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51.
Wilna J. Moree Bin-Feng Li Said Zamani-Kord Jinghua Yu Timothy Coon Charles Huang Dragan Marinkovic Fabio C. Tucci Siobhan Malany Margaret J. Bradbury Lisa M. Hernandez Jianyun Wen Hua Wang Samuel R.J. Hoare Robert E. Petroski Kayvon Jalali Chun Yang Aida Sacaan Ajay Madan Paul D. Crowe Graham Beaton 《Bioorganic & medicinal chemistry letters》2010,20(19):5874-5878
Analogs of the known H1-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study. 相似文献
52.
Non-structural poliovirus 2B protein induces plasma membrane permeabilization and has been recently implicated in triggering apoptosis via the mitochondrial pathway. Here we describe that the pore-forming P3 peptide, based on the 2B amphipathic domain, translocates through the plasma membrane of culture cells and targets mitochondria. Cell permeabilization by P3 versions of different lengths, together with peptide uptake analyses supported an internalization mechanism dependent on P3 capacity to interact physically with lipid bilayers and establish permeating pores therein. Internalized P3 was found associated with mitochondria, but contrary to the parental 2B protein, the short peptide did not affect the morphology or cell distribution of these organelles, nor induced apoptosis. We conclude that P3 constitutes a mitochondriotropic sequence, which is however devoid of 2B pro-apoptotic activity. 相似文献
53.
Structural characterization of AtmS13, a putative sugar aminotransferase involved in indolocarbazole AT2433 aminopentose biosynthesis
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Shanteri Singh Youngchang Kim Fengbin Wang Lance Bigelow Michael Endres Madan K. Kharel Gyorgy Babnigg Craig A. Bingman Andrzej Joachimiak Jon S. Thorson George N. Phillips Jr. 《Proteins》2015,83(8):1547-1554
AT2433 from Actinomadura melliaura is an indolocarbazole antitumor antibiotic structurally distinguished by its unique aminodideoxypentose‐containing disaccharide moiety. The corresponding sugar nucleotide‐based biosynthetic pathway for this unusual sugar derives from comparative genomics where AtmS13 has been suggested as the contributing sugar aminotransferase (SAT). Determination of the AtmS13 X‐ray structure at 1.50‐Å resolution reveals it as a member of the aspartate aminotransferase fold type I (AAT‐I). Structural comparisons of AtmS13 with homologous SATs that act upon similar substrates implicate potential active site residues that contribute to distinctions in sugar C5 (hexose vs. pentose) and/or sugar C2 (deoxy vs. hydroxyl) substrate specificity. Proteins 2015; 83:1547–1554. © 2015 Wiley Periodicals, Inc. 相似文献
54.
Shanteri Singh Karolina Michalska Lance Bigelow Michael Endres Madan K. Kharel Gyorgy Babnigg Ragothaman M. Yennamalli Craig A. Bingman Andrzej Joachimiak Jon S. Thorson George N. Phillips Jr. 《The Journal of biological chemistry》2015,290(43):26249-26258
Classical UDP-glucose 6-dehydrogenases (UGDHs; EC 1.1.1.22) catalyze the conversion of UDP-α-d-glucose (UDP-Glc) to the key metabolic precursor UDP-α-d-glucuronic acid (UDP-GlcA) and display specificity for UDP-Glc. The fundamental biochemical and structural study of the UGDH homolog CalS8 encoded by the calicheamicin biosynthetic gene is reported and represents one of the first studies of a UGDH homolog involved in secondary metabolism. The corresponding biochemical characterization of CalS8 reveals CalS8 as one of the first characterized base-permissive UGDH homologs with a >15-fold preference for TDP-Glc over UDP-Glc. The corresponding structure elucidations of apo-CalS8 and the CalS8·substrate·cofactor ternary complex (at 2.47 and 1.95 Å resolution, respectively) highlight a notably high degree of conservation between CalS8 and classical UGDHs where structural divergence within the intersubunit loop structure likely contributes to the CalS8 base permissivity. As such, this study begins to provide a putative blueprint for base specificity among sugar nucleotide-dependent dehydrogenases and, in conjunction with prior studies on the base specificity of the calicheamicin aminopentosyltransferase CalG4, provides growing support for the calicheamicin aminopentose pathway as a TDP-sugar-dependent process. 相似文献
55.
