Bioactivation of 2,3-Diaminopyridine-Containing Bradykinin B 1 Receptor Antagonists: Irreversible Binding to Liver Microsomal Proteins and Formation of Glutathione Conjugates (original) (raw)
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Marek_et_al-2016-Journal_of_Labelled_Compounds_and_Radiopharmaceuticals.pdf
The labeling of unsaturated γ‐hydroxybutyric acid by heavy isotopes of hydrogen: iridium complex‐mediated H/D exchange by C─H bond activation vs reduction by boro‐deuterides/tritides 3‐Hydroxycyclopent‐1‐ene‐1‐carboxylic acid (HOCPCA (1)) is a potent ligand for high‐affinity γ‐hydroxybutyric acid binding sites in the central nervous system. Various approaches to the introduction of a hydrogen label onto the HOCPCA skeleton are reported. The outcomes of the feasible C─H activation of olefin carbon (C‐2) by iridium catalyst are compared with the reduction of the carbonyl group (C‐3) by freshly prepared borodeuterides. The most efficient iridium catalysts proved to be Kerr bulky phosphine N‐heterocyclic species providing outstanding deuterium enrichment (up to 91%) in a short period of time. The highest deuterium enrichment (>99%) was achieved through the reduction of ketone precursor 2 by lithium trimethoxyborodeuteride. Hence, analogical conditions were used for the tritiation experiment. [ 3 H]‐HOCPCA selectively labeled on the position C‐3 was synthetized with radiochemical purity >99%, an isolated yield of 637 mCi and specific activity = 28.9 Ci/mmol. KEYWORDS C─H activation, borotritides, hydrogen/deuterium exchange, iridium catalyst, tritium‐ labeled γ‐hydroxybutyric acid 1 | INTRODUCTION γ‐Hydroxybutyric acid (GHB, Figure 1) is an endogenous substance that is present in micromolar concentrations in the mammalian brain. It is a metabolite of the major inhibitory neurotransmitter γ‐aminobutyric acid (GABA) (Figure 1), but it is also believed to be a neuromodulator on its own, 1 although the specific function of GHB remains to be elucidated. GHB is administered orally for the treatment of narcolepsy (sodium oxybate) 2 and alcoholism. 3 GHB is tasteless and odorless, and because of its effects on the central nervous system (mild euphoria, sedation, respiratory depression, and, after high doses, eventually coma), it is a hazardous drug of abuse (Fantasy). We have previously described 3‐hydroxycyclopent‐1‐ene‐1‐carbox-ylic acid (HOCPCA) (1) (Figure 1) as a very selective ligand for the high‐affinity GHB binding site (1 has 27 times higher affinity than GHB itself), which has, unlike GHB, no affinity for the GABA B receptor. 4 Given the close structural relationship of 1 to GHB and its relatively small size, 1 is a highly attractive compound for the investigation of GHB‐like pharmacology. Therefore, we have decided to explore the synthetic routes for the labeling of 1 by hydrogen isotopes and thus facilitate in vivo studies. Egan and Filer reported in 2003 the protocol for the tritium labeling of GHB by a Pd‐catalyzed reduction of the corresponding dehydrobutyrolactone. 5 They isolated [ 3 H]‐GHB labeled at positions 2, 3, and 4 with a specific activity of 37 Ci/mmol. We have recently reported a new preparative synthetic route to tritium‐labeled 1, based on a reduction of the ketone group by in‐house synthesized LiB(OMe) 3 T. 6 In order to avoid the formation of a multistep synthesis of such a borotritide, we have decided to study a feasible and elegant approach to labeling, using iridium catalyzed ortho‐directed hydrogen‐isotope exchange. This paper reports a detailed study comparing both methodologies.
