RESUMEN
On the basis of high binding affinity of 3'-aminoadenosine derivatives 2b at the human A3 adenosine receptor (AR), 3'-acetamidoadenosine derivatives 3a-e were synthesized from 1,2:5,6-di-O-isopropylidene-D-glucose via stereoselective hydroboration as a key step. Although all synthesized compounds were totally devoid of binding affinity at the human A3AR, our results revealed that 3'-position of adenosine can only be tolerated with small size of a hydrogen bonding donor like hydroxyl or amino group in the binding site of human A3AR.
Asunto(s)
Agonistas del Receptor de Adenosina A3 , Adenosina/análogos & derivados , Adenosina/síntesis química , Adenosina/farmacología , Adenosina/metabolismo , Sitios de Unión , Humanos , Enlace de Hidrógeno , Receptor de Adenosina A3/metabolismo , Estereoisomerismo , Especificidad por SustratoRESUMEN
Novel iso D-2',3'-dideoxythianucleoside derivatives 1-3 were designed and asymmetrically synthesized to search for new anti-HIV agents. Final compounds 1-3 were evaluated against a variety of viruses including HIV-1 and 2. Only cytosine analog 3 showed a potent anti-VSV activity (EC(50) = 9.43 microg/mL). This result implies that iso 2',3'-dideoxy sugar templates might play a role of a sugar surrogate of nucleosides for the development of anti-RNA virus agent.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Lamivudine/análogos & derivados , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Antivirales/química , Línea Celular , Chlorocebus aethiops , Diseño de Fármacos , VIH-1/efectos de los fármacos , VIH-2/efectos de los fármacos , Células HeLa , Humanos , Lamivudine/síntesis química , Lamivudine/química , Lamivudine/farmacología , Pruebas de Sensibilidad Microbiana , Estereoisomerismo , Células Vero , Virus de la Estomatitis Vesicular Indiana/efectos de los fármacosRESUMEN
Apio fluoroneplanocin A (apio F-NPA, 3) and its uracil analogue 4 have been designed and asymmetrically synthesized starting from D-ribose. Introduction of fluoro group into vinylic position of 5 was accomplished successfully over 5 steps employing key reactions such as iodination according to an addition-elimination reaction mechanism, stereo- and regioselective reduction of alpha,beta-unsaturated ketone, and electrophilic fluorination. This methodology can be adapted to the synthesis of fluoro compounds extensively.
Asunto(s)
Adenosina/análogos & derivados , Adenosilhomocisteinasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Adenosina/síntesis química , Adenosina/química , Adenosina/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacologíaRESUMEN
Pseudo-L-vinylcyclopropyl adenine and guanine nucleosides 11 and 12 were designed and enantiopurely synthesized starting from (S)-epichlorohydrin using tandem alkylation, regioselective oxirane-ring opening, and chemoselective reduction as key steps.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Herpesviridae/efectos de los fármacos , Nucleósidos/síntesis química , Nucleósidos/farmacología , Adenosina/análogos & derivados , Adenosina/síntesis química , Adenosina/química , Adenosina/farmacología , Alquilación , Antivirales/química , Diseño de Fármacos , Guanosina/análogos & derivados , Guanosina/síntesis química , Guanosina/química , Guanosina/farmacología , Nucleósidos/química , Oxidación-Reducción , Estereoisomerismo , Compuestos de Vinilo/síntesis química , Compuestos de Vinilo/químicaRESUMEN
Pseudo-D-vinylcyclopropyl nucleosides 10-12 bearing a quaternary carbon were designed and synthesized starting from (R)-epichlorohydrin using a tandem reaction of double alkylation and lactonization via oxirane-ring opening reaction, a Wittig reaction, and chemoselective reduction as potential anti-herpesvirus agent.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Herpesviridae/efectos de los fármacos , Nucleósidos/síntesis química , Nucleósidos/farmacología , Alquilación , Antivirales/química , Diseño de Fármacos , Epiclorhidrina/química , Nucleósidos/química , Estereoisomerismo , Compuestos de Vinilo/síntesis química , Compuestos de Vinilo/químicaRESUMEN
Stereoselective functionalization of the 1'-position of 4'-thionucleosides was achieved using a stereoselective S(N)2 reaction controlled by 5-membered ring coordination.
