Health, Medicine

Development of α1,6-fucosyltransferase inhibitors through the diversity-oriented syntheses of GDP-fucose mimics using the coupling between alkyne and sulfonyl azide

Publication date: Available online 28 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Yoshiyuki Manabe, Satomi Kasahara, Yohei Takakura, Xiaoxiao Yang, Shinji Takamatsu, Yoshihiro Kamada, Eiji Miyoshi, Daisuke Yoshidome, Koichi Fukase
We developed α 1,6-fucosyltransferase (FUT8) inhibitors through a diversity-oriented synthesis. The coupling reaction between the fucose unit containing alkyne and the guanine unit containing sulfonyl azide under various conditions afforded a series of Guanosine 5′-diphospho-β-L-fucose (GDP-fucose) analogs. The synthesized compounds displayed FUT8 inhibition activity. A docking study revealed that the binding mode of the inhibitor synthesized with FUT8 was similar to that of GDP-fucose.

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Health, Medicine

Development of α1,6-fucosyltransferase inhibitors through the diversity-oriented syntheses of GDP-fucose mimics using the coupling between alkyne and sulfonyl azide

Publication date: Available online 28 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Yoshiyuki Manabe, Satomi Kasahara, Yohei Takakura, Xiaoxiao Yang, Shinji Takamatsu, Yoshihiro Kamada, Eiji Miyoshi, Daisuke Yoshidome, Koichi Fukase
We developed α 1,6-fucosyltransferase (FUT8) inhibitors through a diversity-oriented synthesis. The coupling reaction between the fucose unit containing alkyne and the guanine unit containing sulfonyl azide under various conditions afforded a series of Guanosine 5′-diphospho-β-L-fucose (GDP-fucose) analogs. The synthesized compounds displayed FUT8 inhibition activity. A docking study revealed that the binding mode of the inhibitor synthesized with FUT8 was similar to that of GDP-fucose.

Graphical abstract

image

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http://ift.tt/2mC0hcY

Health, Medicine

Development of α1,6-fucosyltransferase inhibitors through the diversity-oriented syntheses of GDP-fucose mimics using the coupling between alkyne and sulfonyl azide

Publication date: Available online 28 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Yoshiyuki Manabe, Satomi Kasahara, Yohei Takakura, Xiaoxiao Yang, Shinji Takamatsu, Yoshihiro Kamada, Eiji Miyoshi, Daisuke Yoshidome, Koichi Fukase
We developed α 1,6-fucosyltransferase (FUT8) inhibitors through a diversity-oriented synthesis. The coupling reaction between the fucose unit containing alkyne and the guanine unit containing sulfonyl azide under various conditions afforded a series of Guanosine 5′-diphospho-β-L-fucose (GDP-fucose) analogs. The synthesized compounds displayed FUT8 inhibition activity. A docking study revealed that the binding mode of the inhibitor synthesized with FUT8 was similar to that of GDP-fucose.

Graphical abstract

image

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http://ift.tt/2mC0hcY

Health, Medicine

Xanthine oxidase inhibitory activity of nicotino/isonicotinohydrazides: A systematic approach from in vitro, in silico to in vivo studies

Publication date: Available online 28 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Humaira Zafar, Muhammad Hayat, Sumayya Saied, Momin Khan, Uzma Salar, Rizwana Malik, M. Iqbal Choudhary, Khalid Mohammed Khan
Change in life style and eating habits has led to an increased prevalence of hyperuricemia worldwide. The role of hyperuricemia is no more restricted to gout, but it has a central role in progression of CVD, hypertension, metabolic syndrome, and arthritis. Among the different factors involved in regulation of serum uric acid, xanthine oxidase (XO) is the best pharmacological target to control the levels of serum uric acid as it catalyzes the final steps in uric acid production. In the current study, a systemic search for the inhibitors of xanthine oxidase, starting from synthesis to in vitro screening and leading to in vivo studies is presented. Benzylidine nicotino/isonicotinohydrazides (1-54) were synthesized by treating nicotinic/isonicotinic hydrazides with substituted aromatic aldehyde, and characterized by EI-MS and 1H-NMR. Elemental analysis was also performed. All synthetic compounds were screened for xanthine oxidase inhibitory activity initially using an in vitro spectroscopic XO inhibition assay. Among them twenty-two derivatives were found to be active with IC50 values between 0.96- 330.4 µM, as compared to standard allopurinol IC50 = 2.00 ± 0.01 µM. Kinetic studies of five most active compounds (8, 35, 36, 39, and 45) with low IC50 values between 0.96 to 54.8 µM showed a competitive mode of inhibition. Further in silico molecular docking was carried out to study the interactions of these inhibitors with catalytically important amino acid residues in XO. Three compounds 8, 35, and 36 with IC50 values of 10, 12.4, and 0.96 µM, respectively, were found to be non-cytotoxic, and thus selected for in vivo studies. A simple and physiologically relevant animal model was used to analyze the in vivo XO inhibitory activity of these compounds. Among these, two compounds 35, and 36 showed a significant inhibition in male Wistar rats, and identified as potential lead molecules for anti-hyperuricemic drug development.

