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Chandra, Girish,Moon, Yang Won,Lee, Yoonji,Jang, Ji Yong,Song, Jayoung,Nayak, Akshata,Oh, Kawon,Mulamoottil, Varughese A.,Sahu, Pramod K.,Kim, Gyudong,Chang, Tong-Shin,Noh, Minsoo,Lee, Sang Kook,Choi, American Chemical Society 2015 Journal of medicinal chemistry Vol.58 No.12
<P>On the basis of the potent inhibitory activity of neplanocin A (1) against S-adenosylhomocysteine (AdoHcy) hydrolase, we analyzed the comprehensive structure-activity relationships by modifying the adenine and carbasugar moiety of 1 to find the pharmacophore in the active site of the enzyme. The introduction of 7-deazaadenine instead of adenine eliminated the inhibitory activity against the AdoHcy hydrolase, while 3-deazaadenine maintained the inhibitory activity of the enzyme, indicating that N-7 is essential for its role as a hydrogen bonding acceptor. The substitution of hydrogen at the 6'-position with fluorine increased the inhibitory activity Of the enzyme. The one-carbon homologation at the 5'-position generally decreased the inhibitory activity of the enzyme, indicating that steric repulsion exists. A molecular docking study also supported these experimental data. In this study, 6'-fluoroneplanocin A (2) was the most potent inhibitor of AdoHcy hydrolase (IC50 = 0.24 mu M). It showed a potent anti-VSV activity (EC50 = 0.43 mu M) and potent anticancer activity in all the human tumor cell lines tested.</P>
Asymmetric Synthesis of (−)-6′-β-Fluoro-aristeromycin via Stereoselective Electrophilic Fluorination
Kim, Gyudong,Yoon, Ji-seong,Jarhad, Dnyandev B.,Shin, Young Sup,Majik, Mahesh S.,Mulamoottil, Varughese A.,Hou, Xiyan,Qu, Shuhao,Park, Jiyong,Baik, Mu-Hyun,Jeong, Lak Shin THE AMERICAN CHEMICAL SOCIETY 2017 ORGANIC LETTERS Vol.19 No.21
<P>(-)-6 '-beta-Fluoro-aristeromycin (2), a potent inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase, has been synthesized via stereoselective electrophilic fluorination followed by a purine base build-up approach. Interestingly, purine base condensation using a cyclic sulfate resulted in a synthesis of (+)-5 '-beta-fluoro-isoaristeromycin (2a). Computational analysis indicates that the fluorine atom controlled the regioselectivity of the purine base substitution.</P>
Design, synthesis and anticancer activity of fluorocyclopentenyl-purines and – pyrimidines
Yoon, Ji-seong,Jarhad, Dnyandev B.,Kim, Gyudong,Nayak, Akshata,Zhao, Long Xuan,Yu, Jinha,Kim, Hong-Rae,Lee, Ji Yun,Mulamoottil, Varughese A.,Chandra, Girish,Byun, Woong Sub,Lee, Sang Kook,Kim, Yong-Ch Elsevier 2018 European journal of medicinal chemistry Vol.155 No.-
<P><B>Abstract</B></P> <P>Based on the potent anticancer activity of 6′-fluorocyclopentenyl-cytosine <B>2b</B> in phase IIa clinical trials for the treatment of gemcitabine-resistant pancreatic cancer, we carried out a systematic structure-activity relationship study of 6′-fluorocyclopentenyl-pyrimidines <B>3a</B>-<B>i</B> and -purines <B>3j</B>-<B>o</B> to discover novel anticancer agents. We also synthesized the phosphoramidate prodrug <B>3p</B> of adenine derivative <B>1b</B> to determine if the anticancer activity depended on the inhibition of DNA and/or RNA polymerase in cancer cells and/or on the inhibition of <I>S</I>-adenosylhomocysteine (SAH) hydrolase. All of the synthesized pyrimidine nucleosides exhibited much less potent anticancer activity <I>in vitro</I> than the cytosine derivative <B>2b</B>, acting as RNA and/or DNA polymerase inhibitor, indicating that they could not be efficiently converted to their triphosphates for anticancer activity. Among all the synthesized purine nucleosides, adenine derivative <B>1b</B> and <I>N</I> <SUP>6</SUP>-methyladenine derivative <B>3k</B> showed potent anticancer activity, showing equipotent inhibitory activity as the positive control, neplanocin A (<B>1a</B>) or Ara-C. However, the phosphoramidate prodrug <B>3p</B> showed less anticancer activity than <B>1b</B>, indicating that it did not act as a RNA and/or DNA polymerase inhibitor like <B>2b</B>. This result also demonstrates that the anticancer activity of <B>1b</B> largely depends on the inhibition of histone methyltransferase, resulting from strong inhibition of SAH hydrolase. The deamination of the <I>N</I> <SUP>6</SUP>-amino group, the addition of the bulky alkyl group at the <I>N</I> <SUP>6</SUP>-amino group, or the introduction of the amino group at the C2 position almost abolished the anticancer activity.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Eighteen 6′-fluorocyclopentenyl-pyrimidines and -purines were designed and synthesized. </LI> <LI> The mechanism of action of the cytosine analog <B>2b</B> is related to the inhibition of DNA/RNA polymerase. </LI> <LI> The mechanism of action of the adenosine analogs, <B>1b</B> and <B>3k</B> is related to the inhibition of SAH hydrolase. </LI> <LI> The inhibition of SAH hydrolase is associated with the inhibition of histone methyltransferase. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>