Biomedical subjects
Publications and source records attributed to Yulin Lam.
[Structure: see text] An efficient and regioselective procedure for the synthesis of 1,2,3-triazoles via a [3+2] cycloaddition of polymer-bound vinyl sulfone and sodium azide is described. Microwave irradiation provided significant rate enhancement in all steps of the three-step protocol. A representative set of 23 compounds was prepared.
Current treatments for chronic hepatitis B virus (HBV) infection include the use of interferon-alpha and of nucleoside analogs lamivudine, adefovir and entecavir. However, the use of interferon-alpha has many side effects while that of nucleosidic inhibitors can lead to the emergence of resistant viruses. Hence, new drugs for the treatment of HBV infection are still highly desired. Oxadiazoles have been observed to exhibit antiviral activities against RNA viruses. In this study, a facile synthesis of 2-benzenesulfonylalkyl-5-substituted-sulfanyl-[1,3,4]-oxadiazoles is reported. The compounds were then evaluated for their anti-HBV activity. 1-[2-[5-(1-Benzenesulfonyl-propyl)-[1,3,4]oxadiazol-2-yl-sulfanyl]-ethyl]-4-(2-methoxy-phenyl)-piperazine (1i) was able to inhibit the expression of the viral antigens, HBsAg and HBeAg in a concentration-dependent manner with no cytotoxic effects and without any effects on the expression of viral transcripts. Concentration- and time-dependent reductions in virion production were also observed. The inhibition of virion production was comparable to that of lamivudine and EC(50) values of 1.63 and 2.96 microM were obtained for compound 1i and lamivudine, respectively. Thus, in addition to the antiviral effects on RNA viruses, oxadiazoles also have anti-HBV activities.
[reaction: see text] The preparation of pyrazoline and isoxazoline derivatives with traceless solid-phase sulfone linker strategy is described. Key steps involved in the solid-phase synthetic procedure include (i) sulfinate S-alkylation, (ii) sulfone anion alkylation, (iii) gamma-hydroxy sulfone --> gamma-ketosulfone oxidation, and (iv) traceless product release via elimination-cyclization. A library of 12 pyrazolines and isoxazolines was synthesized.
[formula: see text] The preparation of the first library of imidazo[1,2-a]pyridine derivatives on a solid support is described. A sulfone linker strategy was applied in the synthesis. Key steps involved in the solid-phase synthetic procedure include (i) alpha-haloketone resin formation by sulfinate-->sulfone alkylation, (ii) imidazo[1,2-a]pyridine ring formation by treatment with 2-aminopyridine, (iii) sulfone anion alkylation, and (iv) traceless product release by oxidation-elimination. A library of 12 imidazo[1,2-a]pyridines was synthesized.
The preparation of substituted imidazoles, thiazoles, and oxazoles using traceless solid-phase sulfone linker strategy is described. Key steps involved are (i) sulfinate acidification, (ii) sulfinic acid condensation with aldehyde and amine, and (iii) traceless product release by a one-pot elimination-cyclization reaction. The elimination reaction was carried out in the presence of a thiazolium catalyst that facilitated the in situ formation of the alpha-ketoamide, which was subsequently converted to the corresponding imidazoles, oxazoles, and thiazoles by treatment with amines, PPh(3)/I(2) or Lawesson's reagent. A library of 18 compounds was synthesized.
The preparation of pyrimidine-2-thione, pyrimidine-2-one, pyrimidine, and benzo[b][1,4]diazepine derivatives using traceless solid-phase sulfone linker strategy is described. Key steps involved are (i) sulfinate S-alkylation, (ii) sulfone anion alkylation with an epoxide, (iii) gamma-hydroxyl sulfone --> gamma-ketosulfone oxidation, and (iv) traceless product release by a one-pot elimination-cyclization process. Elimination-cyclization was carried out under basic conditions with thiourea, methyl thiourea, methyl urea, guanidine hydrochloride, benzamidine hydrochloride and ortho-phenylene diamine. Twenty-three compounds were prepared, and 14 of them were evaluated by the Batrachotoxin (BTX) radioligand binding assay for their binding affinity to neuronal sodium channels. Compound 7c was found to be a potential neuronal sodium channels blocker.
The facile preparation of 3,4-dihydropyrimidine-2-one derivatives with traceless solid-phase sulfone linker strategy is described. Key steps involved in the solid-phase synthetic procedure include (i) sulfinate acidification, (ii) condensation of urea or thiourea with aldehydes and sulfinic acid, and (iii) traceless product release via a one-pot cyclization-dehydration process. A library of 18 compounds was synthesized.
A highly regioselective and traceless solid-phase route to N1,N7-disubstituted purines has been developed. Key steps in the reaction strategy involves (i) coupling of 6-chloropurine to the REM resin (Michael addition), (ii) oxidation, (iii) N1-alkylation, (iv) quaternization, and (v) product release through Hofmann elimination. A library of 15 N1,N7-disubstituted purines was synthesized.
A first solid-phase route to 1,3-substituted xanthines has been developed using PS-MB-CHO resin. Cyclocondensation of the polymer-bound aminoimidazole with isocyanates followed by alkylation provided 1,3-substituted xanthines in high yields. Libraries of 12 xanthines and 4 thioxanthines were prepared.
A microwave-assisted parallel synthesis of 2,4-disubstituted 5-aminoimidazoles has been developed. Significant rate enhancement was observed for all steps in the three-step protocol. The overall reaction time was shortened to 25 min, as compared to 53 h for the conventional procedures. A representative set of 2,4-disubstituted 5-aminoimidazoles was prepared using commercially available parallel reactors.
A traceless solid-phase route to substituted xanthines, based on the late-stage pyrimidine ring closure, has been developed. This method is especially useful for the preparation of xanthines containing a variety of substituents at the N1, N3, N7, and C8 positions in an unambiguous manner. A representative set of 22 compounds was prepared.