Reddy BV Rajeswari N Sarangapani M Roopa Reddy G Madan Ch Pranay Kumar K Srinivasa Rao M 《Bioorganic & medicinal chemistry letters》2011,21(21):6510-6514
Indole and its derivatives undergo smooth conjugate addition onto en-1,4-dione derived from isatin and acetophenone, in the presence of a catalytic amount of molecular iodine in acetonitrile under mild conditions to afford a novel class of 3-(1-(1H-indol-3-yl)-2-oxo-2-phenylethyl)indolin-2-one derivatives in good yields with high degree of 1,4-selectivity. Some of these compounds are found to exhibit modest antibacterial and antifungal properties. 相似文献
56.
Huang C Moree WJ Zamani-Kord S Li BF Tucci FC Malany S Wen J Wang H Hoare SR Yang C Madan A Crowe PD Beaton G 《Bioorganic & medicinal chemistry letters》2011,21(3):947-951
Structure-activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H1-antihistamines. Reductions in pKa via incorporation of a β-fluoro substituent or a heteroaryl moiety were shown to reduce contributions to metabolism through this pathway. Several compounds, including 8l, 8o, and 12f were identified with promising primary in vitro profiles and reduced biotransformation via CYP2D6. 相似文献
57.
Autotaxin (ATX) is an attractive target for the anticancer therapeutics that inhibits angiogenesis, invasion and migration. ATX is an extracellular lysophospholipase D that hydrolyzes lysophosphatidylcholine to form the bioactive lipid lysophosphatidic acid. The aromatic phosphonate S32826 was the first described nanomolar inhibitor of ATX. However, the tridecylamide substituent on aromatic ring contributed to its poor solubility and bioavailability, severely limiting its utility in vivo. c Log P calculations revealed that the lipophilicity of S32826 could be lowered by shortening its hydrophobic chain and by introducing substituents alpha to the phosphonate. Herein, we describe the synthesis of a small set of α-substituted phosphonate analogs of S32826, and we show that shortening the chain and adding α-halo or α-hydroxy substituents increased solubility; however, ATX inhibition was reduced by most substitutions. An optimal compound was identified for examination of biological effects of ATX inhibition in vivo. 相似文献
58.
Kamal N Chowdhury S Madan T Sharma D Attreyi M Haq W Katti SB Kumar A Sarma PU 《Molecular and cellular biochemistry》2005,275(1-2):223-231
The role of tryptophan (Trp17) in immunoreactivity of P1, the diagnostically relevant peptide from a major allergen/antigen of Aspergillus fumigatus, was evaluated by chemically modifying tryptophanyl residue of P1. In BIAcore kinetic studies, unmodified P1 showed a 100-fold higher binding with ABPA (Allergic Bronchopulmonary Aspergillosis) patients’ IgG [KD (equilibrium dissociation constant) = 2.74 e−8 ± 0.13 M] than the controls’ IgG (KD = 2.97 e−6± 0.14 M), whereas chemically-modified P1 showed similar binding [KD patients’ IgG = 3.25 e−7± 0.16 M, KD controls’ IgG = 3.86 e−7± 0.19 M] indicating loss of specific immunoreactivity of P1 on tryptophan modification. Modified P1 showed loss of specific binding to IgE and IgG antibodies of ABPA patients in ELISA (Enzyme-Linked Immunosorbent Assay). The study infers that tryptophan residue (Trp17) is essential for immunoreactivity of P1. 相似文献
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