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Title: 6-Cyclohexylmethyl-3-hydroxypyrimidine-2,4-dione as an inhibitor scaffold of HIV reverase transcriptase: Impacts of the 3-OH on inhibiting RNase H and polymerase

Abstract

3-Hydroxypyrimidine-2,4-dione (HPD) represents a versatile chemical core in the design of inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated RNase H and integrase strand transfer (INST). We report herein the design, synthesis and biological evaluation of an HPD subtype (4) featuring a cyclohexylmethyl group at the C-6 position. Antiviral testing showed that most analogues of 4 inhibited HIV-1 in the low nanomolar to submicromolar range, without cytotoxicity at concentrations up to 100 μM. Biochemically, these analogues dually inhibited both the polymerase (pol) and the RNase H functions of RT, but not INST. Co-crystal structure of 4a with RT revealed a nonnucleoside RT inhibitor (NNRTI) binding mode. Interestingly, chemotype 11, the synthetic precursor of 4 lacking the 3-OH group, did not inhibit RNase H while potently inhibiting pol. Here, by virtue of the potent antiviral activity and biochemical RNase H inhibition, HPD subtype 4 could provide a viable platform for eventually achieving potent and selective RNase H inhibition through further medicinal chemistry.

Authors:
 [1];  [2];  [2];  [2];  [2];  [1];  [2];  [1]
+ Show Author Affiliations
  1. Univ. of Minnesota, Minneapolis, MN (United States)
  2. Univ. of Missouri School of Medicine, Columbia, MO (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Inst. of Health
OSTI Identifier:
1349118
Alternate Identifier(s):
OSTI ID: 1419352
Grant/Contract Number:  
AC02-06CH11357; AI100890
Resource Type:
Accepted Manuscript
Journal Name:
European Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 128; Journal Issue: C; Journal ID: ISSN 0223-5234
Publisher:
Elsevier
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 3-Hydroxypyrimidine-2,4-dione (HPD); human immunodeficiency virus (HIV); RNase H; polymerase; inhibitors

Citation Formats

Tang, Jing, Kirby, Karen A., Huber, Andrew D., Casey, Mary C., Ji, Juan, Wilson, Daniel J., Sarafianos, Stefan G., and Wang, Zhengqiang. 6-Cyclohexylmethyl-3-hydroxypyrimidine-2,4-dione as an inhibitor scaffold of HIV reverase transcriptase: Impacts of the 3-OH on inhibiting RNase H and polymerase. United States: N. p., 2017. Web. doi:10.1016/j.ejmech.2017.01.041.
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Tang, Jing, Kirby, Karen A., Huber, Andrew D., Casey, Mary C., Ji, Juan, Wilson, Daniel J., Sarafianos, Stefan G., & Wang, Zhengqiang. 6-Cyclohexylmethyl-3-hydroxypyrimidine-2,4-dione as an inhibitor scaffold of HIV reverase transcriptase: Impacts of the 3-OH on inhibiting RNase H and polymerase. United States. https://doi.org/10.1016/j.ejmech.2017.01.041
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Tang, Jing, Kirby, Karen A., Huber, Andrew D., Casey, Mary C., Ji, Juan, Wilson, Daniel J., Sarafianos, Stefan G., and Wang, Zhengqiang. Mon . "6-Cyclohexylmethyl-3-hydroxypyrimidine-2,4-dione as an inhibitor scaffold of HIV reverase transcriptase: Impacts of the 3-OH on inhibiting RNase H and polymerase". United States. https://doi.org/10.1016/j.ejmech.2017.01.041. https://www.osti.gov/servlets/purl/1349118.
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@article{osti_1349118,
title = {6-Cyclohexylmethyl-3-hydroxypyrimidine-2,4-dione as an inhibitor scaffold of HIV reverase transcriptase: Impacts of the 3-OH on inhibiting RNase H and polymerase},
author = {Tang, Jing and Kirby, Karen A. and Huber, Andrew D. and Casey, Mary C. and Ji, Juan and Wilson, Daniel J. and Sarafianos, Stefan G. and Wang, Zhengqiang},
abstractNote = {3-Hydroxypyrimidine-2,4-dione (HPD) represents a versatile chemical core in the design of inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated RNase H and integrase strand transfer (INST). We report herein the design, synthesis and biological evaluation of an HPD subtype (4) featuring a cyclohexylmethyl group at the C-6 position. Antiviral testing showed that most analogues of 4 inhibited HIV-1 in the low nanomolar to submicromolar range, without cytotoxicity at concentrations up to 100 μM. Biochemically, these analogues dually inhibited both the polymerase (pol) and the RNase H functions of RT, but not INST. Co-crystal structure of 4a with RT revealed a nonnucleoside RT inhibitor (NNRTI) binding mode. Interestingly, chemotype 11, the synthetic precursor of 4 lacking the 3-OH group, did not inhibit RNase H while potently inhibiting pol. Here, by virtue of the potent antiviral activity and biochemical RNase H inhibition, HPD subtype 4 could provide a viable platform for eventually achieving potent and selective RNase H inhibition through further medicinal chemistry.},
doi = {10.1016/j.ejmech.2017.01.041},
journal = {European Journal of Medicinal Chemistry},
number = C,
volume = 128,
place = {United States},
year = {Mon Jan 30 00:00:00 EST 2017},
month = {Mon Jan 30 00:00:00 EST 2017}
}
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https://doi.org/10.1016/j.ejmech.2017.01.041
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