , Jerome S. Pinkner , Christoffer Bengtsson , Thomas Sainte-Luce Banchelin , Sofie Edvinsson , Anna Linusson , Scott J. Hultgren , Fredrik Almqvist
Pilicides prevent pili formation and thereby the development of bacterial biofilms in Escherichia coli. We have performed a comprehensive structure activity relationship (SAR) study of the dihydrothiazolo ring-fused 2-pyridone pilicide central fragment by varying all open positions. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) was used to distinguish active from inactive compounds in which polarity proved to be the most important factor for discrimination. A quantitative SAR (QSAR) partial least squares (PLS) model was calculated on the active compounds for prediction of biofilm inhibition activity. In this model, compounds with high inhibitory activity were generally larger, more lipophilic, more flexible and had a lower HOMO. Overall, this resulted in both highly valuable SAR information and potent inhibitors of type 1 pili dependent biofilm formation. The most potent biofilm inhibitor had an EC50 of 400nM.

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Synthesis and cytotoxic activity evaluation of dihydrocucurbitacin B and cucurbitacin B derivatives

August 7, 2014, 10:22 pm

≫ Next: Synthesis of methoxylated goniothalamin, aza-goniothalamin and γ-pyrones and their in vitro evaluation against human cancer cells

≪ Previous: Mapping pilicide anti-virulence effect in Escherichia coli, a comprehensive structure–activity study

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Publication date: 1 May 2012
Source:Bioorganic & Medicinal Chemistry, Volume 20, Issue 9
Author(s): Karen Luise Lang , Izabella Thaís Silva , Lara Almida Zimmermann , Vanessa Rocha Machado , Marina Rodrigues Teixeira , María Ivana Lapuh , Mariana Alejandra Galetti , Jorge Alejandro Palermo , Gabriela Myriam Cabrera , Lílian Sibelle Campos Bernardes , Cláudia Maria Oliveira Simões , Eloir Paulo Schenkel , Miguel Soriano Balparda Caro , Fernando Javier Durán
Two cucurbitacins, dihydrocucurbitacin B (1) and cucurbitacin B (2), which can be obtained in large amounts from the roots of Wilbrandia ebracteata and from the fruits of Luffa operculata, respectively, were used as starting materials for the preparation of a library of 29 semi-synthetic derivatives. The structural changes that were performed include the removal, modification or permutation of functional groups in rings A and B as well as in the side chain. All new semisynthetic compounds, as well as 1 and 2, were tested in vitro for their cytotoxic effects on non-small-cell lung cancer cells (A549 cells). Some of these compound displayed potent to moderate activity against A549 tumor cells, especially those cucurbitacin B derivatives which were modified at ring A.

Graphical abstract

Synthesis of methoxylated goniothalamin, aza-goniothalamin and γ-pyrones and their in vitro evaluation against human cancer cells

August 7, 2014, 10:22 pm

≫ Next: N4-Phenyl-substituted 2-acetylpyridine thiosemicarbazones: Cytotoxicity against human tumor cells, structure–activity relationship studies and investigation on the mechanism of action

≪ Previous: Synthesis and cytotoxic activity evaluation of dihydrocucurbitacin B and cucurbitacin B derivatives

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Publication date: 1 June 2012
Source:Bioorganic & Medicinal Chemistry, Volume 20, Issue 11
Author(s): Rosimeire Coura Barcelos , Julio Cezar Pastre , Vanessa Caixeta , Débora Barbosa Vendramini-Costa , João Ernesto de Carvalho , Ronaldo Aloise Pilli
The present work describes the preparation of three novel series of compounds based on the structure of goniothalamin, a natural styryl lactone which has been found to display cytotoxic and antiproliferative activities against a variety of cancer cell lines. A focused library of 29 novel goniothalamin analogues was prepared and evaluated against seven human cancer cell lines. While the γ-pyrones and the aza-goniothalamin analogues were less potent than the lead compound, 2,4-dimethoxy analogue 88 has shown to be more potent in vitro than goniothalamin against all cancer cell lines evaluated. Furthermore, it was more potent than doxorubicin against NCI-ADR/RES, OVCAR-03 and HT-29 while being less toxic to human keratinocytes (HaCat). The 3,5-dimethoxy analogue 90 and 2,4,5-trimethoxy analogue 92 also displayed promising antiproliferative activity when compared to goniothalamin (1). These results provide new elements for the design and synthesis of novel representatives of this family of natural compounds.

