RESUMEN
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.
RESUMEN
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.
Asunto(s)
Nucleótidos de Desoxiguanina/síntesis química , Nucleótidos de Desoxiguanina/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Nucleótidos de Desoxiguanina/química , Relación Dosis-Respuesta a Droga , Femenino , Neoplasias Mamarias Animales , Ratones , Estructura Molecular , Neoplasias/tratamiento farmacológico , Nylons/síntesis química , Nylons/química , Nylons/farmacología , Pirroles/síntesis química , Pirroles/química , Pirroles/farmacologíaRESUMEN
A cationic rhodium(I) complex- or In(OTf)(3)-catalyzed synthesis of phenol derivatives from cyclohex-2-enone having an ethoxycarbonyl-substituted alkyne has been achieved. This reaction proceeds via enolization and an intramolecular Alder-Rickert reaction.
Asunto(s)
Ciclohexanonas/química , Ácidos de Lewis/química , Mesilatos/química , Compuestos Organometálicos/química , Fenoles/síntesis química , Rodio/química , Catálisis , Estructura Molecular , Fenoles/químicaRESUMEN
(-)-Hybridalactone (1) is a marine eicosanoid isolated from the red alga Laurencia hybrida. This natural product contains cyclopropane, cyclopentane, 13-membered macrolactone and epoxide ring systems incorporating seven stereogenic centers. Moreover, this compound has an acid-labile skipped Z,Z-diene motif. In this paper, we report on the total synthesis of (-)-hybridalactone (1). The unique eicosanoid (-)-hybridalactone (1) was synthesized starting from optically active γ-butyrolactone 2 in a linear sequence comprising 21 steps with an overall yield of 21.9%. A key step in the synthesis of (-)-hybridalactone (1) is the methyl phenylsulfonylacetate-mediated one-pot synthesis of the cis-cyclopropane-γ-lactone derivative. This reaction provided an efficient and stereoselective access to cis-cyclopropane-γ-lactone 12. Further elaboration of the latter compounds through desulfonylation, epoxidation, oxidation, Wittig olefination and Shiina macrolactonization afforded (-)-hybridalactone.
Asunto(s)
Eicosanoides/química , Lactonas/síntesis química , 4-Butirolactona/química , Eicosanoides/síntesis química , Lactonas/química , Oxidación-Reducción , Rhodophyta/química , EstereoisomerismoRESUMEN
The authors described the first synthesis of diterpene isocyanide (-)-kalihinol Y and diterpene isothiocyanate (-)-10-epi-kalihinol I from synthetic intermediates of kalihinol A. The absolute structures of these compounds were confirmed by these syntheses.
Asunto(s)
Diterpenos/química , Diterpenos/síntesis química , Poríferos/química , Animales , IsomerismoRESUMEN
Total synthesis of antimalarial diterpenoid (+)-kalihinol A, isolated from marine sponge Acanthella sp., is achieved. This total synthesis involves regioselective alkylation of an epoxide, construction of a tetrahydropyran ring by iodo-etherification, construction of a cis-decalin ring by intramolecular Diels-Alder reaction, isomerization of cis-decalin to trans-decalin, and subsequent functionalization of the trans-decalin ring.
Asunto(s)
Antimaláricos/síntesis química , Diterpenos/síntesis química , Naftalenos/química , EstereoisomerismoRESUMEN
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.
Asunto(s)
ADN/metabolismo , Desoxiguanosina/química , Expresión Génica/efectos de los fármacos , Nylons/química , Oligonucleótidos Antisentido/química , Oligonucleótidos Antisentido/farmacología , Pirroles/química , Desoxiguanosina/síntesis química , Nylons/síntesis química , Oligonucleótidos Antisentido/síntesis química , Pirroles/síntesis químicaRESUMEN
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.
RESUMEN
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.
