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微生物次级代谢产物的化学结构十分复杂,对其绝对构型的确定十分困难。近年来,电子圆二色谱(electronic circular dichroism,ECD)由于其用量少、精度高等优点,在测定绝对构型方面的应用越来越多,已经成为研究微生物次级代谢产物结构的重要方法。本文就电子圆二色谱在微生物次级代谢产物结构研究中的应用进行综述,以期为今后的研究奠定基础。
The chemistry construction of microbial secondary metabolites is complex, and the determination of their absolute configuration is very difficult. In recent years, electronic circular dichroism (ECD) has been used more and more in the determination of absolute configuration due to its advantages of low dosage and high accuracy, and it has become an important method to study the structure of microbial secondary metabolites. In this paper, the application of ECD in the structure of microbial secondary metabolites was reviewed, which laid a foundation for future research.
微生物的次级代谢物多含立体化学中心,因其结构的多样性和复杂性而有多种药理性质,在药物研发领域具有重要价值[
圆二色性(circular dichroism,CD)[
1985年法国物理学家A. Cotton在研究光学活性物质的旋光性时发现了反常的旋光色散(optical rotatory dispersion,ORD)曲线,即直线偏振光透过旋光性物质时产生偏转的现象[
ECD是一种研究天然产物手性的方法,同时也是一种表征电子跃迁的光谱学方法。其测定原理与紫外光谱相似,所以都需要在溶剂中进行测试。化合物构象的分布遵从玻尔兹曼分布(boltzmann),除了刚性结构外,柔性分子在溶液中往往都含有多个构象,而因其具有的专属性导致每个构象都含有特定的ECD谱,所以一般通过NMR的相关信息来辅助构象分析[
首先要进行构象搜索来确定该分子在溶剂中低能量态构象及分布,目前能够进行构象搜索的软件有Maestro (conformational search)、HyperChem (HypercuBe,gainesville,FL)、Spartan (Wavefunction,Irvine,CA)、Insight (Accerlrys,SanDiego)和Confort (Triposte,MO)等[
ECD谱的计算流程
Calculation flow of ECD spectrum
ECD目前已经在天然产物绝对构型研究中广泛应用[
Chen等[
化合物1/2的实验和计算ECD光谱(在MeOH溶液中)
Experimental and calculated ECD spectra of compound 1/2 (in MeOH)
Li等[
实验和计算化合物3a/3b的ECD谱
Experimental and calculated ECD spectra of compound 3a/3b
Flaviphenalenones A (
实验和计算化合物4的ECD谱
Experimental and calculated ECD spectra of compound 4
Wang等[
实验和计算化合物5的ECD谱
Experimental and calculated ECD spectra of compound 5
Liu等[
化合物6的结构
Structure of compound 6
实验和计算化合物6/7的ECD谱[
Experimental and calculated ECD spectra of compound 6/7[
大多通过ECD确定绝对构型的天然产物都通过结合NMR的相关信息来辅助构象分析,但对于结构较复杂的化合物需要通过多种手性光学技术来协同确立其绝对构型,一般是ORD和振动圆二色谱(vibrational circular dichroism,VCD)。
Mazzeo等[
化合物8的结构
Structure of compound 8
实验和计算化合物8的ORD和ECD谱(在MeOH溶液中)[
Experimental and calculated ECD and ORD spectra of compound 8[
Zhu等[
实验和计算化合物9的ECD、ORD和VCD谱
Experimental and calculated ECD, VCD and ORD spectra of compound 9
Xu等[
实验和计算化合物10的ECD和VCD谱
Experimental and calculated ECD and VCD spectra of compound 10
本文通过综述ECD在微生物次级代谢产物中生物碱、萜类、聚酮类等化合物绝对构型确定方面的应用实例来阐明ECD与绝对构型的关系。微生物次级代谢产物近年来已经成为药物研发的重要方向,ECD的出现使其结构与功能的研究变得更加简单高效。实验ECD的敏感性和理论计算的简单性突出了其在确定天然产物绝对构型方面的优势,ECD的TDDFT计算更简化了ECD与绝对构型之间关系的阐明,也是天然产物绝对构型确定的一种很有前景的方法。ECD有一些固有的弱点和溶剂处理方法存在缺陷、对柔性结构过多和结构复杂的天然产物的计算时间过长的局限性,而且由于信号分辨率低,在不借助激发态量子力学计算的情况下很难将信号分配到特定的发色团位置。获得天然产物的绝对构型不只有一种途径,在柔性结构过多和复杂天然产物的情况下,可协同应用一种以上的手性光学技术来明确分配绝对构型。但是,随着计算技术的不断进步,ECD计算将成为发现先导化合物的有力工具。
Du FX, Guo XM, Yang L, et al. Natural medicinal products of fungal origin[J]. Microbiology China, 2019, 46(9): 2411-2418 (in Chinese)
杜凤翔, 郭晓媚, 杨琳, 等.真菌来源的药用天然产物[J].微生物学通报, 2019, 46(9): 2411-2418
Liu B, Chen N, Xu Y, et al. A new benzophenone with biological activities from metabolites of butyrolactone I in rat faeces[J]. Natural Product Research, 2019. DOI: 10.1080/14786419.2019.1680668
