波谱学杂志 >

2021 , Vol. 38 >Issue 3: 313 - 322

DOI: https://doi.org/10.11938/cjmr20202874

研究论文

盐酸四环素中可交换氢和氢键的核磁共振波谱研究

  • 谢金华 ,
  • 王乐 ,
  • 刘盼 ,
  • 苏稀琪 ,
  • MINGLi-June
展开
  • 1. 上海工程技术大学 化学化工学院, 上海 201620
    2. Department of Chemistry, University of South Florida, Tampa, FL 33620-5250
    3. 宁波大学 新药技术学院, 浙江 宁波 315211

收稿日期: 2020-11-19

  网络出版日期: 2020-12-31

收起

An NMR Spectroscopy Study on the Exchangeable Protons and Hydrogen Bonds in Tetracycline Hydrochloride

  • Jin-hua XIE ,
  • Le WANG ,
  • Pan LIU ,
  • Xi-qi SU ,
  • Li-June MING
Expand
  • 1. College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201620, China
    2. Department of Chemistry, University of South Florida, Tampa, FL 33620-5250, USA
    3. Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China

Received date: 2020-11-19

  Online published: 2020-12-31

Fold

摘要

四环素类抗生素是一类广谱抗生素，对革兰氏阳性菌、革兰氏阴性菌、支原体、衣原体和立克次体感染均具有抗菌活性.本文运用一维（1D）和二维（2D）核磁共振（NMR）技术对盐酸四环素中可交换氢和氢键进行研究，并将研究结果与RNA和蛋白质结合的四环素以及游离药物的晶体结构进行比较，进一步讨论了药物中的氢键构架与药物活性的相关性.最后对盐酸四环素及其同系物的1H和13C NMR信号进行了全归属和分析，并对文献归属结果进行了细微校正.这些结果有助于进一步探索该类药物在更复杂的生物或环境系统中的构效关系.

关键词： 核磁共振; 四环素; 交换氢; 氢键

本文引用格式

谢金华 , 王乐 , 刘盼 , 苏稀琪 , MINGLi-June . 盐酸四环素中可交换氢和氢键的核磁共振波谱研究[J]. 波谱学杂志, 2021 , 38(3) : 313 -322 . DOI: 10.11938/cjmr20202874

Abstract

Tetracyclines are a class of broad-spectrum antibiotics that have antibacterial activities against Gram-positive and Gram-negative bacteria, including Mycoplasma, Chlamydia, and Rickettsia. In this paper, we report the one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) studies on the exchangeable protons and hydrogen bound in tetracycline hydrochloride (TC). The NMR results were compared with the results obtained from the crystal structures of free tetracycline and RNA- and protein-bound complexes. The H-bonding frameworks in the drug and their correlation with drug activity were discussed. The1H and 13C NMR signals of TC and its derivatives were fully assigned and interpreted, and the misassigned signals in previous reports were corrected. The results of this study could be conducive to further exploration of the structure-function correlation of this drug family in more complex biological and environmental systems.

