ABSTRACT
Griseofulvin (1) is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Comprehensive SAR studies have led to the identification of 2'-benzyloxy griseofulvin 2, a more potent analogue with low micromolar anticancer potency in vitro. Analogue 2 was also shown to retard tumor growth through inhibition of centrosomal clustering in murine xenograft models of colon cancer and multiple myeloma. However, similar to griseofulvin, compound 2 exhibited poor metabolic stability and aqueous solubility. In order to improve the poor pharmacokinetic properties, 11 griseofulvin analogues were synthesized and evaluated for biological activity and physiological stabilities including SGF, plasma, and metabolic stability. Finally, the most promising compounds were investigated in respect to thermodynamic solubility and formulation studies. The 2'-benzylamine analogue 10 proved to be the most promising compound with low µM in vitro anticancer potency, a 200-fold increase in PBS solubility over compound 2, and with improved metabolic stability. Furthermore, this analogue proved compatible with formulations suitable for both oral and intravenous administration. Finally, 2'-benzylamine analogue 10 was confirmed to induce G2/M cell cycle arrest in vitro.
Subject(s)
Antineoplastic Agents/chemistry , Griseofulvin/pharmacokinetics , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Cell Cycle Checkpoints/drug effects , Drug Stability , Griseofulvin/administration & dosage , Griseofulvin/chemical synthesis , Humans , Mice , Solubility , Xenograft Model Antitumor AssaysABSTRACT
Pseudo-complementary oligonucleotide analogues and mimics provide novel opportunities for targeting duplex structures in RNA and DNA. Previously, a pseudo-complementary A-T base pair has been introduced. Towards sequence unrestricted targeting, a pseudo-complementary G-C base pair consisting of the unnatural nucleobases n6-methoxy-2,6-diaminopurine (previously described in a DNA context) and N4-benzoylcytosine is now presented for design of pseudo-complementary PNA oligomers (pcPNAs).
ABSTRACT
In continuation of previous studies showing promising metal-molecule contact properties a variety of C(60) end-capped "molecular wires" for molecular electronics were prepared by variants of the Prato 1,3-dipolar cycloaddition reaction. Either benzene or fluorene was chosen as the central wire, and synthetic protocols for derivatives terminated with one or two fullero[c]pyrrolidine "electrode anchoring" groups were developed. An aryl-substituted aziridine could in some cases be employed directly as the azomethine ylide precursor for the Prato reaction without the need of having an electron-withdrawing ester group present. The effect of extending the π-system of the central wire from 1,4-phenylenediamine to 2,7-fluorenediamine was investigated by absorption, fluorescence, and electrochemical methods. The central wire and the C(60) end-groups were found not to electronically communicate in the ground state. However, the fluorescence of C(60) was quenched by charge transfer from the wire to C(60). Quantum chemical calculations predict and explain the collapse of coherent electronic transmission through one of the fulleropyrrolidine-terminated molecular wires.
ABSTRACT
We present a strategy for chemical preparation of multiple copies of single-molecule electronic devices that is based on chemical self-assembly under equilibrium conditions in aqueous solution. As a first step in the realization of this, we show that thiol end-capped oligo(phenylenevinylene)s (OPVs) can be rendered water-soluble by forming well-defined stoichiometric supramolecular complexes with α-cyclodextrins. On the basis of fluorescence intensity measurements in water, a 1:3 stoichiometry was determined for the complexes with equilibrium constants of the order of 5 × 10(-2) M(-2). The photophysical properties of the OPV3s as free molecules in solution, as nanoaggregates in aqueous suspension, and embedded in cyclodextrins in water, are reported, and the prospects of using these complexes as nucleation sites for growth of gold nanorods bridged by electronically active thiol end-capped molecules is discussed.
ABSTRACT
Treatment of 1,2-diols with diphenylphosphinoyl chloride in pyridine produces beta-chloroethyl phosphinates which react with complete control of stereochemistry to give epoxides and azido-alcohols, useful intermediates in cyclopropane synthesis.
