1,720,977 research outputs found
Preparation of a new carboranyl lactoside for the treatment of cancer by boron neutron capture therapy: Synthesis and toxicity of fluoro carboranyl glycosides for in vivo F-19-NMR spectroscopy
No full textThe synthesis of new ortho-carboranyl lactosides 8, 17, 19 and glucosides 22 and 23 for the use in boron neutron capture therapy is reported. Carboranyl lactosides 17 and 19 as well as the glucosides 22 and 23 contain a fluorine atom to allow a noninvasive determination of these compounds in tumor cells by F-19-NMR spectroscopy. In cloning efficiency tests on human bronchial carcinoma cells the carboranyl lactosides 17 and 19 displayed almost no cytotoxicity. Thus, the considerably cytotoxic carboranyl alcohol 11 is detoxified when linked to a sugar moiety such as in carboranyl glucoside 22
Synthesis and Biological Studies of Different Duocarmycin Based Glycosidic Prodrugs for Their Use in the Antibody-Directed Enzyme Prodrug Therapy
No full textThe synthesis and biological evaluation of novel prodrugs for use in the antibody directed enzyme prodrug therapy (ADEPT) of cancer based on the cytotoxic antibiotic duocarmycin SA (1) are described. In this approach, we investigated the influence of the sugar moiety of the glycosidic prodrug on the QIC(50) values as well as on the stability and the water solubility. The best result was found for prodrug 22 containing an alpha-mannoside moiety with a QIC(50) value of 4500
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
Antitumor Agents: Development of Highly Potent Glycosidic Duocarmycin Analogues for Selective Cancer Therapy
No full textChemInform Abstract: A Comprehensive View on 4‐Methyl‐2‐quinazolinamine, a New Microbial Alkaloid from Streptomyces of TCM Plant Origin.
No full textA comprehensive view on 4-methyl-2-quinazolinamine, a new microbial alkaloid from Streptomyces of TCM plant origin
No full textIn the course of our chemical and biological screening program for yet unidentified microbial metabolites, we selected plants of Traditional Chinese Medicine (TCM) as habitats for talented Streptomycetes producer strains for the first time. Liquid pure cultures of strain Streptomyces sp. GS DV232 were found to contain 4-methyl-2-quinazolinamine (1), a potent alkaloid yet unknown from nature. In this study, we investigated the chemical and crystal structure of 1, as well as its antiproliferative bioactivity, and addressed the unusual biosynthesis using feeding experiments. The Journal of Antibiotics (2009) 62, 439-444; doi:10.1038/ja.2009.68; published online 7 August 200
Synthesis of Highly Functionalized Anthraquinones and Evaluation of Their Antitumor Activity
No full textHighly functionalized anthraquinones which derive from the natural products mensacarcin, islandicin, and chrysophanol have been efficiently synthesized using a Diels-Alder reaction as key step. The introduction of the proposed pharmaco-phoric side chain unit has been achieved by an addition of an aryllithimn species onto different aldehydes. Furthermore, the antitumor activity of these novel compounds has been studied by the in vitro growth inhibition of human lung carcinoma cells of line A549. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Novel strategies for the synthesis of anthrapyran antibiotics: discovery of a new antitumor agent and total synthesis of (S)-espicufolin
No full textTwo high-yielding strategies for the synthesis of 4H-anthra[1,2-b]pyran antibiotics have been developed giving access to novel antitumor agent 24 (ED50 1.5 mu M) and to (S)-espicufolin (3). A key step for the assembly of the tetracyclic 4H-anthra[1,2-b]pyran-4,7,12-trione skeleton is the nucleophilic addition of an aryl lithium species onto an aldehyde which allows the introduction of either an ynone or 1,3-diketo side chain, serving as precursors for an acid-catalysed cyclisation
SYNTHESIS AND BIOLOGICAL EVALUATION OF A NOVEL ACRONYCINE/DUOCARMYCIN HYBRID NATURAL PRODUCT
No full textThe design of novel natural product hybrids consisting of parts of two or more bioactive compounds may allow an access to new drugs. Here we describe the synthesis of 3, a hybrid of the cytotoxic acronycine (2) and seco-duocarmycin (seco-1), which was prepared via a selective bromination of 7 followed by the introduction of an alkyne moiety, which was further manipulated to give the epoxide 12. Cyclisation and chlorination of the formed primary hydroxy group yielded 3, which in situ would give the desired hybrid 4. The in-vitro-cytotoxicity test revealed a slightly higher bioactivity of the hybrid 3 compared to acronycine (2).Konrad-Adenauer-Foundatio
Photoactivatable Prodrugs of Highly Potent Duocarmycin Analogues for a Selective Cancer Therapy
No full textA main problem of common cancer chemotherapy is the occurrence of severe side effects caused by insufficient selectivity of the applied drugs. A possible concept to overcome this limitation is light-driven prodrug monotherapy. The synthesis as well as photochemical and biological evaluation of new photoactivatable prodrugs is described. Best results were obtained with prodrug (S,S)-7?a. The photochemical labile protecting groups in (S,S)-7?a can easily be removed by irradiation with UV-A light in 30 min with a power of only 2 J?cm-2. The determination of the in vitro cytotoxicity by using an HTCFA-test reveals a QIC50 value of 8200 and the prodrug is more than two million times less cytotoxic than the corresponding seco-drug (-)-(S,S)-5 with an IC50 value of about 110 fM. The big therapeutic window makes (S,S)-7?a very suitable for its use in selective cancer therapy
- …