Key words： NMR; tetracycline; exchangeable protons; hydrogen bond

参考文献

1 FUOCO D . Classification framework and chemical biology of tetracycline-structure-based drugs[J]. Antibiotics, 2012, 1 (1): 1- 3.
2 CHOPRA I , ROBERTS M . Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance[J]. Microbiol Mol Biol R, 2001, 65 (2): 232- 260.
3 PRINGLE M , FELLSTROM C , JOHANSSON K E . Decreased susceptibility to doxycycline associated with a 16S rRNA gene mutation in Brachyspira hyodysenteriae[J]. Vet Microbiol, 2007, 123 (1): 245- 248.
4 ONAL A . Overview on liquid chromatographic analysis of tetracycline residues in food matrices[J]. Food Chem, 2011, 127 (1): 197- 203.
5 RAHNAN M S , KOH Y S . Omadacycline, a magic antibiotics for bacterial infections[J]. JBV, 2018, 48 (3): 109- 112.
6 NELSON M L , LEVY S B . The history of the tetracyclines[J]. Ann Acad Sci, 2011, 1241 (1): 17- 32.
7 CHEN Y , CAI Z , KE Z . Antineuroinflammation of minocycline in stroke[J]. Neurologist, 2017, 22 (4): 120- 126.
8 CLAUDIA B , GIULIA S , PIETRO L V , et al. Doxycycline counteracts neuroinflammation restoring memory in Alzheimer's disease mouse models[J]. Neurobiol Aging, 2018, 70, 128- 139.
9 KIM H S , SUH Y H . Minocycline and neurodegenerative diseases[J]. Behav Brain Res, 2009, 196 (2): 168- 179.
10 GARRIDO-MESA N , ZARZUELO A , GALVEZ J . What is behind the non-antibiotic properties of minocycline?[J]. Pharmacol Res, 2013, 67 (1): 18- 30.
11 RAVA M , D'ANDREA A , NICOLI P , et al. Therapeutic synergy between tigecycline and venetoclax in a preclinical model of MYC/BCL2 double-hit B cell lymphoma[J]. Sci Transl Med, 2018, 10 (426): 1- 9.
12 ZHANG T , NONG J , ALZAHRANI N , et al. Self-assembly of DNA-minocycline complexes by metal ions with controlled drug release[J]. ACS Appl Mater Inter, 2019, 11 (33): 29512- 29521.
13 PULICHARLA R , HEGDE K , BRAR S K , et al. Tetracyclines metal complexation: Significance and fate of mutual existence in the environment[J]. Environ Pollut, 2017, 221, 1- 14.
14 OU M , ZHANG Z , WEN Y , et al. Cytotoxic study in the treatment of tetracycline by using magnetic Fe3O4-PAMAM-antibody complexes[J]. Environ Chem Lett, 2019, 17 (1): 543- 549.
15 CHEN G , ZHAO L , DONG Y H . Oxidative degradation kinetics and products of chlortetracycline by manganese dioxide[J]. J Hazard Mater, 2011, 193, 128- 138.
16 DAGHRIR R , DROGUI P . Tetracycline antibiotics in the environment: a review[J]. Environ Chem Lett, 2013, 11 (3): 209- 227.
17 WANG X , RYU D , HOUTKOOPER R H , et al. Antibiotic use and abuse: A threat to mitochondria and chloroplasts with impact on research, health, and environment[J]. Bioessays, 2015, 37 (10): 1045- 1053.
18 YANG L H , YING G G , SU H C , et al. Growth-inhibiting effects of 12 antibacterial agents and their mixtures on the freshwater microalga Pseudokirchneriella subcapitata[J]. Environ Toxicol Chem, 2008, 27 (5): 1201- 1208.
19 WITTENAU M S V , BLACKWOOD R K . Proton magnetic resonance spectra of tetracyclines[J]. J Org Chem, 1966, 31 (2): 613- 615.
20 ASELSON G L , STOEL L J , NEWMAN E C , et al. NMR spectra of tetracyclines: Assignment of additional protons[J]. J Pharm Sci-us, 1974, 63 (7): 1144- 1146.
21 CASY A F , YASIN A . The identification and stereochemical study of tetracycline antibiotics by 1H nuclear magnetic resonance spectroscopy[J]. J Pharmaceut Biomed, 1983, 1 (3): 281- 292.
22 CASY A F , YASIN A . Stereochemical studies of tetracycline antibiotics and their common impurities by 400 MHz 1H NMR spectroscopy[J]. Magn Reson Chem, 1985, 23 (9): 767- 770.