Graphical abstract

N4-Phenyl-substituted 2-acetylpyridine thiosemicarbazones: Cytotoxicity against human tumor cells, structure–activity relationship studies and investigation on the mechanism of action

August 7, 2014, 10:22 pm

≫ Next: Change or be changed Reflections of the workshop ‘Future in Medicinal Chemistry’

≪ Previous: Synthesis of methoxylated goniothalamin, aza-goniothalamin and γ-pyrones and their in vitro evaluation against human cancer cells

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Publication date: 1 June 2012
Source:Bioorganic & Medicinal Chemistry, Volume 20, Issue 11
Author(s): Marcella A. Soares , Josane A. Lessa , Isolda C. Mendes , Jeferson G. Da Silva , Raquel G. dos Santos , Lívia B. Salum , Hikmat Daghestani , Adriano D. Andricopulo , Billy W. Day , Andreas Vogt , Jorge L. Pesquero , Willian R. Rocha , Heloisa Beraldo
N ⁴-Phenyl 2-acetylpyridine thiosemicarbazone (H2Ac4Ph; N-(phenyl)-2-(1-(pyridin-2-yl)ethylidene)hydrazinecarbothioamide) and its N ⁴-ortho-, -meta- and -para-fluorophenyl (H2Ac4oFPh, H2Ac4mFPh, H2Ac4pFPh), N ⁴-ortho-, -meta- and -para-chlorophenyl (H2Ac4oClPh, H2Ac4mClPh, H2Ac4pClPh), N ⁴-ortho-, -meta- and -para-iodophenyl (H2Ac4oIPh, H2Ac4mIPh, H2Ac4pIPh) and N ⁴-ortho-, -meta- and -para-nitrophenyl (H2Ac4oNO2Ph, H2Ac4mNO2Ph, H2Ac4pNO2Ph) derivatives were assayed for their cytotoxicity against human malignant breast (MCF-7) and glioma (T98G and U87) cells. The compounds were highly cytotoxic against the three cell lineages (IC50: MCF-7, 52–0.16nM; T98G, 140–1.0nM; U87, 160–1.4 nM). All tested thiosemicarbazones were more cytotoxic than etoposide and did not present any haemolytic activity at up to 10⁻⁵ M. The compounds were able to induce programmed cell death. H2Ac4pClPh partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization.

Graphical abstract

Change or be changed Reflections of the workshop ‘Future in Medicinal Chemistry’

August 7, 2014, 10:22 pm

≫ Next: Fingerprint-based in silico models for the prediction of P-glycoprotein substrates and inhibitors

≪ Previous: N4-Phenyl-substituted 2-acetylpyridine thiosemicarbazones: Cytotoxicity against human tumor cells, structure–activity relationship studies and investigation on the mechanism of action

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Publication date: 15 June 2012
Source:Bioorganic & Medicinal Chemistry, Volume 20, Issue 12
Author(s): Ruth Brenk , Daniel Rauh

Graphical abstract

Fingerprint-based in silico models for the prediction of P-glycoprotein substrates and inhibitors

August 7, 2014, 10:22 pm

≫ Next: Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain

≪ Previous: Change or be changed Reflections of the workshop ‘Future in Medicinal Chemistry’

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Publication date: 15 September 2012
Source:Bioorganic & Medicinal Chemistry, Volume 20, Issue 18
Author(s): Vasanthanathan Poongavanam , Norbert Haider , Gerhard F. Ecker
P-Glycoprotein (P-gp, ABCB1) plays a significant role in determining the ADMET properties of drugs and drug candidates. Substrates of P-gp are not only subject to multidrug resistance (MDR) in tumor therapy, they are also associated with poor pharmacokinetic profiles. In contrast, inhibitors of P-gp have been advocated as modulators of MDR. However, due to the polyspecificity of P-gp, knowledge on the molecular basis of ligand–transporter interaction is still poor, which renders the prediction of whether a compound is a P-gp substrate/non-substrate or an inhibitor/non-inhibitor quite challenging. In the present investigation, we used a set of fingerprints representing the presence/absence of various functional groups for machine learning based classification of a set of 484 substrates/non-substrates and a set of 1935 inhibitors/non-inhibitors. Best models were obtained using a combination of a wrapper subset evaluator (WSE) with random forest (RF), kappa nearest neighbor (kNN) and support vector machine (SVM), showing accuracies >70%. Best P-gp substrate models were further validated with three sets of external P-gp substrate sources, which include Drug Bank (n =134), TP Search (n =90) and a set compiled from literature (n =76). Association rule analysis explores the various structural feature requirements for P-gp substrates and inhibitors.

