1,721,005 research outputs found
Synthesis of New Water‐Soluble DNA‐Binding Subunits for Analogues of the Cytotoxic Antibiotic CC‐1065 and Their Prodrugs
No full textNovel water-soluble indole-2-carboxylic acid derivatives (7, 13, 21 and 25) bearing a substituent with a tertiary amino functionality at C-5 have been prepared. These new DNAbinding subunits can be used for the synthesis of new analogues of the cytotoxic antibiotic CC-1065 and their corresponding prodrugs for antibody-directed enzyme prodrug therapy (ADEPT) within a selective treatment of cancer. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006
Major Felix Agnus' claim for back pay, 26 July 1865
No full textClaim of Major Felix Agnus for back pay, 26 July 1865
CD-Spectroscopy As a Powerful Tool for Investigating the Mode of Action of Unmodified Drugs in Live Cells
No full textCircular dichroism (CD) spectroscopy is a well-known method for the analysis of chiral chemical compounds and is often used for studying the structure and interaction of proteins, DNA and bioactive compounds in solution. Here we demonstrate that CD spectroscopy is also a powerful tool for investigating the cellular uptake and mode of action of drugs in live cells. By means of CD spectroscopy, we identified DNA as the cellular target of several novel anticancer agents based on the highly cytotoxic natural antibiotic CC-1065. Furthermore, time-dependent changes in the CD spectra of drug-treated cells enabled us to rationalize differences in drug cytotoxicity. The anticancer agents rapidly penetrate the cell membrane and bind to cellular DNA as their intracellular target. Thereby, the formation of a reversible noncovalent complex with the DNA is followed by a covalent binding of the drugs to the DNA and the more toxic compounds show a higher stability and a lower alkylation rate. Since no drug manipulation is necessary for this kind of investigation and achiral compounds bound to chiral biomolecules may also show induced CD signals, CD spectroscopy of live cells is not limited to the study of analogues of CC-1065. Thus, it constitutes a general approach for studying the mode of action of bioactive compounds on the cellular and molecular level
Synthesis of a novel pentagastrin-drug conjugate for a targeted tumor therapy
No full textThe synthesis of the novel pentagastrin seco-CBI conjugate 3, which is based on the highly cytotoxic antitumor antibiotic (+)-duocarmycin SA (1), is reported. A key step in the synthesis is the palladium -catalyzed carbonylation of aryl bromide 7 to give the benzyl ester 16, which is transformed into the new seco-CBI derivative, 21 bearing a carboxylic acid ester moiety. Subsequent transformation of 21 into an activated ester followed by the introduction of beta-alanine and tetragastrin led to the new pentagastrin drug 3 that contains a peptide moiety for targeting cancer cells expressing CCK-B/gastrin receptors
Block of delayed-rectifier potassium channels by reduced haloperidol and related compounds in mouse cortical neurons
No full textHaloperidol is known as an antagonist of dopamine D2 receptors. However, it also blocks a variety of ion channels at concentrations above the therapeutic range. Reduced haloperidol (R-haloperidol), one of the main metabolites of haloperidol, has been reported to accumulate in certain tissues, particularly in brain cortex, and it may produce the pharmacological effects associated with haloperidol treatment. In this study, we assessed the effect of R-haloperidol and other related compounds on native delayed-rectifier potassium channels (K-DR) in mouse cortical neurons by using the whole-cell patch-clamp technique. Although R-haloperidol has much lower affinity to D2 receptors than haloperidol, the IC50 of R-haloperidol to block K-DR currents was 4.4 mu M, similar to its parent compound. The binding site of R-haloperidol is on the cytoplasmic side of the channel because its quaternary derivative preferentially inhibited the currents from intracellular side. 4-Chlorophenyl-4-hydroxypiperidine (4C4HP) is the active fragment of haloperidol because other compounds containing this moiety, including L-741,626 (3-[4-(4-chlorophenyl)-4-hydroxypiperidin-L-yl]-methyl-1H-indole) and loperamide, also blocked K-DR channels. The potency of the 4C4HP fragment positively correlated with the hydrophobicity index (clogP) of the compounds tested. We conclude that R-haloperidol is a K-DR channel blocker, although it does not interfere with the normal channel function at a clinically relevant concentration
Efficient synthesis of an enantiopure thiasteroid by a double heck reaction
No full textThe thiaestrane 7 was synthesized by two sequential Heck reactions starting from the thiophene derivatives 8a - 8c, which contain a (Z)-halogenovinyl group, and the enantiopure hydrindene 2a. The first intermolecular Pd-catalyzed reaction leads to 11a and 11b in a highly regio- and diastereoselective manner. A subsequent intramolecular Heck reaction catalyzed by the palladacycle 4 then gave the thiasteroid 7 with an unusual cis-junction of the rings B and C
Antitumor Agents: Development of Highly Potent Glycosidic Duocarmycin Analogues for Selective Cancer Therapy
No full textSpecial Order No. 105, Appointing Major Felix Agnus to a General Court-Martial, 28 April 1864
No full textSpecial Order No. 105, appointing Major Felix Agnus to a General Court-Martial, 28 April 1864
Form V., Treasury Department, Second Auditor's Office, suspending Major Felix Agnus, 8 May 1866
No full textForm V., Treasury Department, Second Auditor's Office, suspending Major Felix Agnus, 8 May 1866
Muster-In Roll of Major Felix Agnus, 165th New York, 2 September 1863
No full textMuster-In Roll of Major Felix Agnus, 165th New York, 2 September 1863
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