23 BRODERSEN D E , CLEMONS W M , CARTER A P , et al. The structural basis for the action of the antibiotics tetracycline, pactamycin, and hygromycin B on the 30S ribosomal subunit[J]. Cell, 2000, 103 (7): 1143- 1154.
24 HEFFRON S E , MUI S , AORORA A , et al. Molecular complementarity between tetracycline and the GTPase active site of elongation factor Tu[J]. Acta Crystallogr Section D Biol Crystallogr, 2006, 62 (11): 1392- 1400.
25 ASLESON G L , FRANK C W . Carbon-13 nuclear magnetic resonance spectral analysis of tetracycline hydrochloride and related antibiotics[J]. J Am Chem Soc, 1975, 97 (21): 6246- 6248.
26 MAZZOLA E P , MELIN J A , WAYLAND L G . 13C-NMR spectroscopy of three tetracycline antibiotics: Minocycline hydrochloride, meclocycline, and rolitetracycline[J]. J Pharm Sci, 1980, 69 (2): 229- 230.
27 CASY A F , YASIN A . Application of 13C nuclear magnetic resonance spectroscopy to the analysis and structural investigation of tetracycline antibiotics and their common impurities[J]. J Pharmaceut Biomed, 1984, 2 (1): 19- 36.
28 MOOIBROEK S , WASYLISHEN R E . A carbon-13 nuclear magnetic resonance study of solid tetracyclines[J]. Can J Chem, 1987, 65 (2): 357- 362.
29 TAKEUCHI Y , IMAFUKU Y , NISHIKAWA M . Reassignment of the 13C NMR spectrum of minomycin[J]. ARKIVOC, 2003, 2003 (15): 39- 46.
30 ORTH P , SCHNAPPINGER D , HILLEN W , et al. Structural basis of gene regulation by the tetracycline inducible Tet repressor-operator system[J]. Nat Struct Biol, 2000, 7 (3): 215- 219.
31 STEZOWSHI J J . Chemical-structural properties of tetracycline derivatives. 1. Molecular structure and conformation of the free base derivatives[J]. J Am Chem Soc, 1976, 98 (19): 6012- 6018.
32 STEZOWSHI J J . Chemical-structural properties of tetracycline antibiotics. 4. Ring A tautomerism involving the protonated amide substituent as observed in the crystal structure of alpha-6-deoxyoxytetracycline hydrohalides[J]. J Am Chem Soc, 1977, 99 (4): 1122- 1129.
33 CAIRA MINO R , NASSIMBENI LUIGI R , RUSSELL JILL C . The Crystal and molecular structure of tetracycline hexahydrate[J]. Acta Cryst, 1977, B33, 1171- 1176.
34 PALENIK G J , BENTLEY J A . Structural studies of tetracyclines. Crystal and molecular structure of tetracycline methyl betaine pentahydrate[[J]. J Am Chem Soc, 1978, 100 (9): 2863- 2867.
35 HUGHES L J , STEZOWSKI J J , HUGHES R E . Chemical-structural properties of tetracycline derivatives. 7. Evidence for the coexistence of the zwitterionic and nonionized forms of the free base in solution[J]. J Am Chem Soc, 1979, 101 (26): 7655- 7657.
36 BORDNER J . Structure of β-6-deoxyoxytetracycline hydrochloride[J]. Acta Cryst, 1979, B35, 219- 222.
37 KOZIOL A E , DAVIS J , PALENIK R C , et al. Structural studies of two tetracyclines: 4-dedimethylaminotetracycline hydrate and 6-methylene-5-oxytetracycline hydrochloride[J]. J Cryst Spect Rese, 1992, 22 (4): 493- 501.
38 MING L J. Biological and biomedical aspects of metal phenolates[M]. PATAI'S Chemistry of Functional Groups. American Cancer Society, 2014.
39 HERSCHLAG D , PINNEY M M . Hydrogen bonds: Simple after all?[J]. Biochemistry, 2018, 57 (24): 3338- 3352.
40 CLELAND W W , FREY P A , GERLT J A . The low barrier hydrogen bond in enzymatic catalysis[J]. J Biol Chem, 1998, 44 (40): 25529- 25532.
41 MOCK W L , MORSCH L A . Low barrier hydrogen bonds within salicylate mono-anions[J]. Tetrahedron, 2001, 57 (15): 2957- 2964.
42 WALTER DURCKHEIMER . Tetracyclines: chemistry, biochemistry, and structure-activity relations[J]. Angew Chem Int Ed Engl, 1973, 14 (11): 721- 774.
Options
文章导航

/

〈 〉

网站设计版权所有 © 2017 《波谱学杂志》编辑部
地址：湖北省武汉市武昌区小洪山西30号 中科院精密测量科学与技术创新研究院波谱楼 《波谱学杂志》编辑部
邮编：430071　电话/传真：(086)027－87198791   E-mail: magres@wipm.ac.cn
本系统由北京玛格泰克科技发展有限公司设计开发