RESUMO
Writer's blocks: The first synthesis of RNA purine building blocks, 4'-selenoadenosine and 4'-selenoguanosine was achieved from D-ribose by regioisomeric rearrangement, which was confirmed by X-ray crystallography. 4'-Selenoadenosine exists in an unusual mixture of north and south conformers in the solid state.
Assuntos
Adenosina/análogos & derivados , Guanosina/análogos & derivados , Nucleosídeos/síntese química , Compostos Organosselênicos/síntese química , Purinas/síntese química , RNA/química , Ribose/química , Adenosina/síntese química , Adenosina/química , Cristalografia por Raios X , Guanosina/síntese química , Guanosina/química , Conformação Molecular , Estrutura Molecular , Nucleosídeos/química , Compostos Organosselênicos/química , Purinas/química , EstereoisomerismoRESUMO
Distinguishing compounds' agonistic or antagonistic behavior would be of great utility for the rational discovery of selective modulators. We synthesized truncated nucleoside derivatives and discovered 6c (Ki = 2.40 nM) as a potent human A3 adenosine receptor (hA3AR) agonist, and subtle chemical modification induced a shift from antagonist to agonist. We elucidated this shift by developing new hA3AR homology models that consider the pharmacological profiles of the ligands. Taken together with molecular dynamics (MD) simulation and three-dimensional (3D) structural network analysis of the receptor-ligand complex, the results indicated that the hydrogen bonding with Thr943.36 and His2727.43 could make a stable interaction between the 3'-amino group with TM3 and TM7, and the corresponding induced-fit effects may play important roles in rendering the agonistic effect. Our results provide a more precise understanding of the compounds' actions at the atomic level and a rationale for the design of new drugs with specific pharmacological profiles.
Assuntos
Agonistas do Receptor A3 de Adenosina/farmacologia , Antagonistas do Receptor A3 de Adenosina/farmacologia , Receptor A3 de Adenosina/química , Receptor A3 de Adenosina/metabolismo , Agonistas do Receptor A3 de Adenosina/química , Antagonistas do Receptor A3 de Adenosina/química , Animais , Células CHO , Domínio Catalítico , Cricetinae , Cricetulus , Células HEK293 , Humanos , Ligantes , Modelos Químicos , Modelos Moleculares , Simulação de Dinâmica Molecular , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
The 2'-substituted-4'-selenoribofuranosyl pyrimidines 3a-3j were synthesized from D-ribose and assayed for anticancer activity. The 2'-azido and 2'-fluoro groups with a ribo configuration were introduced by the regioselective opening of the O2,2'-anhydronucleosides with sodium azide and (HF)x-pyridine, respectively. Among the compounds tested, only 2'-fluoro derivative 3j was found to exhibit significant anticancer activity, but was much less potent than the corresponding 2'-arabino analogue 2c. This study will provide medicinal chemists with the insight into the identification of structural requirements for the anticancer activity for the developments of biologically active nucleosides.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Azidas , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Relação Estrutura-AtividadeRESUMO
Based on the potent anticancer activity of the D-arabino-configured cytosine nucleoside ara-C, novel 2'-substituted-4'-selenoarabinofuranosyl pyrimidines 3a-3u, comprising azido, fluoro, and hydroxyl substituents at C-2' were designed, synthesized, and evaluated for anticancer activity. The 2'-azido group was stereoselectively introduced by the Mitsunobu reaction using diphenylphosphoryl azide (DPPA), and the 2'-fluoro group was stereoselectively introduced through the double inversions of stereochemistry via the episelenium intermediate, which was formed by the participation of the selenium atom. Among the compounds tested, the 2'-fluoro derivative 3t (X = NH2, Y = H, R = F) was found to be the most potent anticancer agent and showed more potent anticancer activity than the control, ara-C in all tested human cancer cell lines (HCT116, A549, SNU638, T47D, and PC-3) except the leukemia cell lines (K562). The anticancer activity of the 2'-substituted-4'-selenonucleosides is in the following order: 2'-F > 2'-OH > 2'-N3.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Selênio/química , Linhagem Celular Tumoral , Humanos , Modelos Moleculares , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
An improved synthesis of DNA-dependent protein kinase inhibitor, IC86621 is described. This developed method provides an easy access to this simple molecule by using amination, acetylation and Fries rearrangement reactions.