Graphical abstract

Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain

August 7, 2014, 10:22 pm

≫ Next: [18F]FE@SNAP—A new PET tracer for the melanin concentrating hormone receptor 1 (MCHR1): Microfluidic and vessel-based approaches

≪ Previous: Fingerprint-based in silico models for the prediction of P-glycoprotein substrates and inhibitors

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Publication date: 1 October 2012
Source:Bioorganic & Medicinal Chemistry, Volume 20, Issue 19
Author(s): Atilla Akdemir , Ewald Edink , Andrew J. Thompson , Sarah C.R. Lummis , Albert J. Kooistra , Chris de Graaf , Iwan J.P. de Esch
A hierarchical in silico screening procedure using the crystal structure of an agonist bound chimeric α7/Ls-AChBP protein was successfully applied to both proprietary and commercial databases containing drug-like molecules. An overall hit rate of 26% (pK i ⩾5.0) was obtained, with an even better hit rate of 35% for the commercial compound collection. Structurally novel and diverse ligands were identified. Binding studies with [³H]epibatidine on chimeric α7/5-HT3 receptors yielded submicromolar inhibition constants for identified hits. Compared to a previous screening procedure that utilized the wild type Ls-AChBP crystal structure, the current study shows that the recently obtained α7/Ls-AChBP chimeric protein crystal structure is a better template for the identification of novel α7 receptor ligands.

Graphical abstract

[18F]FE@SNAP—A new PET tracer for the melanin concentrating hormone receptor 1 (MCHR1): Microfluidic and vessel-based approaches

August 7, 2014, 10:22 pm

≫ Next: Adamantyl carboxamides and acetamides as potent human 11β-hydroxysteroid dehydrogenase type 1 inhibitors

≪ Previous: Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain

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Publication date: 1 October 2012
Source:Bioorganic & Medicinal Chemistry, Volume 20, Issue 19
Author(s): Cécile Philippe , Johanna Ungersboeck , Eva Schirmer , Milica Zdravkovic , Lukas Nics , Markus Zeilinger , Karem Shanab , Rupert Lanzenberger , Georgios Karanikas , Helmut Spreitzer , Helmut Viernstein , Markus Mitterhauser , Wolfgang Wadsak
Changes in the expression of the melanin concentrating hormone receptor 1 (MCHR1) are involved in a variety of pathologies, especially obesity and anxiety disorders. To monitor these pathologies in-vivo positron emission tomography (PET) is a suitable method. After the successful radiosynthesis of [¹¹C]SNAP-7941—the first PET-Tracer for the MCHR1, we aimed to synthesize its [¹⁸F]fluoroethylated analogue: [¹⁸F]FE@SNAP. Therefore, microfluidic and vessel-based approaches were tested. [¹⁸F]fluoroethylation was conducted via various [¹⁸F]fluoroalkylated synthons and direct [¹⁸F]fluorination. Only the direct [¹⁸F]fluorination of a tosylated precursor using a flow-through microreactor was successful, affording [¹⁸F]FE@SNAP in 44.3±2.6%.

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Adamantyl carboxamides and acetamides as potent human 11β-hydroxysteroid dehydrogenase type 1 inhibitors

August 7, 2014, 10:22 pm

≫ Next: Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein–ligand crystallography

≪ Previous: [18F]FE@SNAP—A new PET tracer for the melanin concentrating hormone receptor 1 (MCHR1): Microfluidic and vessel-based approaches

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Publication date: 1 November 2012
Source:Bioorganic & Medicinal Chemistry, Volume 20, Issue 21
Author(s): Xiangdong Su , Heather A. Halem , Mark P. Thomas , Cecile Moutrille , Michael D. Culler , Nigel Vicker , Barry V.L. Potter
The modulation of 11β-HSD1 activity with selective inhibitors has beneficial effects on various metabolic disorders including insulin resistance, dyslipidemia and obesity. Here we report the discovery of a series of novel adamantyl carboxamide and acetamide derivatives as selective inhibitors of human 11β-HSD1 in HEK-293 cells transfected with the HSD11B1 gene. Optimization based on an initially identified 11β-HSD1 inhibitor (3) led to the discovery of potent inhibitors with IC50 values in the 100nM range. These compounds are also highly selective 11β-HSD1 inhibitors with no activity against 11β-HSD2 and 17β-HSD1. Compound 15 (IC50 =114nM) with weak inhibitory activity against the key human cytochrome P450 enzymes and moderate stability in incubation with human liver microsomes is worthy of further development. Importantly, compound 41 (IC50 =280nM) provides a new lead that incorporates an adamantyl group surrogate and should enable further series diversification.