Bogdán D, Haessner R, Vágvölgyi M, et al. Stereochemistry and complete 1H and 13C NMR signal assignment of C-20-xime derivatives of posterone 2, 3-cetonide in solution state[J]. Magnetic Resonance in Chemistry, 2018, 56(9): 859-866
Liu B, Wang HF, Zhang LH, et al. Isolation of a new compound from
Zhang ZX, Wu PQ, Li HH, et al. Norcrassin A, a novel C16 tetranorditerpenoid, and bicrotonol A, an unusual dimeric labdane-type diterpenoid, from the roots of
Kuroda Y, Hasegawa K, Noguchi K, et al. Confirmation of the absolute configuration of Stachybotrin C using single-crystal X-ray diffraction analysis of its 4-bromobenzyl ether derivative[J]. The Journal of Antibiotics, 2018, 71(6): 584-591
Takada A, Hashimoto Y, Takikawa H, et al. Total synthesis and absolute stereochemistry of Seragakinone A[J]. Angew andte Chemie (International ed. in English), 2011, 50(10): 2297-2301 DOI: 10.1002/anie.201006528
Matsuo T, Hashimoto S, Nishikawa K, et al. Total synthesis and complete stereochemical assignment of heronapyrroles A and B[J]. Tetrahedron Letters, 2015, 56(39): 5345-5348
Yang HG, Liu XY, Li XY, et al. Enantioselective total synthesis of colomitides and their absolute configuration determination and structural revision[J]. Organic & Biomolecular Chemistry, 2017, 15(17): 3728-3735
Seco JM, Quiñoa, E, Riguera R. Assignment of the absolute configuration of polyfunctional compounds by NMR using chiral derivatizing agents[J]. Chemical Reviews, 2012, 112(8): 4603-4641
Abbate S, Bertucci C, Bari LD, et al. Special issue "chiroptical spectroscopy: instrumentation, experimental aspects and applications" in memory of
Ariantari NP, Ancheeva E, Wang CY, et al. Indole diterpenoids from an endophytic
Beaulieu S, Comby A, Descamps D, et al. Photoexcitation circular dichroism in chiral molecules[J]. Nature Physics, 2018, 14(5): 484-489
Tanaka H, Inoue Y, Nakano T, et al. Absolute configuration determination through the unique intramolecular excitonic coupling in the circular dichroisms of
Zhang YL. The application of quantum chemistry in determining the absolute configuration in the study of natural chiral product[D]. Shanghai: Master's Thesis of East China University of Science and Technology, 2014 (in Chinese)
张友利.量子化学在确定天然产物绝对构型中的应用[D].上海: 华东理工大学硕士学位论文, 2014
Wu RR, Le ZJ, Wang ZZ, et al. Hyperjaponol H, a new bioactive filicinic acid-based meroterpenoid from
Li XC, Ferreira D, Ding YQ. Determination of absolute configuration of natural products: theoretical calculation of electronic circular dichroism as a tool[J]. Current Organic Chemistry, 2010, 14(16): 1678-1697
Albadry MA, Elokely KM, Wang B, et al. Computationally assisted assignment of Kahalalide Y configuration using an NMR-constrained conformational search[J]. Journal of Natural Products, 2013, 76(2): 178-185
Maarisit W, Yamazaki H, Abdjul DB, et al. A new pyranonaphtoquinone derivative, 4-Oxo-rhinacanthin A, from roots of Indonesian
Szatkowska-Wandas P, Koba M. Prediction of Acridinones' ability to interstrand DNA crosslinks formation using connected QSRR and QSAR analysis[J]. Letters in Drug Design & Discovery, 2016, 13(5): 387-394
