Practical Synthesis of a Potent Hepatitis C Virus RNA Replication Inhibitor

Bio, Matthew M.; Xu, Feng; Waters, Marjorie S.; Williams, J. M.; Savary, Kimberly; Cowden, Cameron J.; Yang, Chunhua; Buck, Elizabeth; Song, Zhiguo J.; Tschaen, David M.; Volante, R. P.; Reamer, Robert A.; Grabowski, Edward J. J.

doi:10.1021/jo0491096

Cited by 59 publications

(33 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Ketone compound 15 was prepared as described in the literature (2). A Grignard reaction with ethynylmagnesium bromide followed by protection of the tertiary alcohol by a 2,5-dichlorobenzyl group and deprotection of the acetonide furnished the diol compound 16.…”

Section: Chemistrymentioning

confidence: 99%

Inhibition of Dengue Virus RNA Synthesis by an Adenosine Nucleoside

Chen

Yin

Duraiswamy

et al. 2010

Antimicrob Agents Chemother

View full text Add to dashboard Cite

We recently reported that (2R,3R,4R,5R)-2-(4-amino-pyrrolo[2,3-d]pyrimidin-7-yl)-3-ethynyl-5-hydroxymethyl-tetrahydro-furan-3,4-diol is a potent inhibitor of dengue virus (DENV), with 50% effective concentration (EC 50 ) and cytotoxic concentration (CC 50 ) values of 0.7 M and >100 M, respectively. Here we describe the synthesis, structure-activity relationship, and antiviral characterization of the inhibitor. In an AG129 mouse model, a single-dose treatment of DENV-infected mice with the compound suppressed peak viremia and completely prevented death. Mode-of-action analysis using a DENV replicon indicated that the compound blocks viral RNA synthesis. Recombinant adenosine kinase could convert the compound to a monophosphate form. Suppression of host adenosine kinase, using a specific inhibitor (iodotubercidin) or small interfering RNA (siRNA), abolished or reduced the compound's antiviral activity in cell culture. Studies of rats showed that 14 C-labeled compound was converted to mono-, di-, and triphosphate metabolites in vivo. Collectively, the results suggest that this adenosine inhibitor is phosphorylated to an active (triphosphate) form which functions as a chain terminator for viral RNA synthesis.The family Flaviviridae consists of three genera, Flavivirus, Pestivirus, and Hepacivirus. Many viruses from the genus Flavivirus are arthropod-borne and cause significant human diseases. The four serotypes of dengue virus (DENV) alone pose a health threat to 2.5 billion people worldwide, leading to 50 to 100 million human infections and 500,000 cases of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) each year (11). Besides DENV, other flaviviruses, such as West Nile virus (WNV), Japanese encephalitis virus (JEV), yellow fever virus (YFV), and tick-borne encephalitis virus (TBEV), also cause frequent outbreaks throughout the world. No clinically approved antiviral therapy is currently available for treatment of flavivirus infections. Human vaccines are available only for YFV, JEV, and TBEV. The development of a successful DENV vaccine has been challenging due to the facts that (i) the vaccine should simultaneously induce a long-lasting protection against all four DENV serotypes and (ii) an incompletely immunized individual may be sensitized to the lifethreatening DHF or DSS. The challenge associated with the development of a vaccine underlines the importance of antiviral development for DENV and other flaviviruses.The flavivirus genome is a single-strand RNA of plus-sense polarity. The single open reading frame from the 11-kb viral genome encodes three structural proteins (capsid [C], premembrane [prM], and envelope [E]) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Nonstructural proteins are responsible for viral replication. Of those, NS3 and NS5 have enzymatic activities. The N-terminal domain of NS3 (with NS2B as a cofactor) functions as a serine protease, and the C-terminal domain acts as an RNA helicase, an RNA triphosphatase, and an NTPase (10,34,35). The N-...

show abstract

Section: Chemistrymentioning

confidence: 99%

Inhibition of Dengue Virus RNA Synthesis by an Adenosine Nucleoside

Chen

Yin

Duraiswamy

et al. 2010

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…经过近 30 年的发展, Vorbrüggen 糖基化反应(SilylHilbert-Johnson reaction)已经成为核苷合成的标准方法之一 [13] , 但是该反应在 7-去氮嘌呤核苷的合成中一直没有成功, 其原因可能是由于其 N-9 位的 NH 较之正常的嘌呤碱基(腺嘌呤或者鸟嘌呤)N-9 位的 NH 碱性增强, 因此在 Vorbrüggen 糖基化反应中不能有效进攻路易酸(通常为三氟甲磺酸三甲基硅酯, TMSOTf)作用下形成的端头氧嗡离子 [14] .…”

