Synthesis and biological evaluation of mixed phosphonate derivatives of substituted acyclonucleoside phosphonates

OU Yu; FU Xiaozhong; ZHA Yufeng; ZHANG Shun; SU Hang; DONG Yongxi

doi:10.11665/j.issn.1000-5048.20140605

Journal of China Pharmaceutical University > 2014 > 45(6): 649-656. > DOI: 10.11665/j.issn.1000-5048.20140605

OU Yu, FU Xiaozhong, ZHA Yufeng, ZHANG Shun, SU Hang, DONG Yongxi. Synthesis and biological evaluation of mixed phosphonate derivatives of substituted acyclonucleoside phosphonates[J]. Journal of China Pharmaceutical University, 2014, 45(6): 649-656. DOI: 10.11665/j.issn.1000-5048.20140605

Citation:

PDF (4436 KB)

Synthesis and biological evaluation of mixed phosphonate derivatives of substituted acyclonucleoside phosphonates

More Information

Graphical Abstract

Abstract

Abstract

In order to find structural optimization strategy for substituted mixed phosphonates of acyclonucleoside phosphonates, mono L-amino acid ester, mono NSAID carboxylic ester prodrugs of adefovir was used as lead compound. Based on the structural features of abacavir and alamifovir, sub-structure combination method was used to introduce substituted phenylthio or amino fragments at 6-position of purine ring. Therefore, purine ring substituted acyclonucleside phosphonate mixed phosphonate ester derivatives( 9a-9l )were designed and synthesized, and their structures were confirmed by ¹H NMR, ESI-MS, and ESI-HRMS. HepG2. 2. 2. 15 and HK-2 cell line were used for in vitro anti-HBV activity and renal cell toxicity evaluation models, respectively. Several compounds exhibited anti-HBV activity, of which compound 9a displayed the most potent antiviral activity with higher selectivity index(EC₅₀ 0. 48 μmol/L, SI 763. 72), lower renal cell toxicity, and higher chemical and enzymatic stability, making it a potential anti-HBV candidate for further investigation.
- acyclonucleoside phosphonate,
- abacavir,
- alamifovir,
- non-steroidal anti-inflammatory drugs,
- synthesis,
- antiviral activity

FullText(HTML)

References (13)

References

[1]	Trippier PC, Jansen Labby K, Hawker DD, et al. Target- and mechanism-based therapeutics for neurodegenerative diseases:strength in numbers[J].J Med Chem,2013,56(8):3 121-3 147.
[2]	Raney AK, Hamatake RK, Hong Z. Agents in clinical development for the treatment of chronic hepatitis B[J].Expert Opin Investig Drugs,2003,12(8):1 281-1 295.
[3]	Nozomu T,Kurenai T,Neeraja KH,et al.Adefovir nephrotoxicity:possible role of mitochondrial DNA depletion[J].Human Pathology,2001,32(7):734-740.
[4]	Sweet DH,Bush KT,Nigam SK.The organic anion transporter family:from physiology to ontogeny and the clinic[J].Am J Physiol Renal Physiol,2001,281(2):F 197-205.
[5]	Rubio-Aliaga I,Daniel H.Mammalian peptide transporters as targets for drug delivery[J].Trends Pharmacol Sci,2002,23(9):434-440.
[6]	Mulato AS,Ho ES,Cihlar T.Nonsteroidal anti-inflammatory drugs efficiently reduce the transport and cytotoxicity of adefovir mediated by the human renal organic anion transporter 1[J].J Pharmacol Exp Ther,2000,295(1):10-15.
[7]	Fu XZ,Ou Y,Pei JY,et al.Synthesis,anti-HBV activity and renal cell toxicity evaluation of mixed phosphonate prodrugs of adefovir[J].Eur J Med Chem,2012,49:211-218.
[8]	Ono-Nita SK,Kato N,Shiratori Y,et al.Novel nucleoside analogue MCC-478(LY582563)is effective against wild-type or lamivudine resistant hepatitis B virus[J].Antimicrob Agents Chemother,2002,46(8):2 602-2 605.
[9]	Murakami E,Bao H,Mosley RT,et al.Adenosine deaminase-like protein 1(ADAL1):characterization and substrate specificity in the hydrolysis of N (6)- or O(6)-substituted purine or 2-aminopurine nucleoside monophosphates[J].J Med Chem,2011,54(16):5 902-5 914.
[10]	Fu XZ,Ou Y,Xin J,et al.Design,synthesis and in vitro evaluation of mono(2,2,2- trifluoro -ethyl)esters,mono L-amino acid ester prodrugs of acyclic nucleoside phosphonates as anti- HBV agents[J].Chin Chem Lett,2011,22(12):1 387-1 389.
[11]	Fu XZ,Jiang SH,Yang YS,et al.Design,synthesis and anti-HBV activity of L-amino acid ester prodrugs of acyclic nucleoside phosphonates[J].Acta Pharm Sin(药学学报),2008,43(5):495-503.
[12]	Sells MA,Chen ML,Acs G.Production of hepatitis B virus particles in HepG2 cells transfected with cloned hepatitis B virus DNA[J].Proc Natl Acad Sci U S A,1987,84(4):1 005-1 009.
[13]	Ryan MJ,Johnson G,Kirk J,et al.HK-2:an immortalized proximal tubule epithelial cell line from normal adult human kidney[J].Kidney Int,1994,45(1):48-57.

