ABSTRACT
The total synthesis of the natural bicyclo[3.3.0]furanolactone polyketide, plakortone Q, was achieved in 24 steps from (R)-Roche ester. The main feature of this synthetic strategy is the stereoselective construction of a central tetrahydrofuran moiety with four consecutive stereoisomeric centers using the Upjohn dihydroxylation of oxiranyl-substituted alkenes and acid-mediated 5-endo-tet cyclization.
Subject(s)
Polyketides , Cyclization , Stereoisomerism , AlkenesABSTRACT
MGB polyamide-oligonucleotide conjugates ON 1-4 with linked MGB polyamides at the 2-exocyclic amino group of a guanine base using aminoalkyl linkers were synthesized and evaluated in terms of binding affinity for complementary DNA containing the MGB polyamide binding sequence using T m and CD analyses. The MGB polyamides comprised pyrrole polyamides (Py4- and Py3-), which possess binding affinity for A-T base pairs, and imidazole (Im3-) and pyrrole-γ-imidazole (Py3-γ-Im3-) polyamide hairpin motifs, which possess binding affinity for C-G base pairs. It was found that the stability of modified dsDNA was greatly influenced by the linker length. Py4- and Py3-oligonucleotide conjugates (ON 1 (n = 4) and ON 2 (n = 4)) containing the 4-aminobutyl linker formed stable dsDNA with complementary DNA. Although Im3-oligonucleotide conjugate ON 3 (n = 4) containing the 4-aminobutyl linker formed stable dsDNA with complementary DNA, stabilization of dsDNA by the imidazole amide moiety of ON 3 (n = 4) was lower compared with the pyrrole amide moiety of ON 2 (n = 4). The Py3-γ-Im3-oligonucleotide conjugate ON 4 (n = 2), which possesses binding affinity for C-G base pairs via a pyrrole/imidazole combination and contains a 2-aminoethyl linker, showed high binding ability for complementary DNA. Furthermore, the DNA sequence recognition of MGB polyamide-oligonucleotide conjugates was investigated using single-base mismatch DNAs, which possess a mismatch base in the MGB polyamide binding sequence. The Py3-γ-Im3-oligonucleotide conjugate ON 4 (n = 2) showed high sequence recognition ability for complementary DNA.
ABSTRACT
Plakortone Q and plakdiepoxide are natural polyketides isolated from the marine sponge Plakortis simplex. Bicyclo[3.3.0]furanolactone compounds, including plakortone Q, are expected to exhibit a wide range of pharmacological activities. Therefore, developing a simple and versatile synthetic method to produce these compounds is an important research goal. We have achieved the first total synthesis of plakortone Q and plakdiepoxide through an efficient protecting-group-free strategy. The key transformation was an acid-mediated tandem 5-endo-tet/5-endo-tet cyclization of vicinal diepoxide to build the tetrahydrofuran-γ-lactone motif.
Subject(s)
Polyketides , Porifera , Animals , Biomimetics , Cyclization , Lactones , Polyketides/pharmacology , StereoisomerismABSTRACT
This study reports the stereoselective total syntheses of the antipodes of the unique 3/10 bicyclic skeletal sesquiterpenoids, namely, hypocoprin A and hypocoprin B. The synthesis involved conjugate addition accelerated by trimethylsilyl chloride, construction of the ten-membered ring via the intramolecular SN2 reaction promoted by 1,8-diazabicyclo[5.4.0]undec-7-ene, and osmium-mediated π-facial selective dihydroxylation to functionalize the 1,1-disubstituted alkene.
ABSTRACT
Eiseniachloride B is a marine chlorinated oxylipin isolated from the brown alga Eisenia bicyclis. This natural product contains cyclopentane, chlorohydrin, and 14-membered lactone systems that incorporate five stereogenic centers. In this paper, we report on the total synthesis of structurally unique oxylipin eiseniachloride B from optically active lactol via ecklonialactone B in a linear sequence comprising 11 steps with a 12.1% overall yield.