Graphical abstract

Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein–ligand crystallography

August 7, 2014, 10:22 pm

≫ Next: Novel R-roscovitine NO-donor hybrid compounds as potential pro-resolution of inflammation agents

≪ Previous: Adamantyl carboxamides and acetamides as potent human 11β-hydroxysteroid dehydrogenase type 1 inhibitors

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Publication date: 15 November 2012
Source:Bioorganic & Medicinal Chemistry, Volume 20, Issue 22
Author(s): Cornelis Matijssen , M. Cris Silva-Santisteban , Isaac M. Westwood , Samerene Siddique , Vanessa Choi , Peter Sheldrake , Rob L.M. van Montfort , Julian Blagg
Two closely related binding modes have previously been proposed for the ATP-competitive benzimidazole class of checkpoint kinase 2 (CHK2) inhibitors; however, neither binding mode is entirely consistent with the reported SAR. Unconstrained rigid docking of benzimidazole ligands into representative CHK2 protein crystal structures reveals an alternative binding mode involving a water-mediated interaction with the hinge region; docking which incorporates protein side chain flexibility for selected residues in the ATP binding site resulted in a refinement of the water-mediated hinge binding mode that is consistent with observed SAR. The flexible docking results are in good agreement with the crystal structures of four exemplar benzimidazole ligands bound to CHK2 which unambiguously confirmed the binding mode of these inhibitors, including the water-mediated interaction with the hinge region, and which is significantly different from binding modes previously postulated in the literature.

Graphical abstract

Novel R-roscovitine NO-donor hybrid compounds as potential pro-resolution of inflammation agents

August 7, 2014, 10:22 pm

≫ Next: Covalent inhibition of SUMO and ubiquitin-specific cysteine proteases by an in situ thiol–alkyne addition

≪ Previous: Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein–ligand crystallography

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Publication date: 1 April 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 7
Author(s): Gabriele Montanaro , Massimo Bertinaria , Barbara Rolando , Roberta Fruttero , Christopher D. Lucas , David A. Dorward , Adriano G. Rossi , Ian L. Megson , Alberto Gasco
Neutrophils play a pivotal role in the pathophysiology of multiple human inflammatory diseases. Novel pharmacological strategies which drive neutrophils to undergo programmed cell death (apoptosis) have been shown to facilitate the resolution of inflammation. Both the cyclin-dependent kinase inhibitor (CDKi) R-roscovitine and nitric oxide (NO) have been shown to enhance apoptosis of neutrophils and possess pro-resolution of inflammation properties. In order to search for new multi-target pro-resolution derivatives, here we describe the design, synthesis and investigation of the biological potential of a small series of hybrid compounds obtained by conjugating R-roscovitine with two different NO-donor moieties (compounds 2, 9a, 9c). The synthesized compounds were tested as potential pro-resolution agents, with their ability to promote human neutrophil apoptosis evaluated. Both compound 9a and 9c showed an increased pro-apoptotic activity when compared with either R-roscovitine or structurally related compounds devoid of the ability to release NO (des-NO analogues). Inhibition of either NO-synthase or soluble guanylate cyclase did not affect the induction of apoptosis by the R-roscovitine derivatives, similar to that reported for other classes of NO-donors. In contrast the NO scavenger PTIO prevented the enhanced apoptosis seen with compound 9a over R-roscovitine. These data show that novel compounds such as CDKi–NO-donor hybrids may have additive pro-resolution of inflammation effects.