[1]	ZHAO Xiaomei, WANG Xin, JI Xia, ZHANG Hua, ZHANG Pingping, HU Guoqiang. Synthesis and antitumor activities of 1, 2-benzothiazines［1, 3, 4］thiadiazolo［3, 2-a］［1, 3, 5］triazin derivatives[J]. Journal of China Pharmaceutical University, 2020, 51(1): 24-28. DOI: 10.11665/j.issn.1000-5048.20200104
[2]	LI Jing, REN Yuejiao, GUAN Su, ZHANG Lei. Synthesis and xanthine oxidase inhibitory activities of 2-phenyl-tetrahydrothiopyrano［4, 3-d］ pyrimidine derivatives[J]. Journal of China Pharmaceutical University, 2015, 46(3): 294-300. DOI: 10.11665/j.issn.1000-5048.20150306
[3]	DENG Lian-bai, LI Ai-xiu, JIN Yu-rui. Advances in the study on inhibitors of RNase H,a novel anti-HIV drug target[J]. Journal of China Pharmaceutical University, 2011, 42(6): 578-584.
[4]	DU Ping, ZHANG Di, ZHANG Guo-min, REN Shu-juan, GONG Guo-qing, XU Yun-gen. Synthesis and Na⁺/H⁺ exchanger 1 inhibitory activity of substituted benzoylguanidine-trimetazidine conjugates[J]. Journal of China Pharmaceutical University, 2011, 42(1): 22-28.
[5]	Synthesis and Biological Activity Study on N-( 3,4- Dimethoxyphenylethyl )-4-Subtituted Phenylpiperazine-1- Acetamide Series as α1-Adrenoceptor Antagonists[J]. Journal of China Pharmaceutical University, 2004, (1): 9-13.
[6]	Synthesis and Biologic Activities on 1-{1-[2-(3,4-Dimethoxy)Phenylethyl]-5-Cyano-6-Methyl-Uracil-3yl}-3-Substituted Amino-2-Propanol Compounds[J]. Journal of China Pharmaceutical University, 2003, (5): 10-13.
[7]	Synthesis andAntihypertensive Activity of 1-Phenylethyl(or 3,4-Dimethyloxyphenylethyl)-4-substitutedAryloxypiperidines[J]. Journal of China Pharmaceutical University, 2001, (3): 22-26.
[8]	Synthesis and Bioactivity of 1-Aryl-3-Alkyl-1, 4-Dihydro-4-Substituted-5H-1,2,4-triazolinones-5[J]. Journal of China Pharmaceutical University, 1999, (5): 323-327.
[9]	Synthesis and Inhibitor Activity to Phosphodiesterase of Thieno [3, 4-d] Pyrimidine-2,4-Dione Derivatives[J]. Journal of China Pharmaceutical University, 1991, (3): 142-144.
[10]	Synthesis of Thieno [3,4-d] Pyrimidine-2,4-Dione Derivatives[J]. Journal of China Pharmaceutical University, 1990, (4): 193-197.

Cited By

Get Citation

PDF

XML

Article views (1228) PDF downloads (1026)

Turn off MathJax

Article Contents

Abstract

References

Synthesis and biological evaluation of mixed phosphonate derivatives of substituted acyclonucleoside phosphonates

Abstract

References

Related Articles

Catalog

Synthesis and biological evaluation of mixed phosphonate derivatives of substituted acyclonucleoside phosphonates

Abstract

References

Related Articles

Catalog

Export File

Citation

Format

Content