Assuntos
Acetofenonas/síntese química , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Desenho de Fármacos , Morfolinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Acetofenonas/química , Acetofenonas/farmacologia , Aminação , Técnicas de Química Sintética/métodos , Estrutura Molecular , Morfolinas/química , Morfolinas/farmacologia , Fenóis/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologiaRESUMO
On the basis of the potent biological activity of cyclopentenyl-pyrimidines, fluorocyclopentenyl-pyrimidines were designed and synthesized from D-ribose. Among these, the cytosine derivative 5a showed highly potent antigrowth effects in a broad range of tumor cell lines and very potent antitumor activity in a nude mouse tumor xenograft model implanted with A549 human lung cancer cells. However, its 2'-deoxycytidine derivative 5b did not show any antigrowth effects, indicating that 2'-hydroxyl group is essential for the biological activity.
Assuntos
Antineoplásicos/síntese química , Ciclopentanos/síntese química , Citosina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclopentanos/farmacologia , Citosina/farmacologia , Humanos , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Truncated N(6)-substituted-4'-oxo- and 4'-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A(2A) and A(3) adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross-coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA(2A)AR, but hydrophobic C8 substitution abolished binding at the hA(2A)AR. However, most of synthesized compounds displayed medium to high binding affinity at the hA(3)AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA(2A)AR agonists. C2 substitution probed geometrically through hA(2A)AR docking was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA(2A)AR agonist and hA(3)AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases.
Assuntos
Agonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A3 de Adenosina/síntese química , Adenosina/análogos & derivados , Adenosina/síntese química , Receptor A3 de Adenosina/metabolismo , Receptores A2 de Adenosina/metabolismo , Tiofenos/síntese química , Adenosina/farmacologia , Agonistas do Receptor A2 de Adenosina/farmacologia , Antagonistas do Receptor A3 de Adenosina/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/biossíntese , Células HEK293 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Masculino , Modelos Moleculares , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/farmacologiaRESUMO
The first synthesis of 4'-selenothymidine (1), a novel DNA building block, and 4'-seleno-AZT (2) was accomplished from 2-deoxy-d-ribose via stereoselective formation of 2-deoxy-4-seleno-d-furanose 17 and a Pummerer-type base condensation as key steps. 4'-Selenothymidine (1) was discovered to adopt the same 2'-endo/3'-exo conformation as thymidine, which is unusual in that 4'-selenouridine has the opposite conformation to that of uridine.
Assuntos
Fármacos Anti-HIV/farmacologia , DNA/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Timidina/análogos & derivados , Zidovudina/análogos & derivados , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Cristalografia por Raios X , DNA/química , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Timidina/síntese química , Timidina/química , Timidina/farmacologia , Zidovudina/síntese química , Zidovudina/química , Zidovudina/farmacologiaRESUMO
The truncated C2- and C8-substituted-4'-thioadenosine derivatives 4a-d were synthesized from D-mannose, using palladium-catalyzed cross coupling reactions as key steps. In this study, an A(3) adenosine receptor (AR) antagonist, truncated 4'-thioadenosine derivative 3 was successfully converted into a potent A(2A)AR agonist 4a (K(i) = 7.19 ± 0.6 nM) by appending a 2-hexynyl group at the C2-position of a derivative of 3 that was N(6)-substituted. However, C8-substitution greatly reduced binding affinity at the human A(2A)AR. All synthesized compounds 4a-d maintained their affinity at the human A(3)AR, but 4a was found to be a competitive A(3)AR antagonist/A(2A)AR agonist in cyclic AMP assays. This study indicates that the truncated C2-substituted-4'-thioadenosine derivatives 4a and 4b can serve as a novel template for the development of new A(2A)AR ligands.