RESUMO
MLN4924 (1), which is in clinical trials as an anticancer agent, was stereoselectively synthesized from d-ribose via a route involving stereoselective reduction, regioselective cleavage of an isopropylidene moiety, and selective displacement of a cyclic sulfate moiety as key steps.
Assuntos
Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Ubiquitinas/antagonistas & inibidores , Ciclopentanos/química , Pirimidinas/química , Estereoisomerismo , Especificidade por Substrato , Ubiquitinas/metabolismoRESUMO
We synthesized homologated truncated 4'-thioadenosine analogues 3 in which a methylene (CH(2)) group was inserted in place of the glycosidic bond of a potent and selective A(3) adenosine receptor antagonist 2. The analogues were designed to induce maximum binding interaction in the binding site of the A(3) adenosine receptor. However, all homologated nucleosides were devoid of binding affinity at all subtypes of adenosine receptors, indicating that free rotation through the single bond allowed the compound to adopt an indefinite number of conformations, disrupting the favorable binding interaction essential for receptor recognition.
Assuntos
Antagonistas do Receptor A3 de Adenosina/síntese química , Antagonistas do Receptor A3 de Adenosina/farmacologia , Adenosina/análogos & derivados , Desenho de Fármacos , Receptor A3 de Adenosina/metabolismo , Tionucleosídeos/síntese química , Tionucleosídeos/farmacologia , Adenosina/síntese química , Adenosina/química , Adenosina/farmacologia , Antagonistas do Receptor A3 de Adenosina/química , Sítios de Ligação , Humanos , Modelos Moleculares , Conformação Molecular , Receptor A3 de Adenosina/química , Estereoisomerismo , Relação Estrutura-Atividade , Tionucleosídeos/químicaRESUMO
On the basis of potent anti-hepatitis C virus (HCV) activity of 2'-C-hydroxymethyladenosine, 3'-C-substituted-methyl-ribofuranosyl pyrimidine and purine nucleosides were designed and synthesized from D-xylose. Among compounds tested, all adenine analogues, 4a, 4d, and 4g showed significant anti-HCV activity in a replicon-based cell assay irrespective of the substituent (Y=OH, N3, or F) at the 3'-C-substituted methyl position, among which 4g (Y=N3) was the most potent, but it is also cytotoxic. This study guarantees the 3'-C-substituted-methyl nucleoside serves as a new template for the development of new anti-HCV agents.
Assuntos
Adenosina/análogos & derivados , Antivirais/síntese química , Hepacivirus/efeitos dos fármacos , Nucleosídeos de Purina/química , Nucleosídeos de Pirimidina/química , Adenosina/síntese química , Adenosina/química , Adenosina/farmacologia , Antivirais/química , Antivirais/farmacologia , Nucleosídeos de Purina/síntese química , Nucleosídeos de Purina/farmacologia , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
On the basis of a bioisosteric rationale, 4'-thionucleoside analogues of IB-MECA (N(6)-(3-Iodo-benzyl)-9-(5'-methylaminocarbonyl-beta-d-ribofuranosyl)adenine), which is a potent and selective A(3) adenosine receptor (AR) agonist, were synthesized from d-gulonic acid gamma-lactone. The 4'-thio analogue (5h) of IB-MECA showed extremely high binding affinity (K(i)=0.25 nM) at the human A(3)AR and was more potent than IB-MECA (K(i)=1.4 nM). Bulky substituents at the 5'-uronamide position, such as cyclohexyl and 2-methylbenzyl, in this series of 2-H nucleoside derivatives were tolerated in A(3)AR binding, although small alkyl analogues were more potent.
Assuntos
Agonistas do Receptor A3 de Adenosina , Amidas/síntese química , Tionucleosídeos/síntese química , Amidas/química , Amidas/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Cinética , Espectroscopia de Ressonância Magnética , Ensaio Radioligante , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Tionucleosídeos/química , Tionucleosídeos/farmacologiaRESUMO
On the basis of potent and selective binding affinity of truncated 4'-thioadenosine derivatives at the human A(3) adenosine receptor (AR), their bioisosteric 4'-oxo derivatives were designed and synthesized from commercially available 2,3-O-isopropylidene-D-erythrono lactone. The derivatives tested in AR binding assays were substituted at the C2 and N(6) positions. All synthesized nucleosides exhibited potent and selective binding affinity at the human A(3) AR. They were less potent than the corresponding 4'-thio analogues, but showed still selective to other subtypes. The 2-Cl series generally were better than the 2-H series in view of binding affinity and selectivity. Among compounds tested, compound 5d (X=Cl, R=3-bromobenzyl) showed the highest binding affinity (K(i)=13.0+/-6.9 nM) at the hA(3) AR with high selectivity (at least 88-fold) in comparison to other AR subtypes. Like the corresponding truncated 4'-thio series, compound 5d antagonized the action of an agonist to inhibit forskolin-stimulated adenylate cyclase in hA(3) AR-expressing CHO cells. Although the 4'-oxo series were less potent than the 4'-thio series, this class of human A(3) AR antagonists is also regarded as another good template for the design of A(3) AR antagonists and for further drug development.