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Health, Medicine

Xanthine oxidase inhibitory activity of nicotino/isonicotinohydrazides: A systematic approach from in vitro, in silico to in vivo studies

Publication date: Available online 28 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Humaira Zafar, Muhammad Hayat, Sumayya Saied, Momin Khan, Uzma Salar, Rizwana Malik, M. Iqbal Choudhary, Khalid Mohammed Khan
Change in life style and eating habits has led to an increased prevalence of hyperuricemia worldwide. The role of hyperuricemia is no more restricted to gout, but it has a central role in progression of CVD, hypertension, metabolic syndrome, and arthritis. Among the different factors involved in regulation of serum uric acid, xanthine oxidase (XO) is the best pharmacological target to control the levels of serum uric acid as it catalyzes the final steps in uric acid production. In the current study, a systemic search for the inhibitors of xanthine oxidase, starting from synthesis to in vitro screening and leading to in vivo studies is presented. Benzylidine nicotino/isonicotinohydrazides (1-54) were synthesized by treating nicotinic/isonicotinic hydrazides with substituted aromatic aldehyde, and characterized by EI-MS and 1H-NMR. Elemental analysis was also performed. All synthetic compounds were screened for xanthine oxidase inhibitory activity initially using an in vitro spectroscopic XO inhibition assay. Among them twenty-two derivatives were found to be active with IC50 values between 0.96- 330.4 µM, as compared to standard allopurinol IC50 = 2.00 ± 0.01 µM. Kinetic studies of five most active compounds (8, 35, 36, 39, and 45) with low IC50 values between 0.96 to 54.8 µM showed a competitive mode of inhibition. Further in silico molecular docking was carried out to study the interactions of these inhibitors with catalytically important amino acid residues in XO. Three compounds 8, 35, and 36 with IC50 values of 10, 12.4, and 0.96 µM, respectively, were found to be non-cytotoxic, and thus selected for in vivo studies. A simple and physiologically relevant animal model was used to analyze the in vivo XO inhibitory activity of these compounds. Among these, two compounds 35, and 36 showed a significant inhibition in male Wistar rats, and identified as potential lead molecules for anti-hyperuricemic drug development.

Graphical abstract

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Health, Medicine

Design and characterization of opioid ligands based on cycle-in-macrocycle scaffold

Publication date: Available online 28 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Anna Adamska-Bartłomiejczyk, Rossella De Marco, Luca Gentilucci, Alicja Kluczyk, Anna Janecka
The study reports on a series of novel cyclopeptides based on the structure Tyr-[D-Lys-Phe-Phe-Asp]NH2, a mixed mu and kappa opioid receptor agonist with low nanomolar affinity, in which Phe4 residue was substituted by cyclic amino acids, such as Pro or its six-membered surrogates, piperidine-2-, 3- or 4-carboxylic acids (Pip, Nip and Inp, respectively). All derivatives exhibited high mu- and moderate delta-opioid receptor affinity, and almost no binding to the kappa-opioid receptor. Conformational analysis suggested that the cis conformation of the peptide bond Phe3-Xaa4 influences receptor selectivity through the control of the position of Phe3 side chain. The results substantiate the use of the cycle-macrocyle scaffolds for fine-tuning receptor selectivity.

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Health, Medicine

Identification of spirobisnaphthalene derivatives with anti-tumor activities from the endophytic fungus Rhytidhysteron rufulum AS21B

Publication date: Available online 27 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Ittipon Siridechakorn, Zongwei Yue, Yanisa Mittraphab, Xiaoguang Lei, Khanitha Pudhom
The cultivation of the mangrove-derived fungus Rhytidhysteron rufulum AS21B in acidic condition changed its secondary metabolite profile. Investigation of the culture broth extract led to the isolation and identification of two new spirobisnaphthalenes (1 and 2) together with eleven known compounds (3–13) from the crude extract of the fungus grown under an acidic condition as well as six known compounds (4, 10, 14-17) were isolated from the crude extract of the fungus grown under an neutral condition. Their structures were elucidated on the basis of extensive spectroscopic data. The isolated compounds were evaluated for their cytotoxicity against two human cancer cell lines, Ramos lymphoma and drug resistant NSCLC H1975. Compounds 2 and 10 displayed the most promising anti-tumor activity against both cancer cell lines.

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