Bioorganic & Medicinal Chemistry, 2002
Bioisosteric replacement of the pyridine pharmacophoric element in (AE)-pyrido[3.4-b]homotropane (PHT) and pyrido[3.4-b]tropane with the pyridazine and pyrimidine nucleus resulted in hitherto unknown nAChR ligands such as 5-8. Inverse type Diels-Alder reactions constitute the key steps in the new routes to the pyridazine-or pyrimidine-annulated bioisosteres. The enantiopure (+)-2-tropinone (11) from the 'chiral pool' is transformed to the ring-expanded silyl enol ether 12 and to the enamine 15. Both proved to be highly dienophilic species in the inverse type [4+2] cycloaddition reactions with the 1,2,4,5-tetrazines 13 and 16a,b or with the 1,3,5-triazine 19 to provide the enantiopure target compounds 5-7. In the same way the racemic pyrimidineannulated species 8 was obtained from 3-tropanone 21. The new ligands were tested for their in vitro affinity for (a4) 2 (b2) 3 and a7* nAChR subtype. In comparison to PHT, well known to exhibit affinity for agonist binding sites in rat brain approximately equivalent to that of (+)-anatoxin-a (1), replacement of the pyridine by the bioisosteric pyridazine resulted in 30-fold lower affinity at the (a4) 2 (ß2) 3 subtype. The annulated diazinotropanes 6-8, ligands with ferruginine-like structures more or less retained the affinity of (À)-norferruginine (3) except of compound 7. Remarkably, all of the novel ligands are devoid of affinity at the a7* subtype.
Synthesis of potentially bioactive compounds and tools for biological studies
2014
NMR-Spektroskopie gehort zu einer der vielseitigsten Methoden um Strukturen und strukturelle Parameter organischer und bioorganischer Stoffe zu untersuchen. In Kombination mit Labeling-Methoden ist sie eine auserst geeignete Technik um NMR-Spektren von Makromolekulen zu vereinfachen. NMR-Spektroskopie wird unter anderem zur Untersuchung von Proteinen, sowie deren Falteigenschaften und chemischen und biochemischen Reaktionen benutzt. Proteine haben typischerweise eine hohe Molekulmasse sowie eine hohe Anzahl an Spin-Systemen, die fur schwer interpretierbare NMR Spektren verantwortlich sind, weshalb es notwendig ist 13C- und 15N- Isotope in das Molekul zu integrieren um die jeweiligen Spektren zu vereinfachen. Die Entwicklung einer neuen synthetischen Route, ausgehend von wirtschaftlich tragbaren und einfach zuganglichen Ausgangsprodukten, hin zu 13C Isotopen-markiertem Phenylalanin, ist der Hauptfokus dieser Arbeit. Zur Markierung wurden [13C]-Essigsaure, [13C]-Formaldehyd, [13C]-All...
Smart Science, 2015
Smart Science 164 2. Experimental 2.1 Materials and methods All chemicals were purchased from Merck or Fluka. Methanol and water used were of HPLC grade and were purchased from sigma Aldrich Pvt. Ltd. Mumbai, India. Melting points were determined in open capillaries and are uncorrected. Silica gel mesh GF 254 plates were used for TLC. GC (chromatogram) analyser model Shimadzu 1700 (Perkin Elmer) was used for sampling conversion. IR spectra were recorded on FTIR spectrophotometer (Perkin Elmer) using KBr disc method. 1H NMR and 13C NMR spectra were determined on Varian Gemini 200 MHz (IICT-Hyderabad) instrument. UV chamber (Perkin Elmer) were used in this study. 2.2 Experimental procedure for preparation of dimethyl 3amino-4-(p-tolyloxy)-[1, 1'-biaryl]-2, 6-di-carboxylates To a mechanically stirred solution of aldehyde (1 mole), 4-methyl phenol (1 mole) and ZnO 2 (5 mol%) in methanol-water (10 mL: 10 mL, v/v) was added malononitrile (2 mole). The mechanical stirring was continued for 3 hours at 800 rpm. The precipitate was checked with thin layer chromatography (mobile phase, ethyl acetate: nhexane 5:5) and conformed. The filtered product was washed with 50 ml methanol to isolate the final product. Data has been given below for all compounds. Compound (4b): mp 218-220 0 C, 1 H NMR (DMSO-d6) δ = 2.