Assuntos
Antagonistas do Receptor A3 de Adenosina , Adenosina/análogos & derivados , Furanos/química , Purinas/química , Tionucleosídeos/química , Adenosina/síntese química , Adenosina/química , Adenosina/farmacologia , Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Adenilil Ciclases/química , Adenilil Ciclases/metabolismo , Adenilil Ciclases/farmacologia , Animais , Células CHO , Linhagem Celular , Colforsina/química , Colforsina/farmacologia , Cricetinae , Cricetulus , Furanos/síntese química , Furanos/farmacologia , Humanos , Purinas/síntese química , Purinas/farmacologia , Receptor A1 de Adenosina/metabolismo , Receptor A3 de Adenosina/metabolismo , Receptores A2 de Adenosina/metabolismo , Relação Estrutura-Atividade , Tionucleosídeos/síntese química , Tionucleosídeos/farmacologiaRESUMO
The 6'-fluorinated aristeromycins were designed as dual-target antiviral compounds aimed at inhibiting both the viral RNA-dependent RNA polymerase (RdRp) and the host cell S-adenosyl-l-homocysteine (SAH) hydrolase, which would indirectly target capping of viral RNA. The introduction of a fluorine at the 6'-position enhanced the inhibition of SAH hydrolase and the activity against RNA viruses. The adenosine and N6-methyladenosine analogues 2a-e showed potent inhibition against SAH hydrolase, while only the adenosine derivatives 2a-c exhibited potent antiviral activity against all tested RNA viruses such as Middle East respiratory syndrome-coronavirus (MERS-CoV), severe acute respiratory syndrome-coronavirus, chikungunya virus, and/or Zika virus. 6',6'-Difluoroaristeromycin (2c) showed the strongest antiviral effect for MERS-CoV, with a â¼2.5 log reduction in infectious progeny titer in viral load reduction assay. The phosphoramidate prodrug 3a also demonstrated potent broad-spectrum antiviral activity, possibly by inhibiting the viral RdRp. This study shows that 6'-fluorinated aristeromycins can serve as starting points for the development of broad-spectrum antiviral agents that target RNA viruses.
Assuntos
Adenosina/análogos & derivados , Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Vírus de RNA/efeitos dos fármacos , Adenosina/síntese química , Adenosina/farmacologia , Adenosil-Homocisteinase/antagonistas & inibidores , Animais , Antivirais/síntese química , Chlorocebus aethiops , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Halogenação , Humanos , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Células VeroRESUMO
The first synthesis of 4'-selenonucleosides was achieved using a Pummerer-type condensation as a key step. All stereoelectronic effects shown in 4'-oxonucleosides were overwhelmed by the size of selenium and steric interactions, driving the conformation to the C2'-endo/ C3'-exo twist (Southern) conformation.
Assuntos
Nucleosídeos/síntese química , Compostos Organosselênicos/síntese química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Conformação de Ácido Nucleico , Nucleosídeos/química , Compostos Organosselênicos/químicaRESUMO
On the basis of potent and selective A(3) adenosine receptor (AR) antagonist, 2-chloro-N(6)-(3-iodobenzyl)-4'-thioadenosine-5'-N,N-dimethyluronamide, structure-activity relationships were studied for a series of 5'-N,N-dialkyluronamide derivatives, synthesized from D-gulonic gamma-lactone. From this study, it was revealed that removal of the hydrogen bond-donating ability of the 5'-uronamide was essential for the pure A(3)AR antagonism. 5'-N,N-Dimethyluronamide derivatives exhibited higher binding affinity than larger 5'-N,N-dialkyl or 5'-N,N-cycloalkylamide derivatives, indicating that steric factors are crucial in binding to the human A(3)AR. A N(6)-(3-bromobenzyl) derivative 6c (K(i)=9.32 nM) exhibited the highest binding affinity at the human A(3)AR with very low binding affinities to other AR subtypes.
Assuntos
Antagonistas do Receptor A3 de Adenosina , Amidas/química , Amidas/farmacologia , Ácidos Urônicos/química , Ácidos Urônicos/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
On the basis of potent anti-HIV activity of 2',3'-dideoxynucleosides (ddNs), their bioisosteric analogues, 2',3'-dideoxy-4'-selenonucleosides (4'-seleno-ddNs) were first synthesized from a chiral template, d-glutamic acid using stereoselective ring-closure reaction of the dimesylate with Se(2-) and Pummerer type condensation of the selenoxide with nucleobases as key steps. X-ray crystallographic analysis indicated that 4'-seleno-ddNs adopted the same C2'-endo/C3'-exo (South) conformation as anti-HIV active ddNs, but did not show anti-HIV activity, indicating that RT seems to prefer the C2'-exo/C3'-endo (North) conformation on binding with their triphosphates.
