RESUMO
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.
Assuntos
Agonistas do Receptor A3 de Adenosina , Adenosina/análogos & derivados , Adenosina/síntese química , Adenosina/farmacologia , Adenosina/metabolismo , Sítios de Ligação , Humanos , Ligação de Hidrogênio , Receptor A3 de Adenosina/metabolismo , Estereoisomerismo , Especificidade por SubstratoRESUMO
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.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Lamivudina/análogos & derivados , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Antivirais/química , Linhagem Celular , Chlorocebus aethiops , Desenho de Fármacos , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Células HeLa , Humanos , Lamivudina/síntese química , Lamivudina/química , Lamivudina/farmacologia , Testes de Sensibilidade Microbiana , Estereoisomerismo , Células Vero , Vírus da Estomatite Vesicular Indiana/efeitos dos fármacosRESUMO
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.
Assuntos
Adenosina/análogos & derivados , Adenosil-Homocisteinase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Adenosina/síntese química , Adenosina/química , Adenosina/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologiaRESUMO
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.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Herpesviridae/efeitos dos fármacos , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Adenosina/análogos & derivados , Adenosina/síntese química , Adenosina/química , Adenosina/farmacologia , Alquilação , Antivirais/química , Desenho de Fármacos , Guanosina/análogos & derivados , Guanosina/síntese química , Guanosina/química , Guanosina/farmacologia , Nucleosídeos/química , Oxirredução , Estereoisomerismo , Compostos de Vinila/síntese química , Compostos de Vinila/químicaRESUMO
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.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Herpesviridae/efeitos dos fármacos , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Alquilação , Antivirais/química , Desenho de Fármacos , Epicloroidrina/química , Nucleosídeos/química , Estereoisomerismo , Compostos de Vinila/síntese química , Compostos de Vinila/químicaRESUMO
Stereoselective functionalization of the 1'-position of 4'-thionucleosides was achieved using a stereoselective S(N)2 reaction controlled by 5-membered ring coordination.
Assuntos
Tionucleosídeos/síntese química , Antagonistas do Receptor A3 de Adenosina , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Estereoisomerismo , Tionucleosídeos/química , Tionucleosídeos/farmacologiaRESUMO
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.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Antivirais/química , Desenho de Fármacos , Humanos , Indicadores e Reagentes , Nucleosídeos/químicaRESUMO
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.
Assuntos
Agonistas do Receptor A3 de Adenosina , Adenosina/análogos & derivados , Antineoplásicos/química , Antineoplásicos/farmacologia , Tionucleosídeos/química , Tionucleosídeos/farmacologia , Adenosina/síntese química , Adenosina/química , Adenosina/farmacologia , Antineoplásicos/síntese química , Desenho de Fármacos , Células HL-60 , Humanos , Tionucleosídeos/síntese química , Proteínas Wnt/antagonistas & inibidoresRESUMO
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.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Timidina/análogos & derivados , Fármacos Anti-HIV/química , Compostos Bicíclicos com Pontes/química , Desenho de Fármacos , Humanos , Timidina/síntese química , Timidina/química , Timidina/farmacologiaRESUMO
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.
Assuntos
Agonistas do Receptor A3 de Adenosina , Desoxiadenosinas/síntese química , Desoxiadenosinas/farmacologia , Proteínas Mutantes/agonistas , Nitrogênio/química , Desoxiadenosinas/química , Desenho de Fármacos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Pirimidinas/químicaRESUMO
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.
Assuntos
Antineoplásicos/síntese química , Antivirais/síntese química , Nucleosídeos/síntese química , 2-Aminopurina/análogos & derivados , 2-Aminopurina/química , Antineoplásicos/química , Antivirais/química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Nucleosídeos/químicaRESUMO
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.
Assuntos
Adenosina/análogos & derivados , Adenosil-Homocisteinase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Adenosina/síntese química , Adenosina/química , Adenosina/farmacologia , Desenho de Fármacos , Nucleosídeos/química , EstereoisomerismoRESUMO
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.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Imidas/química , Imidas/síntese química , Perileno/análogos & derivados , Vírus da Estomatite Vesicular Indiana/efeitos dos fármacos , Antivirais/química , Desenho de Fármacos , Vírus da Encefalomiocardite/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Molecular , Perileno/síntese química , Perileno/química , EstereoisomerismoRESUMO
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.
Assuntos
Agonistas do Receptor A3 de Adenosina , Adenosina/análogos & derivados , Tionucleosídeos/síntese química , Tionucleosídeos/farmacologia , Adenosina/síntese química , Adenosina/química , Adenosina/metabolismo , Adenosina/farmacologia , Animais , Células CHO , Cricetinae , AMP Cíclico/metabolismo , Desenho de Fármacos , Humanos , Técnicas In Vitro , Cinética , Ligantes , Espectroscopia de Ressonância Magnética , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Proteínas Recombinantes/agonistas , Relação Estrutura-Atividade , Tionucleosídeos/química , Tionucleosídeos/metabolismoRESUMO
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.
Assuntos
Agonistas do Receptor A3 de Adenosina , Adenosina/análogos & derivados , Adenosina/farmacologia , Amidas/farmacologia , Ácidos Urônicos/farmacologia , Adenosina/química , Agonistas do Receptor A1 de Adenosina , Agonistas do Receptor A2 de Adenosina , Amidas/síntese química , Amidas/química , Animais , Células CHO , Cricetinae , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Ácidos Urônicos/síntese química , Ácidos Urônicos/químicaRESUMO
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.
Assuntos
Fármacos Anti-HIV/síntese química , Compostos Bicíclicos com Pontes/síntese química , Timidina/análogos & derivados , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , HIV/efeitos dos fármacos , Humanos , Linfócitos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Molecular , Estereoisomerismo , Timidina/síntese química , Timidina/química , Timidina/farmacologiaRESUMO
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.
Assuntos
Agonistas do Receptor A3 de Adenosina , Adenosina/análogos & derivados , Receptor A3 de Adenosina/química , Tionucleosídeos/química , Acetatos/química , Adenosina/química , Animais , Furanos/química , Gluconatos/química , Humanos , Cinética , Lactonas/química , Ligantes , Modelos Químicos , Nucleosídeos/química , Oxigênio/química , Ligação Proteica , RatosRESUMO
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.
Assuntos
Ciclopentanos/química , Ciclopentanos/síntese química , Biologia Molecular/métodos , Nucleosídeos/química , Álcoois/química , Catálise , Modelos Químicos , Oxigênio/química , Ribose/química , EstereoisomerismoRESUMO
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.