Asunto(s)
Tionucleósidos/síntesis química , Antagonistas del Receptor de Adenosina A3 , Diseño de Fármacos , Humanos , Enlace de Hidrógeno , Estereoisomerismo , Tionucleósidos/química , Tionucleósidos/farmacologíaRESUMEN
Novel 2'-C-methyl-cyclopropyl-fused carbocyclic nucleosides as potential anti-HCV agents were stereoselectively synthesized, utilizing regioselective cleavage of the isopropylidene group and cyclic sulfate chemistry as key steps.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Nucleósidos/síntesis química , Nucleósidos/farmacología , Antivirales/química , Diseño de Fármacos , Humanos , Indicadores y Reactivos , Nucleósidos/químicaRESUMEN
On the basis of potent and selective binding affinity of Cl-IB-MECA to the human A(3) adenosine receptor, its 4'-thioadenosine derivatives were efficiently synthesized starting from D-gulonic gamma-lactone. Among compounds tested, 2-chloro-N(6)-(3-iodobenzyl)- and 2-chloro-N(6)-methyl-4' -thioadenosine-5' -methyluronamides (7a and 7b) exhibited nanomolar range of binding affinity (K(i) = 0.38 nM and 0.28 nM, respectively) at the human A(3)AR. These compounds showed anti-growth effects on HL-60 leukemia cell, which resulted from the inhibition of Wnt signaling pathway.
Asunto(s)
Agonistas del Receptor de Adenosina A3 , Adenosina/análogos & derivados , Antineoplásicos/química , Antineoplásicos/farmacología , Tionucleósidos/química , Tionucleósidos/farmacología , Adenosina/síntesis química , Adenosina/química , Adenosina/farmacología , Antineoplásicos/síntesis química , Diseño de Fármacos , Células HL-60 , Humanos , Tionucleósidos/síntesis química , Proteínas Wnt/antagonistas & inhibidoresRESUMEN
Novel L-bicyclocarba-d4T (1), an enantiomer of D-N-MCd4T has been enantiopurely synthesized as a potent anti-HIV agent starting from (R)-epichlorohydrin using tandem alkylation, chemoselective reduction of ester in the presence of lactone functional group, Grignard reaction, RCM reaction, and Mitsunobu reaction as key steps. L-N-MCd4T (1) was found to be very potent anti-HIV-1 (EC(50) = 6.76 microg/mL) agent with no cytotoxicity.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/farmacología , VIH-1/efectos de los fármacos , VIH-2/efectos de los fármacos , Timidina/análogos & derivados , Fármacos Anti-VIH/química , Compuestos Bicíclicos con Puentes/química , Diseño de Fármacos , Humanos , Timidina/síntesis química , Timidina/química , Timidina/farmacologíaRESUMEN
Several N6-substituted 3 '-ureidoadenosine derivatives were efficiently synthesized starting from D-glucose for the development of H272E mutant A3 adenosine receptor (AR) agonists. Among compounds tested, 3 '-ureido-N6-(3-iodobenzyl)adenosine (2c) exhibited the highest binding affinity (Ki = 0.22 micro M) at the H272E mutant A3 AR without binding to the natural A3AR.
Asunto(s)
Agonistas del Receptor de Adenosina A3 , Desoxiadenosinas/síntesis química , Desoxiadenosinas/farmacología , Proteínas Mutantes/agonistas , Nitrógeno/química , Desoxiadenosinas/química , Diseño de Fármacos , Relación Estructura-ActividadRESUMEN
Synthesis of fluorocyclopentenyl pyrimidine nucleosides 6-9 was enantiopurely accomplished employing oxidative rearrangement, RCM reaction and electrophilic fluorination starting from d-ribose. Cytosine analog 8 was found to exhibit significant anticancer activity in various human tumor cell lines.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Pirimidinas/químicaRESUMEN
Novel apio carbocyclic nucleosides 18-21 were asymmetrically synthesized as potential antiviral and antitumor agent, starting from D-ribose employing aldol reaction, RCM reaction and Mitsunobu reaction as key reactions.