Asunto(s)
Diseño de Fármacos , Expresión Génica/efectos de los fármacos , Nucleósidos , Nylons , Oligonucleótidos , ADN , Nucleósidos/síntesis química , Nucleósidos/química , Nucleósidos/farmacología , Nylons/síntesis química , Nylons/química , Nylons/farmacología , Oligonucleótidos/síntesis química , Oligonucleótidos/química , Oligonucleótidos/farmacologíaRESUMEN
Xestenone is a marine norditerpenoid found in the northeastern Pacific sponge Xestospongia vanilla. The relative configuration of C-3 and C-7 in xestenone was determined by NOESY spectral analysis. However the relative configuration of C-12 and the absolute configuration of this compound were not determined. The authors have now achieved the total synthesis of xestenone using their developed one-pot synthesis of cyclopentane derivatives employing allyl phenyl sulfone and an epoxy iodide as a key step. The relative and absolute configurations of xestenone were thus successfully determined by this synthesis.
Asunto(s)
Diterpenos/síntesis química , Xestospongia/química , Animales , Diterpenos/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Conformación MolecularRESUMEN
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.
Asunto(s)
Adenosina/análogos & derivados , Oligodesoxirribonucleótidos/síntesis química , Pirroles/química , Adenosina/química , Regulación de la Expresión Génica , Terapia Genética , Oligodesoxirribonucleótidos/químicaRESUMEN
A practical synthesis of a key intermediate for the proteasome inhibitor lactacystin from (R)-4-hydroxymethyl-2-phenyl-4,5-dihydrooxazol-4-ylmethyl acetate was established. (R)-4-Hydroxymethyl-2-phenyl-4,5-dihydrooxazol-4-ylmethyl acetate is a useful chiral building block for the synthesis of biologically active compounds containing alpha-substituted alpha-amino acid moieties.
Asunto(s)
Acetilcisteína/análogos & derivados , Inhibidores de Cisteína Proteinasa/síntesis química , Oxazoles/síntesis química , Acetilcisteína/síntesis química , Cromatografía Líquida de Alta Presión , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Solventes , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría InfrarrojaRESUMEN
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.
Asunto(s)
Antineoplásicos/síntesis química , Guanosina Monofosfato/análogos & derivados , Pirroles/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Carcinoma/tratamiento farmacológico , Guanosina Monofosfato/síntesis química , Guanosina Monofosfato/química , Guanosina Monofosfato/uso terapéutico , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Ratones , Pirroles/química , Pirroles/uso terapéuticoRESUMEN
In the extreme thermophile Thermus thermophilus, a disruption mutant of a gene homologous to speB (coding for agmatinase = agmatine ureohydrolase) accumulated N1-aminopropylagmatine (N8-amidino-1,8-diamino-4-azaoctane, N8-amidinospermidine), a new compound, whereas all other polyamines produced by the wild-type strain were absent from the cells. Double disruption of speB and speE (polyamine aminopropyltransferase) resulted in the disappearance of N1-aminopropylagmatine and the accumulation of agmatine. These results suggested the following. 1) N1-Aminopropylagmatine is produced from agmatine by the action of an enzyme coded by speE. 2) N1-Aminopropylagmatine is a metabolic intermediate in the biosynthesis of unique polyamines found in the thermophile. 3) N1-Aminopropylagmatine is a substrate of the SpeB homolog. They further suggest a new biosynthetic pathway in T. thermophilus, by which polyamines are formed from agmatine via N1-aminopropylagmatine. To confirm our speculation, we purified the expression product of the speB homolog and confirmed that the enzyme hydrolyzes N1-aminopropylagmatine to spermidine but does not act on agmatine.
