RESUMEN
BACKGROUND: Numerous analogs of the antitumor agents epothilones A and B have been synthesized in search of better pharmacological profiles. Insights into the structure-activity relationships within the epothilone family are still needed and more potent and selective analogs of these compounds are in demand, both as biological tools and as chemotherapeutic agents, especially against drug-resistant tumors. RESULTS: A series of pyridine epothilone B analogs were designed, synthesized and screened. The synthesized compounds exhibited varying degrees of tubulin polymerization and cytotoxicity properties against a number of human cancer cell lines depending on the location of the nitrogen atom and the methyl substituent within the pyridine nucleus. CONCLUSIONS: The biological screening results in this study established the importance of the nitrogen atom at the ortho position as well as the beneficial effect of a methyl substituent at the 4- or 5-position of the pyridine ring. Two pyridine epothilone B analogs (i.e. compounds 3 and 4) possessing higher potencies against drug-resistant tumor cells than epothilone B, the most powerful of the naturally occurring epothilones, were identified.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Epotilonas , Compuestos Epoxi/química , Compuestos Epoxi/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Tiazoles/química , Tiazoles/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , División Celular/efectos de los fármacos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos , Compuestos Epoxi/síntesis química , Compuestos Epoxi/uso terapéutico , Humanos , Concentración 50 Inhibidora , Macrólidos/síntesis química , Macrólidos/química , Macrólidos/farmacología , Macrólidos/uso terapéutico , Modelos Moleculares , Estructura Molecular , Piridinas/química , Piridinas/uso terapéutico , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/uso terapéutico , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Células Tumorales CultivadasRESUMEN
Ndelta-Fmoc protected nucleoamino acids of type I (Base = T, C, A) have been synthesized and employed as building blocks for the construction of novel polyamide based nucleic acid analogues. Homopyrimidine oligomer A binds to complementary RNA with significant affinity and in a sequence-specific fashion, while no binding was observed to complementary DNA.
Asunto(s)
Aminoácidos/química , Hibridación de Ácido Nucleico/métodos , Ácidos Nucleicos/síntesis química , Nylons/síntesis química , Pirrolidinas/química , Fenómenos Químicos , Química Física , ADN Complementario/química , Ácidos Nucleicos/química , Nylons/química , ARN Complementario/química , Espectrofotometría UltravioletaRESUMEN
In an effort to discover novel oligonucleotide modifications for antisense therapeutics, we have prepared oligodeoxyribonucleotides containing more than 200 different modifications and measured their affinities for complementary RNA. These include modifications to the heterocyclic bases, the deoxy-ribose sugar and the phosphodiester linkage. From these results, we have been able to determine structure-activity relationships that correlate hybridization affinity with changes in oligonucleotide structure. Data for oligonucleotides containing modified pyrimidine nucleotides are presented. In general, modifications that resulted in the most stable duplexes contained a heteroatom at the 2'-position of the sugar. Other sugar modifications usually led to diminished hybrid stability. Most backbone modifications that led to improved hybridization restricted backbone mobility and resulted in an A-type sugar pucker for the residue 5'to the modified internucleotide linkage. Among the heterocycles, C-5-substituted pyrimidines stood out as substantially increasing duplex stability.
Asunto(s)
ADN/química , Conformación de Ácido Nucleico , ARN Complementario/metabolismo , ADN/metabolismo , Hibridación de Ácido Nucleico , Oligonucleótidos Antisentido/química , Oligonucleótidos Antisentido/metabolismo , Fósforo/química , Purinas/química , Pirimidinas/química , Ribosa/química , Relación Estructura-Actividad , Timina/químicaRESUMEN
The conformational behaviour of host-guest peptides of the type Ac-Ala-Xxx-Ala-Ala-Xxx-Ala-Ala-Xxx-Ala-Ala-NH-PEGM (Xxx = alpha-aminoisobutyric acid (Aib), (S)-2-ethylalanine ((S)-Iva), (S)-2-methylserine ((S)-alpha-MeSer)) has been studied by CD spectroscopy in CF3CH2OH, CH3OH, and water and by i.r. spectroscopy in CHCl3 and in the solid state. In this way the relative helix-inducing potential of the two chiral alpha-methyl-alpha-amino acids (S)-Iva and (S)-alpha-MeSer could be established in comparison to the strong helix-former Aib. The results show that (S)-Iva exerts a comparable helix-inducing effect as Aib, making this amino acid a valuable complementary tool for the stabilization or induction of helices. No significant helix-promoting effect was observed for (S)-alpha-MeSer in polar solvents; however, the i.r.-spectroscopic data in CHCl3 and in the solid state point to a helical conformation under these conditions. Possible reasons for the different behaviour of (S)-Iva and (S)-alpha-MeSer are briefly discussed.