Subject(s)
Biological Products/chemical synthesis , Lactones/chemical synthesis , Oxylipins/chemical synthesis , Biological Products/chemistry , Halogenation , Lactones/chemistry , Molecular Conformation , Oxylipins/chemistry , Phaeophyceae/chemistry , StereoisomerismABSTRACT
Annonaceous acetogenins have a wide range of potential biological activities. The development of simple and diversity-oriented approaches to their synthesis is therefore important. We have achieved the first total synthesis of squafosacin F and assigned its absolute configuration. The key steps were an acid-mediated tandem intramolecular double cyclization to build the hydroxy-flanked mono-tetrahydrofuran core and decoration with the desired functionalities of the target natural product via highly stereoselective reactions.
ABSTRACT
A divergent strategy has been used for the concise and efficient enantioselective formal synthesis of Annonaceous acetogenin cis-solamin. Our synthetic strategy comprises concise preparation of the diepoxyester via an 11-membered silaketal constructed by ring-closing metathesis after the dimerization of chiral epoxides, and uses an acid-catalyzed tandem intramolecular SN2-like reaction to construct the threo-cis-threo configuration of the tetrahydrofuran-diol moiety.
ABSTRACT
Ascospiroketal B was isolated from a marine-derived fungus as a structurally unique polyketide possessing a rare tricyclic core including 5,5-spiroketal-γ-lactone. An asymmetric total synthesis of ent-ascospiroketal B was achieved using an original synthetic route. The synthesis included the stereoselective construction of 5,5-spiroketal for ascospiroketal B and stereocontrolled construction of a quaternary asymmetric carbon by rearrangement of a trisubstituted epoxide.
Subject(s)
Ethers, Cyclic/chemical synthesis , Spiro Compounds/chemical synthesis , Ethers, Cyclic/chemistry , Molecular Conformation , Spiro Compounds/chemistry , StereoisomerismABSTRACT
A new cyclopropane-containing sesquiterpenoid, phellilane L (1), was isolated from the medicinal mushroom Phellinus linteus ("Meshimakobu" in Japanese), a member of the Hymenochaetaceae family and a well-known fungus that is widely used in East Asia. The planar structure of 1 was determined on the basis of spectroscopic analysis. The authors achieved the first total synthesis of 1. Our protecting group-free synthesis features a highly stereoselective one-pot synthesis involving an intermolecular alkylation/cyclization/lactonization strategy for construction of the key cyclopropane-γ-lactone intermediate. Additionally, our synthesis determined the absolute configuration of phellilane L (1).
Subject(s)
Agaricales/chemistry , Basidiomycota/chemistry , Sesquiterpenes/chemistry , Chemistry, Pharmaceutical , Molecular StructureABSTRACT
Two new nitrogenous prenylbisabolanes never before found in Lithistid sponges have been isolated from Theonella swinhoei. These new diterpenes, named amitorine A (1) and amitorine B (2), containing a prenylbisabolane skeleton have been characterized by spectroscopic analyses, and the relative and absolute configurations of 1 and 2 were determined by asymmetric synthesis of both diastereomers via the common bicyclic lactone 6 intermediate.
Subject(s)
Diterpenes/isolation & purification , Theonella/chemistry , Animals , Diterpenes/chemistry , Diterpenes/pharmacology , Japan , Molecular Structure , Nuclear Magnetic Resonance, BiomolecularABSTRACT
Pyrrole polyamide-2'-deoxyguanosine 5'-phosphate hybrid (Hybrid 4) was synthesized and evaluated in terms of the inhibition of mouse mammary carcinoma FM3A cell growth. Hybrid 4 was found to exhibit dose-dependent inhibition of cell growth.
Subject(s)
Deoxyguanine Nucleotides/chemical synthesis , Deoxyguanine Nucleotides/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Deoxyguanine Nucleotides/chemistry , Dose-Response Relationship, Drug , Female , Mammary Neoplasms, Animal , Mice , Molecular Structure , Neoplasms/drug therapy , Nylons/chemical synthesis , Nylons/chemistry , Nylons/pharmacology , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacologyABSTRACT
DNA oligonucleotide-conjugated pyrrole polyamide-2'-deoxyguanosine hybrids were synthesized and examined as novel gene expression control compounds. The T(m) values and circular dichroism spectral analyses showed that the oligonucleotide-conjugated hybrids possess high DNA recognition and a very high binding affinity for DNA that includes the pyrrole polyamide binding sequence.
