RESUMO
Nucleoside analogues play an important role in antiviral, antibacterial and antineoplastic chemotherapy. Herein we report the synthesis, structural characterization and biological activity of some 4'-C -methyl- and -phenyl dioxolane-based nucleosides. In particular, α and ß anomers of all natural nucleosides were obtained and characterized by NMR, HR-MS and X-ray crystallography. The compounds were tested for antimicrobial activity against some representative human pathogenic fungi, bacteria and viruses. Antitumor activity was evaluated in a large variety of human cancer cell-lines. Although most of the compounds showed non-significant activity, 23α weakly inhibited HIV-1 multiplication. Moreover, 22α and 32α demonstrated a residual antineoplastic activity, interestingly linked to the unnatural α configuration. These results may provide structural insights for the design of active antiviral and antitumor agents.
Assuntos
Fármacos Anti-HIV/farmacologia , Antineoplásicos/farmacologia , Dioxolanos/farmacologia , HIV-1/efeitos dos fármacos , Nucleosídeos de Purina/farmacologia , Nucleosídeos de Pirimidina/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Dioxolanos/síntese química , Dioxolanos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Nucleosídeos de Purina/síntese química , Nucleosídeos de Purina/química , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/química , Relação Estrutura-AtividadeRESUMO
Racemic synthesis of novel 2',5',5'-trifluoro-apiose nucleoside phosphonic acid analogs were performed as potent antiviral agents. Phosphonation was performed by direct displacement of triflate intermediate with diethyl (lithiodifluoromethyl) phosphonate to give the corresponding (α,α-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield the nucleoside phosphonate analogs. Deprotection of diethyl phosphonates provided the target nucleoside analogs. An antiviral evaluation of the synthesized compounds against various viruses such as HIV, HSV-1, HSV-2, and HCMV revealed that the pyrimidine analogues have significant anti-HCMV activity.
Assuntos
Antivirais/química , Antivirais/farmacologia , Nucleosídeos/química , Nucleosídeos/farmacologia , Ácidos Fosforosos/química , Ácidos Fosforosos/farmacologia , Antivirais/síntese química , Citomegalovirus/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Nucleosídeos/síntese química , Pentoses/síntese química , Pentoses/química , Pentoses/farmacologia , Ácidos Fosforosos/síntese química , Viroses/tratamento farmacológicoRESUMO
As antiviral nucleosides containing a fluorine atom at 2'-position are endowed with increased stabilization of glycosyl bond, it was of interest to investigate the influence of three fluorine atoms at 2'- and 5'-positions of apiosyl nucleoside phosphonate analogues. Various pyrimidine and purine 2',5',5'-trifluoro-3'-hydroxy-apiose nucleoside phosphonic acid analogues were synthesized from 1,3-dihydroxyacetone. Electrophilic fluorination of lactone was performed using N-fluorodibenzenesulfonimide. Difluorophosphonation was performed by direct displacement of triflate intermediate with diethyl(lithiodifluoromethyl) phosphonate to give the corresponding (α,α-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield nucleoside phosphonate analogues. Deprotection of diethyl phosphonates provided the final phosphonic acid sodium salts. The synthesized nucleoside analogues were subjected to antiviral screening against various viruses.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Citomegalovirus/efeitos dos fármacos , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Ácidos Fosforosos/síntese química , Ácidos Fosforosos/farmacologia , Fármacos Anti-HIV/química , Humanos , Nucleosídeos/química , Ácidos Fosforosos/químicaRESUMO
Novel 2'-deoxy-2'-ß-fluoro-threose purine phosphonic acid analogues were designed and racemically synthesized from 2-propanone-1,3-diacetate. Condensation successfully proceeded from a glycosyl donor 9 under Vorbrüggen conditions. Cross-metathesis of vinyl analogues 13 and 23 with diethyl vinylphosphonate yielded the desired nucleoside phosphonate analogues 14 and 24, respectively. Ammonolysis and hydrolysis of phosphonates yielded the nucleoside phosphonic acid analogues 16, 19, 26, and 29. The synthesized nucleoside analogues were subjected to antiviral screening against human immunodeficiency virus (HIV)-1. Adenine analogue 18 exhibited weak in vitro activities against human immunodeficiency virus (HIV)-1.