Asunto(s)
Agmatina/química , Proteínas Bacterianas/metabolismo , Cisteína Endopeptidasas/metabolismo , Poliaminas/química , Poliaminas/metabolismo , Espermidina Sintasa/metabolismo , Thermus thermophilus/metabolismo , Agmatina/metabolismo , Secuencia de Aminoácidos , Proteínas Bacterianas/genética , Cromatografía de Gases , Cromatografía Líquida de Alta Presión , Cisteína Endopeptidasas/genética , ADN/química , Electroforesis en Gel de Poliacrilamida , Escherichia coli/metabolismo , Genotipo , Hidrólisis , Cinética , Espectrometría de Masas , Modelos Biológicos , Modelos Químicos , Modelos Genéticos , Datos de Secuencia Molecular , Mutación , Oligonucleótidos/química , Plásmidos/metabolismo , Homología de Secuencia de Aminoácido , Espermidina/química , Espermidina Sintasa/genética , Temperatura , Factores de TiempoRESUMEN
Extreme thermophiles produce two types of unusual polyamine: long linear polyamines such as caldopentamine and caldohexamine, and branched polyamines such as quaternary ammonium compounds [e.g. tetrakis(3-aminopropyl)ammonium]. To clarify the physiological roles of long linear and branched polyamines in thermophiles, we synthesized them chemically and tested their effects on the stability of ds (double-stranded) and ss (single-stranded) DNAs and tRNA in response to thermal denaturation, as measured by differential scanning calorimetry. Linear polyamines stabilized dsDNA in proportion to the number of amino nitrogen atoms within their molecular structure. We used the empirical results to derive formulae that estimate the melting temperature of dsDNA in the presence of polyamines of a particular molecular composition. ssDNA and tRNA were stabilized more effectively by tetrakis(3-aminopropyl)ammonium than any of the other polyamines tested. We propose that long linear polyamines are effective to stabilize DNA, and tetrakis(3-aminopropyl)ammonium plays important roles in stabilizing RNAs in thermophile cells.
Asunto(s)
ADN Bacteriano/química , Poliaminas/química , ARN Bacteriano/química , ARN de Transferencia/química , Thermus thermophilus/genética , Desnaturalización de Ácido Nucleico , Temperatura , TermodinámicaRESUMEN
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.
Asunto(s)
Desoxiguanosina/análogos & derivados , Oligodesoxirribonucleótidos Antisentido/química , Pirroles/química , Dicroismo Circular , ADN/química , Desoxiguanosina/síntesis química , Desoxiguanosina/química , Regulación de la Expresión Génica , Terapia Genética , Pirroles/síntesis química , TemperaturaRESUMEN
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.
Asunto(s)
Oligodesoxirribonucleótidos/química , Isótopos de Carbono , ADN/análisis , Espectroscopía de Resonancia MagnéticaRESUMEN
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.
Asunto(s)
Desoxiguanosina/análogos & derivados , Desoxiguanosina/síntesis química , Desoxiguanosina/química , Isótopos de NitrógenoRESUMEN
A pyrrolepolyamide-deoxyguanosine hybrid using the 3-aminopropyl linker (GAP) was designed and synthesized on the basis of previously reported results of a pyrrolepolyamide-adenosine hybrid (Apy) and a pyrrolepolyamide-deoxyguanoside hybrid using the 3-aminopropionyl linker (GBP). An evaluation of the DNA binding sequence selectivity of GAP was performed by analysis of CD spectra and Tm values using three DNA duplexes. It was shown that GAP possessed greater binding specificity than distamycin A, netropsin, Apy and GBP.
Asunto(s)
Desoxiguanosina/análogos & derivados , Nucleósidos/análisis , Nucleósidos/síntesis química , Pirroles/análisis , Pirroles/síntesis química , Aminas/química , Dicroismo Circular , Desoxiguanosina/análisis , Desoxiguanosina/síntesis química , Desoxiguanosina/química , Nucleósidos/química , Pirroles/química , Pirrolidinas/químicaRESUMEN
The 6-(levulinyloxymethyl)-3-methoxy-2-nitrobenzoyl (LMMoNBz) and 2-(levulinyloxymethyl)-5-methoxy-4-nitrobenzoyl (LMMpNBz) groups were developed as novel base-labile protection for the 5'-hydroxy function in solid-phase oligonucleotide synthesis. A comparative study of the LMMoNBz, LMMpNBz and 2-(levulinyloxymethyl)-5-nitrobenzoyl (LMNBz) protecting groups for oligonucleotide synthesis proved strong feasibility for the LMMoNBz group.