아데노신 A3 수용체 작용물질인 새로운 핵산 유도체의 개발
- 아데노신 A3 수용체 작용물질인 새로운 핵산 유도체의 개발
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- Nucleosides are very active and important biomolecules. Most people think that the main role of nucleosides is ‘saving’ genetic information in our DNA, but this is only on side of nucleosides function. Especially adenosine has a lot of other functions. Adenosine plays important roles as a neurotransmitter, signal transmitter (cAMP is second messenger), and energy transfer agent (ATP) during cell regulation. The first seven HIV drugs were modified nucleosides discovered at university or research institutes and not in a big pharmaceutical company. In our body there are over 2000 enzymes related to nucleosides. Therefore modified nucleosides are an important drug class and the chance to find a lead-compound is better than pure chemically synthesized compounds. One of the first anticancer drug-class and antiviral drug-class were modified nucleosides. Since that time many other class of anticancer and antiviral drugs are developed (for example protein kinase inhibitor as anticancer drug and protease inhibitor as antiviral drugs). For university and research institutes with limited budget is the focus on modified nucleosides a good method to develop novel drugs.
1.1. Synthesis of 5-Isoxazol-5-yl-2´-deoxyuridines Exhibiting Antiviral Activity Against HSV and Several RNA Viruses
We describe a simple method for synthesizing a small library of 5-isoxazol-5-yl-2´-deoxyuridines from 5-iodo-2´-deoxyuridine. Nitrile oxides were generated in situ from oximes using a commercial bleaching agent
their cycloaddition with 5-ethynyl-2´-deoxyuridine yielded isoxazoles possessing activity against herpes simplex viruses 1 and 2, Encephalomyocarditis virus, Coxsackie B3, and vesicular stomatitis virus
these isoxazoles were, however, inactive against corona virus, influenza virus, and HIV.
1.2. C5-Modified Nucleosides Exhibiting Anticancer Activity
We describe (i) a simple method for the synthesis of C5-modified nucleosides from 5-iodo-2´-deoxyuridine and (ii) their activity against six types of human cancer cell lines (HCT15, MM231, NCI-H23, NUGC-3, PC-3, ACHN). We generated nitrile oxides in situ from oximes using a commercial bleaching agent
their cycloadditions with 5-ethynyl-2´-deoxyuridine yielded isoxazole derivatives possessing activity against the cancer cell lines. We synthesized several azides from benzylic bromides and their click reactions with 5-ethynyl-2´-deoxyuridine provided triazole derivatives.
A novel method was carried out to reduce the 5 steps literature synthesis scheme for C5-azide-2’-deoxyuridine to one step reaction.
2.1 Novel adenosine scaffolds displaying in vitro and in vivo anticancer activities
We have prepared novel N6-modified adenosines exhibiting in vitro and in vivo anticancer activities. Based on the concept that we could increase the anticancer activity by reducing of the flexibility of the benzyl ring, we synthesized 23 nucleosides through mild PyBOP-mediated couplings using inosine as the starting material and then tested these modified adenosines against six different human cancer cell lines (HCT15, MM231, NCI-H23, NUGC-3, PC-3, ACHN). We performed an in vivo tumor xenocraft study of the compound displaying best activity in the cancer cell assay. Our tetrahydrothienopyridine-containing nucleoside 24 reduced the value of tumor growth inhibition after 11 days by 35.0%
the toxicity of our compound is lower than that of the cancer drug Nexavar. Nexavar treated mice lost 8.1% weight in average, but our compound treated mice lost only 2.0% weight in average.
2.2 N6-Propargyl modified adenosine scaffolds showing in anticancer and rheumatoid arthritis activities
We have prepared novel N6-modified adenosines contain an acetylene moiety as A2a and A3 Adenosine Receptor agonists. However the compound with good in vitro anticancer activity showed no activity in vivo experiment. Compounds from same scaffold showed very good anti rheumatoid activity in vivo experiment.
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