Subject(s)
DNA/metabolism , Deoxyguanosine/chemistry , Gene Expression/drug effects , Nylons/chemistry , Oligonucleotides, Antisense/chemistry , Oligonucleotides, Antisense/pharmacology , Pyrroles/chemistry , Deoxyguanosine/chemical synthesis , Nylons/chemical synthesis , Oligonucleotides, Antisense/chemical synthesis , Pyrroles/chemical synthesisABSTRACT
Pyrrolepolyamide-2'-deoxyguanosine hybrids (Hybrid 2 and Hybrid 3) incorporating the 3-aminopropionyl or 3-aminopropyl linker were designed and synthesized on the basis of previously reported results of a pyrrolepolyamide-adenosine hybrid (Hybrid 1). Evaluation of the DNA binding sequence selectivity of pyrrolepolyamide-2'-deoxyguanosine hybrids was performed by CD spectral and T(m) analyses. It was shown that Hybrid 3 possessed greater binding specificity than distamycin A, Hybrid 1 and Hybrid 2.
ABSTRACT
On the basis of reports that a minor groove binder pyrrolepolyamide can interfere with gene expression by the sequence-specific recognition of DNA, we expected that nucleoside bearing a pyrrolepolyamide would be able to regulate gene expression. Therefore, we designed and synthesized the pyrrolepolyamide-adenosine (Hybrid 1) and -2'-deoxyguanosine hybrids (Hybrid 2 and Hybrid 3) as lead compounds for gene expression control compounds. The pyrrolepolyamide frame of Hybrid 2 and Hybrid 3 combines at the 2-exocyclic amino group of the 2'-deoxyguanosine by a linker and the 2-exocyclic amino group of guanine exists in the minor groove side of the duplex. Hybrid 2 is the 2'-deoxyguanosine-pyrrolepolyamide hybrid using the 3-aminopropionyl linker, while Hybrid 3 uses the 3-aminopropyl linker. An evaluation of the DNA binding sequence selectivity was performed by analysis of T(m) values and CD spectra, using distamycin A as a contrast. Hybrid 3 has provided more excellent sequence-distinguishable ability than other hybrids and Distamycin A. Moreover, on the basis of these results, we synthesized oligonucleotides conjugated to Hybrid 4, which is stable under conditions of DNA oligonucleotide solid phase synthesis, arranged from Hybrid 3. From T(m) values and CD spectral analysis, it was found that oligonucleotides conjugating Hybrid 4 possess high recognition ability and very high binding ability for the DNA that includes the pyrrolepolyamide binding sequence.
Subject(s)
Drug Design , Gene Expression/drug effects , Nucleosides , Nylons , Oligonucleotides , DNA , Nucleosides/chemical synthesis , Nucleosides/chemistry , Nucleosides/pharmacology , Nylons/chemical synthesis , Nylons/chemistry , Nylons/pharmacology , Oligonucleotides/chemical synthesis , Oligonucleotides/chemistry , Oligonucleotides/pharmacologyABSTRACT
DNA oligonucleotide conjugated pyrrolepolyamide- and pyrrole-imidazole polyamide-2'-deoxyguanosine hybrids were efficiently synthesized by a post-synthetic modification method through condensation of the 2-fluoro-2'-deoxyinosine moiety of oligonucleotide 9 and FmocNH-PyXPyPy (X = Py or Im) derivatives.