Asunto(s)
Antineoplásicos/síntesis química , Antivirales/síntesis química , Nucleósidos/síntesis química , 2-Aminopurina/análogos & derivados , 2-Aminopurina/química , Antineoplásicos/química , Antivirales/química , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Nucleósidos/químicaRESUMEN
Homo-apioneplanocin A (1) as a potential inhibitor of S-adenosylhomocysteine hydrolase was synthesized from D-ribose, employing stereoselective hydroxymethylation, regioselective oxidation, and regio- and chemoselective hydroboration as key steps.
Asunto(s)
Adenosina/análogos & derivados , Adenosilhomocisteinasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Nucleósidos/síntesis química , Nucleósidos/farmacología , Adenosina/síntesis química , Adenosina/química , Adenosina/farmacología , Diseño de Fármacos , Nucleósidos/química , EstereoisomerismoRESUMEN
Novel iso-d-2',3'-dideoxythianucleoside derivatives 1-4 were designed and asymmetrically synthesized as a bioisostere of lamivudine to search for new anti-HIV agents. The information about using sulfur participation occurred on DAST fluorination and Mitsunobu reaction will be of great help in synthesizing sulfur-containing compounds. Final compounds 1-4 were evaluated against HIV-1 and 2, HSV-1 and 2, EMCV, Cox. B3, VSV, FluA (Taiwan), FluA (Johan.), FCV, and FIP. Only cytosine analogue 3 showed a potent anti-VSV activity (EC(50)=9.43microg/mL). This result implies that iso-2',3'-dideoxy sugar templates might play a role of a sugar surrogate of nucleosides for the development of anti-RNA virus agent.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , VIH-1/efectos de los fármacos , VIH-2/efectos de los fármacos , Imidas/química , Imidas/síntesis química , Perileno/análogos & derivados , Virus de la Estomatitis Vesicular Indiana/efectos de los fármacos , Antivirales/química , Diseño de Fármacos , Virus de la Encefalomiocarditis/efectos de los fármacos , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 2/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Perileno/síntesis química , Perileno/química , EstereoisomerismoRESUMEN
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
L-N-MCd4T (1) has been synthesized as a potent anti-HIV agent starting from (R)-epichlorohydrin using tandem alkylation, chemoselective reduction of ester in the presence of lactone functional group, RCM reaction and Mitsunobu reaction as key steps and was found to be a very potent anti-HIV-1 (EC50 = 6.76 microg mL(-1)) agent without cytotoxicity up to 100 microg mL(-1), indicating that the anti-HIV-1 activity found is similar to that of ddI (EC50 = 4.95 microg mL(-1)), which is used clinically for the treatment of AIDS patients.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Compuestos Bicíclicos con Puentes/síntesis química , Timidina/análogos & derivados , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacología , VIH/efectos de los fármacos , Humanos , Linfocitos/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Estereoisomerismo , Timidina/síntesis química , Timidina/química , Timidina/farmacologíaRESUMEN
4'-Thionucleoside derivatives as potent and selective A3 adenosaine receptor agonists were synthesized, starting from D-gulono-gamma-lactone via D-thioribosyl acetate as a key intermediate, among which the 2-chloro-N6-methyladenosine-5-methyluronamide showed the most potent and selective binding affinity (Ki = 0.28 +/- 0.09 nM) at the human A3 adenosine receptor.
Asunto(s)
Agonistas del Receptor de Adenosina A3 , Adenosina/análogos & derivados , Receptor de Adenosina A3/química , Tionucleósidos/química , Acetatos/química , Adenosina/química , Animales , Furanos/química , Gluconatos/química , Humanos , Cinética , Lactonas/química , Ligandos , Modelos Químicos , Nucleósidos/química , Oxígeno/química , Unión Proteica , RatasRESUMEN
The preparative and stereoselective synthesis (45- 50% overall yields, >50 g scale) of the key carbasugars 7a-d was achieved from D-ribose via stereoselective Grignard reaction and oxidative rearrangement as key reactions.
Asunto(s)
Ciclopentanos/química , Ciclopentanos/síntesis química , Biología Molecular/métodos , Nucleósidos/química , Alcoholes/química , Catálisis , Modelos Químicos , Oxígeno/química , Ribosa/química , EstereoisomerismoRESUMEN
Four 5'-substituted fluoro-neplanocin A analogues la-d were designed and synthesized, and the inhibitory activity against SAH was in the following order: NH2 > SH > F, N3, indicating a hydrogen bonding donor is essential for inhibitory activity.