Spectrochimica Acta Part A-molecular and Biomolecular Spectroscopy, 2008
In obtaining some new cytotoxic and chemopreventive agents with potent antiproliferative activity against cancer cells, a series of new -isatin aldehyde-N,N'-thiocarbohydrazone, bis--isatin thiocarbohydrazones, bis--isatin carbohydrazones, N,2-bis(thiophen-2-ylmethylidene) thiocarbohydrazone and N,2-bis(thiophen-2-ylmethylidene) carbohydrazone derivatives was synthesized by microwave oriented reaction and evaluated for their in vitro cytotoxic activity. The newly synthesized compounds were characterized based on spectral (FT-IR, NMR, MS) analyses. The inhibitory effects of synthesized compounds on the proliferation of murine leukemia cells (L1210), human T-lymphocyte cells (CEM) and human cervix carcinoma cells (HeLa) were assayed by using MTT assay. The compounds were also tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-Otetradecanoylphorbol-13-acetate (TPA). In vitro evaluation of these schiff bases revealed mild to moderate cytotoxic activity in a dose dependent manner. The results of the in vitro inhibitory activities of synthetic compounds against EBV-EA activation with IC 50 ranges from 485-535 (mol ratio/32pmol/TPA). Chlorine group containing derivatives did not show increased inhibitory activity against tumor promoter TPA induction. Sulphur containing derivatives also did not show a high inhibitory potency in this system.
International Journal of Advanced Research
Scheme-1 Prop-2-yn-1-yl 3-((tert-butoxycarbonyl)amino)-2,2-dimethylpropanoate Step-1 Dicyclohexylcarbodiimide (1.1 eq.) and triethylamine (2 eq.) were added to a stirred solution of compd-1 (1 eq.) and Compd-2 (1 eq.) in 1 : 1 ratio of Dichloromethane (DCM) : Dimethylformamide (10 mL/ 1 g) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of reaction (checked by TLC), solid waste was filtered. The resultant filtrate was diluted with DCM, followed by washing with water, dried over anhydrous sodium sulphate (Na2SO4) and concentrated. The obtain crude material was purified by Silica gel (100-200 mesh) column chromatography using (2:8) ethyl acetate in hexane.
Journal of Labelled Compounds and Radiopharmaceuticals, 2005
As part of a program aimed at the design of conformationally constrained analogs of glutamic acid, (+)-2-aminobicyclo[3.1.0]hexane-2,6-carboxylic acid (1), identified as a highly potent, selective, group II metabotropic glutamate receptor agonist has been synthesized and studied clinically. Heterocyclic analogs of 1 were subsequently synthesized in which the C-2 methylene has been replaced by an oxygen atom (2) or a sulfur atom (3). C-14 labeled isotopomers of 1, 2 and 3 have been synthesized to facilitate pre-clinical ADME studies. A tritium labeled isotopomer of 1 was also synthesized for use in in vitro experiments. A stable labeled isotopomer of rac-1 was prepared for use as an internal standard for bioanalytical assays. The key step in each of these syntheses was the reaction of chiral ketone 4, 5 or 6 with K 14 CN/(NH 4) 2 CO 3 using the Bucherer-Berg protocol. In the preparation of the stable labeled isotopomer, rac-4-[ 13 C 2 ] was prepared in two steps from ethyl bromoacetate-[UL-13 C 2 ]; subsequent reaction of rac-4-[ 13 C 2 ] with K 13 CN/ 15 NH 4 Cl/Na 2 CO 3 , followed by hydrolysis of the hydantoin yielded rac-1-[ 13 C 3 , 15 N].