Zhang H. Application of electronic circular dichroism spectroscopic methods in determination of absolute configuration of chiral metal complexes[J]. University Chemistry, 2017, 32(3): 1-14 (in Chinese)
章慧.应用电子圆二色光谱方法确定手性金属配合物的绝对构型[J].大学化学, 2017, 32(3): 1-14
Hawkins PCD, Skillman AG, Warren GL, et al. Conformer generation with OMEGA: algorithm and validation using high quality structures from the protein databank and Cambridge structural database[J]. Journal of Chemical Information and Modeling, 2010, 50(4): 572-584
Ren PY, Wu CJ, Ponder JW. Polarizable atomic multipole-based molecular mechanics for organic molecules[J]. Journal of Chemical Theory and Computation, 2011, 7(10): 3143-3161
Sardella R, Ianni F, Macchiarulo A, et al. Elucidation of the chromatographic enantiomer elution order through computational studies[J]. Mini Reviews in Medicinal Chemistry, 2018, 18(2): 88-97
Bilal M, Beerwerth R, Volotka AV, et al.
Jaszuński M, Rizzo A, Ruud K. Molecular electric, magnetic, and optical properties[A]//Leszczynski J, Kaczmarek-Kedziera A, Puzyn T, et al. Handbook of Computational Chemistry[M]. 2nd ed. Cham: Springer, 2017: 497-592
Makarova MV, Semenov SG, Kostikov RR. A quantum chemical study of the acidity of acetylene and 1, 2-dihydrobuckminsterfullerene derivatives[J]. Journal of Structural Chemistry, 2018, 59(1): 43-46
Ding WJ, Fang WH, Chai ZF, et al. Performance of twelve density functional theory methods in the characterization of three trivalent uranium complexes[J]. Acta Physico Chimica Sinica, 2015, 31(7): 1283-1301
Fernandes HS, Ramos MJ, Cerqueira NMFSA. molUP: A VMD plugin to handle QM and ONIOM calculations using the gaussian software[J]. Journal of Computational Chemistry, 2018, 39(19): 1344-1353
Nugroho AE, Morita H. Circular dichroism calculation for natural products[J]. Journal of Natural Medicines, 2014, 68(1): 1-10
Hu XY, Li XM, Yang SQ, et al. Three new sesquiterpenoids from the algal-derived fungus
Wang Q, Tang XL, Liu H, et al. Clavukoellians G-K, new nardosinane and aristolane sesquiterpenoids with angiogenesis promoting activity from the marine soft coral
Chen Y, Liu ZM, Huang Y, et al. Ascomylactams A-C, Cytotoxic 12-or 13-membered-ring macrocyclic alkaloids isolated from the mangrove endophytic fungus
Li HQ, Sun WG, Deng MY, et al. Asperversins A and B, two novel meroterpenoids with an unusual 5/6/6/6 ring from the marine-derived fungus
Zhang LH, Feng BM, Sun Y, et al. Flaviphenalenones A-C, three new phenalenone derivatives from the fungus
Wang C, Wang P, Lin XP, et al. Phloroglucinol heterodimers and bis-indolyl alkaloids from the sponge-derived fungus
Liu B, Li J, Chen MH, et al. Seco-tetracenomycins from the marine-derived actinomycete
Mazzeo G, Santoro E, Andolfi A, et al. Absolute configurations of fungal and plant metabolites by chiroptical methods. ORD, ECD, and VCD studies on phyllostin, scytolide, and oxysporone[J]. Journal of Natural Products, 2013, 76(4): 588-599
Zhu A, Yang MY, Zhang YH, et al. Absolute configurations of 14, 15-hydroxylated prenylxanthones from a marine-derived
Xu LL, Cao F, Yang Q, et al. Experimental and theoretical study of stereochemistry for new pseurotin A3 with an unusual hetero-spirocyclic system[J]. Tetrahedron, 2016, 72(45): 7194-7199