Section: Figureunclassified

“…方法一: Ar 气保护下, 6-氯-7-溴-吡咯[2, 3-d]嘧啶 (7) ( (7) 14,165.40,165.10,152.73,151.63,150.71,133.88,133.65,129.86,129.70,129.23,128.83,128.62,128.57,128.32,126.49,115.93,90.18,86.71,80.63,74.09,71.37,63.47;MS (ESI) (11) …”

Section: -氯-7-溴-9-(235-o-三苯甲酰基-β-d-呋喃核糖基)-吡咯[23-d]嘧啶(11)的合成mentioning

confidence: 99%

An Improved Total Synthesis of Tubercidin

Huang¹,

Ruan²,

Hu³

et al. 2014

Chin. J. Org. Chem.

View full text Add to dashboard Cite

Tubercidin is a naturally occurring pyrrolo [2,3-d]pyrimidine nucleoside with significantly biological activities, such as anti-schistosomal, antibacterial and antitumor. An improved total synthesis of tubercidin is reported using microwave promoted Vorbrüggen glycosylation as the key step. Thus, tubercidin was synthesized in 3 steps with 74% overal yield using 6-chloro-7-bromo-pyrrolo[2,3-d]pyrimidine and 1-O-acetyl-2,3,5-O-tribenzoyl-β-D-ribose as starting materials. The application of micromave irridated one-pot reaction is also reported in the synthesis of 7-deazapurine nucleosides using potassium nonafluoro-1-butanesulfonate, trimethylsilyl chloride and silylation reagent [hexamethyldisilazane or N,O-bis(trimethylsilyl)acetamide].

show abstract

“…It could be successfully achieved by the pathway shown in Chart 1. The geminal dicyano intermediate 2 was prepared from compound 1 21) with malononitrile by heating in N,N-dimethylformamide (DMF) in the presence of anhydrous K 2 CO 3 . Synthesis of compound 3 was carried out by refluxing 2 with thiourea in the presence of potassium tert-butoxide.…”

mentioning

confidence: 99%

Diarylureas and Diarylamides with Pyrrolo[2,3-<i>d</i>]pyrimidine Scaffold as Broad-Spectrum Anticancer Agents

El‐Gamal

2014

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

Cancer is a generic term for a large group of diseases that can affect any part of the body. Lung, stomach, liver, colon, and breast cancer cause the most cancer deaths each year. About 30% of cancer deaths are due to the five leading behavioral and dietary risks: high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco use, and alcohol intake. More than 70% of all cancer deaths occurred in low-and middle-income countries. Deaths from cancer worldwide are projected to exceed 13 million in 2030.1) In spite of the extensive efforts and investment in research, the management of human malignancies still constitutes a major challenge for contemporary medicinal chemistry. There has been an urgent need for development of more efficient anticancer agents with minimal side effects.Diarylureas and diarylamides have been highlighted as potential antiproliferative agents against a variety of cancer cell lines.2-17) Sorafenib (Nexavar ® , Fig. 1) is an example of anticancer diarylureas that has been approved by the U.S. Food and Drug Administration (FDA) for treatment of advanced renal cancer.18) It has also been approved in Europe for treatment of hepatocellular carcinoma (HCC).19) Sorafenib is currently subjected to clinical trials for other types of cancer. Imatinib (Gleevec ® , Fig. 1) is an example of diarylamides which is used for treatment of chronic myeloid leukemia (CML) with diminished side effects. 20)The target pyrrolo [2,3-d] pyrimidine compounds were designed as conformationally restricted analogs of Sorafenib by isosteric replacement of the 4-phenoxypyridine moiety of the lead compound with a pyrrolo[2,3-d] pyrimidine nucleus (Fig. 1). The 50% inhibitory concentration (IC 50 ) values for most of the target compounds over A375P human melanoma cell line only were previously reported.2,3) Upon further testing over NCI-60 cancer cell line panel of nine different cancer types, the target compounds showed broad-spectrum anticancer activities with high efficacies and potencies. Herein the biological results are reported in details. Results and DiscussionChemistry The target pyrrolo[2,3-d] pyrimidine diarylureas and diarylamides were synthesized by the pathway of reactions illustrated in Charts 2-4.

show abstract

Practical Synthesis of a Potent Hepatitis C Virus RNA Replication Inhibitor

Cited by 59 publications

References 18 publications

Inhibition of Dengue Virus RNA Synthesis by an Adenosine Nucleoside

Inhibition of Dengue Virus RNA Synthesis by an Adenosine Nucleoside

An Improved Total Synthesis of Tubercidin

Diarylureas and Diarylamides with Pyrrolo[2,3-<i>d</i>]pyrimidine Scaffold as Broad-Spectrum Anticancer Agents

Contact Info

Product

Resources

About