RESUMEN
Taking 3'-Me-Ado (3'-methyladenosine) and Cladribine as the leading compounds, seventeen 3'-C-methyl-furanonucleosides were designed and synthesized. All the structures were confirmed by 1H NMR and MS. The target compounds were tested in vitro against human pulmonary carcinoma A549, human colon carcinoma LOVO and human leukemia CEM by MTT assay. The results showed that these compounds possessed moderate cytotoxicities.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Adenosina/análogos & derivados , Adenosina/síntesis química , Adenosina/farmacología , Línea Celular Tumoral , Cladribina/síntesis química , Cladribina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura MolecularRESUMEN
A large series of N6-substituted-4'-thioadenosines were synthesized starting from D-gulonic-gamma-lactone, and structure-activity relationships were studied at the human A3 and other subtypes of adenosine receptors (ARs). 2-Chloro-substituted and 2-H analogues were compared. 2-Chloro-N6-methyl-4'-thioadenosine 19b was a highly potent and selective agonist (Ki=0.8+/-0.1 nM in binding) at the A3AR, and displayed the same relative efficacy in receptor activation as a known full agonist, Cl-IB-MECA. Most of N6-substituted-4'-thioadenosines were less potent in binding than the corresponding N6-substituted-adenosines or N6-substituted-4'-thioadenosine-5'-uronamides. N6-(3-Iodobenzyl) derivative 19g was demonstrated to be an A3AR-selective partial agonist displaying a Ki value of 3.2 nM.
Asunto(s)
Agonistas del Receptor de Adenosina A3 , Adenosina/análogos & derivados , Tionucleósidos/síntesis química , Tionucleósidos/farmacología , Adenosina/síntesis química , Adenosina/química , Adenosina/metabolismo , Adenosina/farmacología , Animales , Células CHO , Cricetinae , AMP Cíclico/metabolismo , Diseño de Fármacos , Humanos , Técnicas In Vitro , Cinética , Ligandos , Espectroscopía de Resonancia Magnética , Receptor de Adenosina A1/metabolismo , Receptor de Adenosina A2A/metabolismo , Proteínas Recombinantes/agonistas , Relación Estructura-Actividad , Tionucleósidos/química , Tionucleósidos/metabolismoRESUMEN
We have established structure-activity relationships of novel 4'-thionucleoside analogues as the A(3) adenosine receptor (AR) agonists. Binding affinity, selectivity toward other AR subtypes, and efficacy in inhibition of adenylate cyclase were studied. From this study, 2-chloro-N(6)-methyl-4'-thioadenosine-5'-methyluronamide (36a) emerged as the most potent and selective agonist at the human A(3) AR. We have also revealed that, similar to 4'-oxoadenosine analogues, at least one hydrogen on the 5'-uronamide moiety was necessary for high-affinity binding at the human A(3) AR, presumably to allow this group to donate a H bond within the binding site. Furthermore, bulky substituents on the 5'-uronamide reduced binding affinity, but in some cases large 5'-uronamide substituents, such as substituted benzyl and 2-phenylethyl groups, maintained moderate affinity with reduced efficacy, leading to A(3) AR partial agonists or antagonists. In several cases for which the corresponding 4'-oxonucleosides have been studied, the 4'-thionucleosides showed higher binding affinity to the A(3) AR.
Asunto(s)
Agonistas del Receptor de Adenosina A3 , Adenosina/análogos & derivados , Adenosina/farmacología , Amidas/farmacología , Ácidos Urónicos/farmacología , Adenosina/química , Agonistas del Receptor de Adenosina A1 , Agonistas del Receptor de Adenosina A2 , Amidas/síntesis química , Amidas/química , Animales , Células CHO , Cricetinae , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Ácidos Urónicos/síntesis química , Ácidos Urónicos/químicaRESUMEN
The present work describes the asymmetric synthesis of D- and L-apio-2',3'-dideoxynucleoside analogues, 4 and 5 with 2'-hydroxyl group via a common intermediate 9, starting from D-galactose. Stereoselective dihydroxylation and deoxygenation through radical inversion were successfully employed to synthesize the key intermediate 12 with D-apio structure, while stereoselecetive hydroboration-oxidation was used for the synthesis of another key intermediate 18 with L-apio structure.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Didesoxinucleósidos/síntesis química , Línea Celular Tumoral , Galactosa/química , VIH-1/efectos de los fármacos , Humanos , EstereoisomerismoRESUMEN
4'-Thio analogues 3-5 of Cl-IB-MECA (2) (K(i) = 1.0 +/- 0.2 nM at the human A(3) adenosine receptor) were synthesized from d-gulono-gamma-lactone via 4-thioribosyl acetate 14 as the key intermediate. All synthesized 4'-thionucleosides exhibited higher binding affinity to the human A(3) adenosine receptor than Cl-IB-MECA, among which 4 showed the most potent binding affinity (K(i) = 0.28 +/- 0.09 nM). 4 was also selective for A(3) vs human A(1) and human A(2A) receptors by 4800- and 36000-fold, respectively.