2-(4-Hydroxyphenyl)-3-hydroxymethyl-1,4-benzodioxane-6-aldehyde 8,the key intermediate of sinaiticin 10,was synthesized in 6 step from caffeic acid 4 and 4- hydroxybenzsaldehyde 1.the coupling reaction is the key step.
3-Hydroxymethyl-4-methyl-DCK(3,HMDCK)was discovered previously as a potent HIV non-nucleoside reverse transcriptase inhibitor(NNRTIs)(EC_(50):0.004 μM,TI:6225)with a novel mechanism of action.It exerts anti-HIV activ...3-Hydroxymethyl-4-methyl-DCK(3,HMDCK)was discovered previously as a potent HIV non-nucleoside reverse transcriptase inhibitor(NNRTIs)(EC_(50):0.004 μM,TI:6225)with a novel mechanism of action.It exerts anti-HIV activity by inhibiting the production of HIV-1 double-stranded viral DNA from a single-stranded DNA intermediate,rather than blocking the generation of single-stranded DNA from a RNA template,which is the mechanism of action of current HIV-1 RT inhibitors.However,the insufficient metabolic stability of 3 limits its further clinical development.In the current study,a series of ester prodrugs of 3 was designed and synthesized to explore the new drug candidates as NNRTIs.The L-alanine ester prodrug 10 exhibited desirable pharmacokinetic properties in vitro and in vivo and showed improved oral bioavailability of 26%in rat,and would be a potential clinical candidate as a new anti-AIDS drug.展开更多
文摘2-(4-Hydroxyphenyl)-3-hydroxymethyl-1,4-benzodioxane-6-aldehyde 8,the key intermediate of sinaiticin 10,was synthesized in 6 step from caffeic acid 4 and 4- hydroxybenzsaldehyde 1.the coupling reaction is the key step.
基金supported by grants from the Ministry of Science and Technology of the People’s Republic of China(2009ZX09102–008)Beijing Municipal Science&Technology Commission(D0206001040191)。
文摘3-Hydroxymethyl-4-methyl-DCK(3,HMDCK)was discovered previously as a potent HIV non-nucleoside reverse transcriptase inhibitor(NNRTIs)(EC_(50):0.004 μM,TI:6225)with a novel mechanism of action.It exerts anti-HIV activity by inhibiting the production of HIV-1 double-stranded viral DNA from a single-stranded DNA intermediate,rather than blocking the generation of single-stranded DNA from a RNA template,which is the mechanism of action of current HIV-1 RT inhibitors.However,the insufficient metabolic stability of 3 limits its further clinical development.In the current study,a series of ester prodrugs of 3 was designed and synthesized to explore the new drug candidates as NNRTIs.The L-alanine ester prodrug 10 exhibited desirable pharmacokinetic properties in vitro and in vivo and showed improved oral bioavailability of 26%in rat,and would be a potential clinical candidate as a new anti-AIDS drug.