ABSTRACT
Acyclic, achiral nucleoside derivatives 1b-e of adenine, cytosine, 5-methylcytosine, and guanine, containing a 3-hydroxy-2-(hydroxymethyl)prop-1-enyl group on N-1 or N-9, have been prepared analogously to the previously described thymine derivative 1a. In contrast to the adenine and guanine derivatives, the cytosine derivative 9 was unstable, and was obtained in a low yield due to side reactions. These include cleavage of the propenyl group from the base, and the formation of a bicyclic compound. The thymine derivative, although stable under neutral conditions, likewise underwent a reversible cyclization reaction (Michael addition) in the presence of acids or bases. The 5-methylcytosine derivative was stable under neutral and basic conditions. Four other nucleoside derivatives 26a-d containing a 2,3-dihydroxy-2-(hydroxymethyl)propyl group on N-1 or N-9, three of which are new, have likewise been prepared. All compounds were evaluated as antiviral agents against HIV-1 and HSV-1 but were devoid of antiviral activity.
Subject(s)
Antiviral Agents/chemical synthesis , Nucleosides/chemical synthesis , Adenine/analogs & derivatives , Adenine/chemical synthesis , Adenine/pharmacology , Animals , Antiviral Agents/pharmacology , Cells, Cultured , Cytosine/analogs & derivatives , Cytosine/chemical synthesis , Cytosine/pharmacology , Guanine/analogs & derivatives , Guanine/chemical synthesis , Guanine/pharmacology , HIV-1/drug effects , Molecular Structure , Nucleosides/pharmacologyABSTRACT
Preparation of the nucleoside analogues 1 and incorporation of 1, B = T, in deoxyribooligonucleotides by the phosphoramidite method is described. A two-step deprotection procedure was developed to reduce cleavage of the modified allylic unit. The binding properties of the modified oligonucleotides towards complementary DNA and RNA has been evaluated by Tm measurements showing a deltaTm of -2 to -6.5 degrees C per modification. An oligonucleotide with two modifications at the 3'-end showed considerable resistance towards cleavage by a 3'-exonuclease. No antiviral activity against HIV-1 or HSV-1 was found for 1, B = G or T, or for any of the trihydroxy derivatives 5.
Subject(s)
Nucleosides/chemistry , Nucleosides/chemical synthesis , Oligodeoxyribonucleotides/chemical synthesis , Binding Sites , DNA/chemistry , Indicators and Reagents , Molecular Conformation , Oligodeoxyribonucleotides/chemistry , RNA/chemistry , StereoisomerismABSTRACT
The new monomer 1 seems to be an excellent mimic of nucleosides with different sugar conformations (north, south, and envelope), because of the relatively free rotation around gamma, delta, and chi. The rotation around chi is primarily controlled by the repulsion between H6 and the two hydrogen atoms on C4' and not pi conjugation between the double bond and the nucleobase. A viable synthesis of the guanine monomer 8 is described.
Subject(s)
Nucleosides/chemistry , Nucleosides/pharmacology , Guanine/analogs & derivatives , Guanine/chemical synthesis , Isomerism , Models, Molecular , Molecular Conformation , Nucleosides/chemical synthesis , RotationABSTRACT
The conformations of an acyclic, achiral enamide thymidine analogue 1 have been studied by model building and geometry calculations, as well as by NMR NOE and UV experiments. The results indicate that there are no significant barriers to rotation around any of the sigma bonds, in particular the N1-C1' enamide bond, and that the analogue should be able to accommodate conformations that mimic the conformations of natural nucleosides in A- and B-type helices quite well. For comparison the saturated analogue 2 has been prepared and built into oligonucleotides. It is shown that incorporation of 2 in oligonucleotides results in a much larger depression of the melting temperature (deltaTm -10 to -12.5 degrees C) than does incorporation of 1 (deltaTm -5 to -6.5 degrees C).
Subject(s)
Biomimetic Materials/chemistry , Biomimetic Materials/chemical synthesis , Carbon/chemistry , Nucleotides/chemistry , Nucleotides/chemical synthesis , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Molecular Structure , Nucleic Acid Denaturation , Nucleic Acid Hybridization , Spectrum Analysis , Stereoisomerism , Thymidine/chemistryABSTRACT
An achiral, acyclic nucleoside analogue has been incorporated once or twice in oligodeoxyribonucleotides by the phosphoramidite method, and conditions found which allow deprotection of the oligonucleotides containing a sensitive modified allylic unit. The binding affinity of the modified oligonucleotides towards complementary DNA and RNA was reduced compared to unmodified DNA (DeltaT(m) -2 to -6.5 degrees C). An oligonucleotide with two modifications at the 3'-end showed considerable resistance towards cleavage with a 3'-exonuclease.
