ABSTRACT
A variety of naturally occurring compounds interact with duplex DNA by the formation of covalent cross-links. This review describes recent progress on the total synthesis of four natural product families, including the mitomycins, the structurally and functionally related agent FR-900482, the bis-pyrrole isochrysohermidine and the azinomycins.
Subject(s)
Biological Factors/chemical synthesis , Cross-Linking Reagents/chemical synthesis , DNA/chemistry , Nucleic Acid Heteroduplexes/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Biological Factors/therapeutic use , Cross-Linking Reagents/therapeutic use , HumansABSTRACT
[structure: see text]. Stereocontrolled construction of the 12-membered diene and triene lactones 1, 2, and 3, characteristic of the antitumor agent oximidines I and II, are reported and were based on an intramolecular Castro-Stephens coupling for the construction of a cyclic enyne or dienyne followed by stereoselective reduction of the cyclic alkyne for introduction of the cis-olefin of the targets. A comparison of the effectiveness of this protocol is made with standard macrolactonization.
Subject(s)
Antineoplastic Agents/chemical synthesis , Lactones/chemical synthesis , Organometallic Compounds/chemistry , Selenium Compounds/chemical synthesis , Antineoplastic Agents/chemistry , Cyclization , Indicators and Reagents , Lactones/chemistry , Models, Molecular , StereoisomerismABSTRACT
[structure: see text]. A novel stereoselective approach to the ring system of the mitomycins is described. The synthesis was based on a convergent strategy involving a stereocontrolled addition of a beta-phenyl silyl enol ether to a pyrroline N-acyliminium ion followed by an intramolecular palladium-catalyzed aryl triflate amination to afford the (9R*,9aR*)-tetrahydropyrrolo[1,2-a]indole ring system.
Subject(s)
Alkylating Agents/chemistry , Mitomycin/chemistry , Mitomycin/chemical synthesis , Pyrroles/chemistry , Alkylating Agents/chemical synthesis , Magnetic Resonance Spectroscopy , Models, Chemical , Models, MolecularABSTRACT
This unit describes the synthesis, purification, and analysis of modified oligodeoxynucleotides containing 4-thio-2'-deoxyuridine, and the use of these modified oligodeoxynucleotides in conjunction with bis-electrophilic tethers to form site-specific cross-links with a complementary DNA target. These modified oligodeoxynucleotides provide a flexible tool for studies directed at biophysical investigation of oligonucleotide structure, as well as investigation of DNA hybridization, stability, and sequence-dependent base nucleophilicity.
Subject(s)
Biochemistry/methods , Cross-Linking Reagents/chemistry , DNA/chemistry , Phenylenediamines/chemistryABSTRACT
A computational model for the covalent interstrand DNA cross-linking of the antitumor agent azinomycin B is reported and is based on Monte Carlo simulations of the four possible monoalkylation species and an examination of the low energy conformations of the cross-linked agent. The model was developed using a suitably modified version of the AMBER* force field with the experimentally determined triplet DNA target sequence 5'-d(GCT)-3' in both the native B-form and containing a preformed intercalation site.
Subject(s)
Anti-Bacterial Agents/chemistry , Antibiotics, Antineoplastic/chemistry , Cross-Linking Reagents/chemistry , DNA/chemistry , Glycopeptides , Intercalating Agents/chemistry , Intercellular Signaling Peptides and Proteins , Models, Molecular , Naphthalenes , PeptidesABSTRACT
[structure: see text] Studies on the synthesis of the spirocyclic cyclohexadienone ring system 2 of the schiarisanrin family of natural products 1 are described and were based on the Lewis acid-promoted C-alkylation of the corresponding phenolic precursor.
Subject(s)
Cyclooctanes , Lignans/chemical synthesis , Polycyclic Compounds/chemical synthesis , Plants, Medicinal/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistryABSTRACT
We report a facile, quantitative regeneration of the thiocarbonyl group from S-alkylated 4-thio-2'-deoxyuridine residues by treatment with NaSH within oligodeoxynucleotides.