Assuntos
Antivirais/síntese química , Didesoxinucleosídeos/síntese química , Selênio/química , Antivirais/química , Antivirais/farmacologia , Cristalografia por Raios X , Didesoxinucleosídeos/química , Didesoxinucleosídeos/farmacologia , Desenho de Fármacos , HIV/efeitos dos fármacos , Modelos Químicos , Estrutura MolecularRESUMO
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
Truncated D-4'-thioadenosine derivatives lacking the 4'-hydroxymethylene moiety were synthesized starting from D-mannose, using cyclization to the 4-thiosugar and one-step conversion of the diol to the acetate as key steps. At the human A3 adenosine receptor (AR), N6-substituted purine analogues bound potently and selectively and acted as antagonists in a cyclic AMP functional assay. An N6-(3-chlorobenzyl)purine analogue 9b displayed a Ki value of 1.66 nM at the human A3 AR. Thus, truncated D-4'-thioadenosine is an excellent template for the design of novel A3 AR antagonists to act at both human and murine species.
Assuntos
Adenosina/análogos & derivados , Receptor A3 de Adenosina/metabolismo , Tionucleosídeos/farmacologia , Adenosina/química , Adenosina/farmacologia , Antagonistas do Receptor A3 de Adenosina , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Ligantes , Tionucleosídeos/químicaRESUMO
Synthesis of 2' -beta-hydroxymethyl nucleosides 3-6 was accomplished, using stereoselective hydroxymethylation as a key step. Adenine nucleoside 3 showed potent anti-HCV activity, implying that 2' -beta-hydroxymethyl group has the appropriate electronic properties interfering with HCV polymerase.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Antivirais/química , Desenho de Fármacos , Nucleosídeos/química , Purinas/químicaRESUMO
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
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
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
Agonists to A3 adenosine receptor (A3AR) have been reported to inhibit cell growth and/or induce apoptosis in various tumors. We tested the effect of a novel A3AR agonist generically known as LJ-529 in breast cancer cells. Anchorage-dependent cell growth and in vivo tumor growth were attenuated by LJ-529, independently of its estrogen receptor (ER) alpha status. In addition, apoptosis was induced as evidenced by the activation of caspase-3 and c-poly(ADP)ribose polymerase. Furthermore, the Wnt signaling pathway was down-regulated and p27(kip) was induced by LJ-529. In ER-positive cells, the expression of ER was down-regulated by LJ-529, which might have additionally contributed to attenuated cell proliferation. In ER-negative, c-ErbB2-overexpressing SK-BR-3 cells, the expression of c-ErbB2 and its downstream extracellular signal-regulated kinase pathway were down-regulated by LJ-529. However, such effect of LJ-529 acted independently of its receptor because no A3AR was detected by reverse transcription-PCR in all four cell lines tested. In conclusion, our novel findings open the possibility of LJ-529 as an effective therapeutic agent against both ER-positive and ER-negative breast cancers, particularly against the more aggressive ER-negative, c-ErbB2-overexpressing types.
Assuntos
Agonistas do Receptor A3 de Adenosina , Adenosina/análogos & derivados , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/metabolismo , Tionucleosídeos/uso terapêutico , Adenosina/uso terapêutico , Animais , Apoptose , Neoplasias da Mama/química , Neoplasias da Mama/genética , Caspase 3 , Caspases/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Regulação para Baixo , Receptor alfa de Estrogênio/análise , Receptor alfa de Estrogênio/genética , Humanos , Camundongos , Poli(ADP-Ribose) Polimerases/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Wnt/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
An alternative approach to overcome the inherent lack of specificity of conventional agonist therapy can be the reengineering of the GPCRs and their agonists. A reengineered receptor (neoceptor) could be selectively activated by a modified agonist, but not by the endogenous agonist. Assisted by rhodopsin-based molecular modeling, we pinpointed mutations of the A(3) adenosine receptor (AR) for selective affinity enhancement following complementary modifications of adenosine. Ribose modifications examined included, at 3': amino, aminomethyl, azido, guanidino, ureido; and at 5': uronamido, azidodeoxy. N(6)-Variations included 3-iodobenzyl, 5-chloro-2-methyloxybenzyl, and methyl. An N(6)-3-iodobenzyl-3'-ureido adenosine derivative 10 activated phospholipase C in COS-7 cells (EC(50) = 0.18 microM) or phospholipase D in chick primary cardiomyocytes, both mediated by a mutant (H272E), but not the wild-type, A(3)AR. The affinity enhancements for 10 and the corresponding 3'-acetamidomethyl analogue 6 were >100-fold and >20-fold, respectively. 10 concentration-dependently protected cardiomyocytes transfected with the neoceptor against hypoxia. Unlike 10, adenosine activated the wild-type A(3)AR (EC(50) of 1.0 microM), but had no effect on the H272E mutant A(3)AR (100 microM). Compound 10 was inactive at human A(1), A(2A), and A(2B)ARs. The orthogonal pair comprising an engineered receptor and a modified agonist should be useful for elucidating signaling pathways and could be therapeutically applied to diseases following organ-targeted delivery of the neoceptor gene.