Graphical abstract

Covalent inhibition of SUMO and ubiquitin-specific cysteine proteases by an in situ thiol–alkyne addition

August 7, 2014, 10:22 pm

≫ Next: Remarkable antioxidant properties of a series of hydroxy-3-arylcoumarins

≪ Previous: Novel R-roscovitine NO-donor hybrid compounds as potential pro-resolution of inflammation agents

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Publication date: 1 May 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 9
Author(s): Stefanie Sommer , Nadine D. Weikart , Uwe Linne , Henning D. Mootz
Posttranslational modification of proteins with ubiquitin and ubiquitin-like modifiers such as SUMO can be reverted by specific proteases, also referred to as deubiquitinases and isopeptidases, most of which are cysteine-dependent. We have found that the replacement of the conserved C-terminal glycine with propargylamine converts SUMO and ubiquitin to highly efficient covalent inhibitors of their cognate cysteine proteases. Attack of the catalytic cysteine onto the terminal alkyne results in the formation of a vinyl sulfide linkage. Although this reaction is reminiscent of the inhibitory mechanism of the isosteric nitrile inhibitors it was unexpected due to the low electrophilicity of the alkyne group. We show that a precise location of the functional group in the active site of the protease is crucial for the reaction, which was not inhibited by the presence of a radical scavenger. Furthermore, a mutational study of key catalytic residues in the SUMO-protease Senp1, that is H533A and D550A of the catalytic triad and Q597A as part of the oxyanion hole, revealed that these residues are not required for the observed covalent adduct formation. We therefore propose that the reaction is an in situ thiol–alkyne addition. Due to the high chemical inertness of the alkyne moiety the respective protease inhibitors should be well-suited for cellular and therapeutic applications. In keeping with this idea, selective labeling with propargylated SUMO and Ub probes was observed in lysates of cell lines expressing the cognate proteases after transient transfection.

Graphical abstract

Remarkable antioxidant properties of a series of hydroxy-3-arylcoumarins

August 7, 2014, 10:22 pm

≫ Next: Pseudoperoxidase investigations of hydroperoxides and inhibitors with human lipoxygenases

≪ Previous: Covalent inhibition of SUMO and ubiquitin-specific cysteine proteases by an in situ thiol–alkyne addition

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Publication date: 1 July 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 13
Author(s): Maria João Matos , Fernanda Pérez-Cruz , Saleta Vazquez-Rodriguez , Eugenio Uriarte , Lourdes Santana , Fernanda Borges , Claudio Olea-Azar
In the present work we synthesized a series of hydroxy-3-arylcoumarins (compounds 1–9), some of them previously described as MAO-B selective inhibitors, with the aim of evaluating their antioxidant properties. Theoretical evaluation of ADME properties of all the derivatives was also carried out. From the ORAC-FL, ESR and CV data it was concluded that these derivatives are very good antioxidants, with a very interesting hydroxyl, DPPH and superoxide radicals scavenging profiles. In particular compound 9 is the most active and effective antioxidant of the series (ORAC-FL=13.5, capacity of scavenging hydroxyl radicals=100%, capacity of scavenging DPPH radicals=65.9% and capacity of scavenging superoxide radicals=71.5%). Kinetics profile for protection fluorescein probe against peroxyl radicals by addition of antioxidant molecule 9 was also performed. Therefore, it can operate as a potential candidate for preventing or minimizing the free radicals overproduction in oxidative-stress related diseases.

Graphical abstract

Pseudoperoxidase investigations of hydroperoxides and inhibitors with human lipoxygenases

August 7, 2014, 10:22 pm

≫ Next: Synthesis and biological evaluation of arctigenin ester and ether derivatives as activators of AMPK

≪ Previous: Remarkable antioxidant properties of a series of hydroxy-3-arylcoumarins

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Publication date: 1 July 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 13
Author(s): Eric K. Hoobler , Charles Holz , Theodore R. Holman
Understanding the mode of action for lipoxygenase (LOX) inhibitors is critical to determining their efficacy in the cell. The pseudoperoxidase assay is an important tool for establishing if a LOX inhibitor is reductive in nature, however, there have been difficulties identifying the proper conditions for each of the many human LOX isozymes. In the current paper, both the 234nM decomposition (UV) and iron-xylenol orange (XO) assays are shown to be effective methods of detecting pseudoperoxidase activity for 5-LOX, 12-LOX, 15-LOX-1 and 15-LOX-2, but only if 13-(S)-HPODE is used as the hydroperoxide substrate. The AA products, 12-(S)-HPETE and 15-(S)-HPETE, are not consistent hydroperoxide substrates since they undergo a competing transformation to the di-HETE products. Utilizing the above conditions, the selective 12-LOX and 15-LOX-1 inhibitors, probes for diabetes, stroke and asthma, are characterized for their inhibitory nature. Interestingly, ascorbic acid also supports the pseudoperoxidase assay, suggesting that it may have a role in maintaining the inactive ferrous form of LOX in the cell. In addition, it is observed that nordihydroguaiaretic acid (NDGA), a known reductive LOX inhibitor, appears to generate radical species during the pseudoperoxidase assay, which are potent inhibitors against the human LOX isozymes, producing a negative pseudoperoxidase result. Therefore, inhibitors that do not support the pseudoperoxidase assay with the human LOX isozymes, should also be investigated for rapid inactivation, to clarify the negative pseudoperoxidase result.