Subject(s)
DNA/chemistry , Thiouridine/analogs & derivatives , Base Sequence , Chromatography, High Pressure Liquid , Spectrophotometry, Ultraviolet , Thiouridine/chemistryABSTRACT
A method for the introduction of depurinated lesions in DNA is described, and is based on the formation of a covalent cross-link between an antisense oligonucleotide probe and the target DNA sequence followed by an unexpectedly mild thermal depurination.
Subject(s)
DNA Damage , DNA/chemistry , Acetamides/chemistry , Antisense Elements (Genetics) , Cross-Linking Reagents/chemistry , Deoxyguanosine/chemistry , Heating , Oligonucleotides, Antisense/chemistry , Thiouridine/analogs & derivatives , Thiouridine/chemistryABSTRACT
We describe a solution to a molecular mechanics parameterization problem involving disulfide bonds between thionucleosides. Key torsional and bending parameters developed from ab initio calculations were incorporated into the AMBER* force-field in order to accurately represent the disulfide linkage in DNA cross-linked via this bond.
Subject(s)
DNA/chemistry , Models, Molecular , Thionucleosides/chemistry , Disulfides/chemistryABSTRACT
Full details of the template-directed covalent cross-linking of duplex oligodeoxynucleotides are presented. 4-Thio-2'-deoxyuridine was incorporated synthetically into a 17mer oligodeoxynucleotide, and the thiocarbonyl group of the modified base was alkylated with a variety of alpha-bromoacetyl-derivatized diamines. Covalent cross-linking was initiated by annealing the electrophilic probe oligomers with their complementary sequences, where a dG base was targeted at the position complementary to the modified 4-thio-2'-deoxyuridine. The sequence selectivity of cross-link formation as a function of tether topology and rigidity was examined, and the thermal stability of the modified duplexes was measured by UV melting experiments.
Subject(s)
Cross-Linking Reagents/metabolism , DNA/metabolism , Oligonucleotides/metabolism , Thiouridine/analogs & derivatives , Base Sequence , Chromatography, High Pressure Liquid , DNA Replication , Kinetics , Models, Chemical , Nucleic Acid Conformation , Thiouridine/metabolismABSTRACT
As shared governance increases in organizations that employ nurses, it becomes an essential element of professional socialization and preservice education. Framing a course in concepts of shared governance offers students experiential learning in uses of power, accountability, organizational decision making, and peer negotiation. The authors present concepts and examples of classroom shared governance from student and teacher perspectives.
Subject(s)
Decision Making, Organizational , Education, Nursing, Baccalaureate/organization & administration , Students, Nursing/psychology , Curriculum , Faculty, Nursing , Humans , Power, PsychologicalABSTRACT
The comparative DNA binding properties and cytotoxic activity of CDPIn methyl esters (n = 1-5) vs. PDE-In methyl esters (n = 1-3) are detailed in studies which provide experimental evidence for the intrinsic importance of stabilizing hydrophobic binding and non-covalent van der Waals contacts dominant in the CC-1065/B-DNA minor groove binding. High affinity minor groove binding to DNA was established through: (1) the observation of CDPI3 binding (UV) but not unwinding of supercoiled DNA (phi 174 RFI DNA) thus excluding intercalative binding; (2) the observation of CDPI3 binding to T4 phage DNA (UV, delta Tm) in which the major groove is occluded by glycosylation thus excluding major groove binding; (3) the observation of salt (Na+) concentration independent high affinity CDPI3 binding to poly(dA . poly(dT) thus excluding simple electrostatic binding to the DNA phosphate backbone; and further inferred through (4) the observation of an intense induced dichroism (ICD, poly(dA) . poly(dT) and poly(dG) . poly(dC) [phi]23(358) = 24,000 and 23,500). This high affinity minor groove binding is sufficient to produce a potent cytotoxic effect.(ABSTRACT TRUNCATED AT 400 WORDS)