Subject(s)
Adenosine/analogs & derivatives , Oligodeoxyribonucleotides/chemical synthesis , Pyrroles/chemistry , Adenosine/chemistry , Gene Expression Regulation , Genetic Therapy , Oligodeoxyribonucleotides/chemistryABSTRACT
2-Pyrrolepolyamide-2'-deoxyguanosine 5'-phosphate (hybrid 4) was synthesized and evaluated in terms of the inhibition of mouse mammary carcinoma FM3A cell growth. Hybrid 4 exhibited the highest activity compared with the other hybrids (1, 2, and 3) and distamycin A.
Subject(s)
Antineoplastic Agents/chemical synthesis , Guanosine Monophosphate/analogs & derivatives , Pyrroles/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Carcinoma/drug therapy , Guanosine Monophosphate/chemical synthesis , Guanosine Monophosphate/chemistry , Guanosine Monophosphate/therapeutic use , Mammary Neoplasms, Experimental/drug therapy , Mice , Pyrroles/chemistry , Pyrroles/therapeutic useABSTRACT
Nucleophilic aromatic substitution of 9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-6-chloro-2-fluoro-9H-purine with N-(tert-butyldimethylsilyl) [15N]phthalimide in the presence of a catalytic amount of CsF at room temperature in DMF efficiently afforded the 6-chloro-2-[15N]phthalimidopurine derivative, which was subsequently converted to the [2-15N]guanosine derivative. The 2'-deoxy[2'-15N]guanosine derivative was also efficiently synthesized through a similar procedure.
Subject(s)
Deoxyguanosine/chemical synthesis , Guanosine/analogs & derivatives , Guanosine/chemical synthesis , Phthalimides/chemistry , Deoxyguanosine/chemistry , Guanosine/chemistry , Molecular Structure , Nitrogen IsotopesABSTRACT
DNA oligomers conjugated pyrrolepolyamide (minor groove binder)-deoxyguanosine hybrid were synthesized as novel gene expression control compounds. From T(m) values and CD spectral analysis, it was found that oligomers conjugated hybrid possess high recognition ability and very high binding ability for the DNA that includes pyrrolepolyamide match site.
Subject(s)
Deoxyguanosine/analogs & derivatives , Oligodeoxyribonucleotides, Antisense/chemistry , Pyrroles/chemistry , Circular Dichroism , DNA/chemistry , Deoxyguanosine/chemical synthesis , Deoxyguanosine/chemistry , Gene Expression Regulation , Genetic Therapy , Pyrroles/chemical synthesis , TemperatureABSTRACT
NMR signal assignments for DNA oligomers have been performed by the well-established sequential assignment procedures based on NOESY and COSY. The H4'/H5'/H5'' resonance region is congested and difficult to analyze without the use of isotope-labeled DNA oligomers. Here a DNA dodecamer constructed with 2'-deoxy[5'-(13)C]ribonucleotides, 5'-d(*C*G*C*G*A*A*T*T*C*G*CG)-3' (*N = [5'-(13)C]Nucleotide), was prepared in an effort to analyze the H4'/H5'/H5'' resonance region by 2D 1H-13C HMQC-NOESY. In the C5' and H1' resonance region, weak and strong cross peaks for C5'(i)-H1'(i) and C5'(i)-H1'(i-1), respectively, were found, thus enabling the sequential assignment within this region. A similar sequential assignment route was found between C5' and H2''. Proton pair distances evaluated from the canonical B-DNA as well as A-DNA indicated that these sequential-assignment routes on a 2D 1H-13C HMQC-NOESY spectrum work for most nucleic acid stem regions.
Subject(s)
Oligodeoxyribonucleotides/chemistry , Carbon Isotopes , DNA/analysis , Magnetic Resonance SpectroscopyABSTRACT
Nucleophilic substitution of 9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-6-chloro-2-fluoro-9H-purine, prepared from guanosine, with N-tert-butyldimethylsilyl[(15)N]-phthalimide in the presence of a catalytic amount of CsF at room temperature in DMF efficiently afforded the 6-chloro-2-[(15)N]phthalimidopurine derivative. Treatment of this with sodium 2-cyanoethoxide yielded the [2-(15)N]guanosine derivative. The 2'-deoxy[2-(15)N]guanosine derivative was also efficiently synthesized through a similar procedure.