Graphical abstract

Synthesis and biological evaluation of arctigenin ester and ether derivatives as activators of AMPK

August 7, 2014, 10:22 pm

≫ Next: Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment

≪ Previous: Pseudoperoxidase investigations of hydroperoxides and inhibitors with human lipoxygenases

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Publication date: 1 July 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 13
Author(s): Sida Shen , Jingjing Zhuang , Yijia Chen , Min Lei , Jing Chen , Xu Shen , Lihong Hu
A series of new arctigenin and 9-deoxy-arctigenin derivatives bearing different ester and ether side chains at the phenolic hydroxyl positions are designed, synthesized, and evaluated for activating AMPK potency in L6 myoblasts. Initial biological evaluation indicates that some alkyl ester and phenethyl ether arctigenin derivatives display potential activities in AMPK phosphorylation improvement. Further structure–activity relationship analysis shows that arctigenin ester derivatives 3a, 3h and 9-deoxy-arctigenin phenethyl ether derivatives 6a, 6c, 6d activate AMPK more potently than arctigenin. Moreover, the 2-(3,4-dimethoxyphenyl)ethyl ether moiety of 6c has been demonstrated as a potential functional group to improve the effect of AMPK phosphorylation. The structural optimization of arctigenin leads to the identification of 6c as a promising lead compound that exhibits excellent activity in AMPK activation.

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Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment

August 7, 2014, 10:22 pm

≫ Next: Reaction of 3′,5′-di-O-acetyl-2′-deoxyguansoine with hypobromous acid

≪ Previous: Synthesis and biological evaluation of arctigenin ester and ether derivatives as activators of AMPK

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Publication date: 1 July 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 13
Author(s): Takayuki Inoue , Masataka Morita , Takashi Tojo , Akira Nagashima , Ayako Moritomo , Hiroshi Miyake
Novel thiazole derivatives were synthesized and evaluated as vascular adhesion protein-1 (VAP-1) inhibitors. Although we previously identified a compound (2) with potent VAP-1 inhibitory activity in rats, the human activity was relatively weak. Here, to improve the human VAP-1 inhibitory activity of compound 2, we first evaluated the structure–activity relationships of guanidine bioisosteres as simple small molecules and identified a 1H-benzimidazol-2-amine (5) with potent activity compared to phenylguanidine (1). Based on the structure of compound 5, we synthesized a highly potent VAP-1 inhibitor (37b; human IC50 =0.019μM, rat IC50 =0.0051μM). Orally administered compound 37b also markedly inhibited ocular permeability in streptozotocin-induced diabetic rats after oral administration, suggesting it is a promising compound for the treatment of diabetic macular edema.

Graphical abstract

Reaction of 3′,5′-di-O-acetyl-2′-deoxyguansoine with hypobromous acid

August 7, 2014, 10:22 pm

≫ Next: Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase

≪ Previous: Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment

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Publication date: 1 July 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 13
Author(s): Toshinori Suzuki , Asuka Nakamura , Michiyo Inukai
Hypobromous acid (HOBr) is formed by eosinophil peroxidase and myeloperoxidase in the presence of H2O2, Cl⁻, and Br⁻ in the host defense system of humans, protecting against invading bacteria. However, the formed HOBr may cause damage to DNA and its components in the host. When a guanine nucleoside (3′,5′-di-O-acetyl-2′-deoxyguansoine) was treated with HOBr at pH 7.4, spiroiminodihydantoin, guanidinohydantoin/iminoallantoin, dehydro-iminoallantoin, diimino-imidazole, amino-imidazolone, and diamino-oxazolone nucleosides were generated in addition to an 8-bromoguanine nucleoside. The major products were spiroiminodihydantoin under neutral conditions and guanidinohydantoin/iminoallantoin under mildly acidic conditions. All the products were formed in the reaction with HOCl in the presence of Br⁻. These products were also produced by eosinophil peroxidase or myeloperoxidase in the presence of H2O2, Cl⁻, and Br⁻. The results suggest that the products other than 8-bromoguanine may also have importance for mutagenesis by the reaction of HOBr with guanine residues in nucleotides and DNA.

Graphical abstract

Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase

August 7, 2014, 10:22 pm

≫ Next: 20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs

≪ Previous: Reaction of 3′,5′-di-O-acetyl-2′-deoxyguansoine with hypobromous acid

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Publication date: 15 July 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
Author(s): Oleg Sadovski , Justin W. Hicks , Jun Parkes , Roger Raymond , José Nobrega , Sylvain Houle , Mariateresa Cipriano , Christopher J. Fowler , Neil Vasdev , Alan A. Wilson
Fatty acid amide hydrolase (FAAH), the enzyme responsible for terminating signaling by the endocannabinoid anandamide, plays an important role in the endocannabinoid system, and FAAH inhibitors are attractive drugs for pain, addiction, and neurological disorders. The synthesis, radiosynthesis, and evaluation, in vitro and ex vivo in rat, of an ¹⁸F-radiotracer designed to image FAAH using positron emission tomography (PET) is described. Fluorine-18 labelled 3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate, [¹⁸F]5, was synthesized at high specific activity in a one-pot three step reaction using a commercial module with a radiochemical yield of 17–22% (from [¹⁸F]fluoride). In vitro assay using rat brain homogenates showed that 5 inhibited FAAH in a time-dependent manner, with an IC50 value of 0.82nM after a preincubation of 60min. Ex vivo biodistribution studies and ex vivo autoradiography in rat brain demonstrated that [¹⁸F]5 had high brain penetration with standard uptake values of up to 4.6 and had a regional distribution which correlated with reported regional FAAH enzyme activity. Specificity of binding to FAAH with [¹⁸F]5 was high (>90%) as demonstrated by pharmacological challenges with potent and selective FAAH inhibitors and was irreversible as demonstrated by radioactivity measurements on homogenized brain tissue extracts. We infer from these results that [¹⁸F]5 is a highly promising candidate radiotracer with which to image FAAH in human subjects using PET and clinical studies are proceeding.

Graphical abstract

20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs

August 7, 2014, 10:22 pm

≫ Next: Microwave assisted solid phase synthesis of highly functionalized N-alkylated oligobenzamide α-helix mimetics

≪ Previous: Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase

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Publication date: 15 July 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
Author(s): Junhua Liu , Xu Wang , Peng Liu , Rongxin Deng , Min Lei , Wantao Chen , Lihong Hu
Novel 20(S)-protopanoxadiol (PPD) analogues were designed, synthesized, and evaluated for the chemosensitizing activity against a multidrug resistant (MDR) cell line (KBvcr) overexpressing P-glycoprotein (P-gp). Structure–activity relationship analysis showed that aromatic substituted aliphatic amine at the 24-positions (groups V) effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as docetaxel (DOC), vincristine (VCR), and adriamycin (ADM). PPD derivatives 12 and 18 showed 1.3–2.6 times more effective reversal ability than verapamil (VER) for DOC and VCR. Importantly, no cytotoxicity was observed by the active PPD analogues (5μM) against both non-MDR and MDR cells, suggesting that PPD analogues serve as novel lead compounds toward a potent and safe resistance modulator. Moreover, a preliminary mechanism study demonstrated that the chemosensitizing activity of PPD analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells.

Graphical abstract

Microwave assisted solid phase synthesis of highly functionalized N-alkylated oligobenzamide α-helix mimetics

August 7, 2014, 10:22 pm

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Publication date: 15 July 2013
Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
Author(s): Kérya Long , Thomas A. Edwards , Andrew J. Wilson
Protein–protein interactions (PPIs) mediate cellular pathways and are implicated in numerous aberrant conditions. α-Helix mimetics—small molecules that reproduce the spatial projection of key residues from an α-helix involved in a PPI—are attractive generic templates for development of screening libraries, however library syntheses of α-helix mimetics with diverse functionality are less established. This manuscript describes the automated, microwave assisted solid phase synthesis based on one such scaffold; an N-alkylated oligobenzamide.

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