Professional Education


  • Bachelor of Science, Wuhan University (2013)
  • Doctor of Philosophy, Johns Hopkins University (2018)

Stanford Advisors


All Publications


  • Independent Generation and Time-Resolved Detection of 2'-Deoxyguanosin-N2-yl Radical. Angewandte Chemie (International ed. in English) Zheng, L., Dai, X., Su, H., Greenberg, M. M. 2020

    Abstract

    Guanine radicals are important reactive intermediates in DNA damage. Hydroxyl radical (HO) has long been believed to react with 2'-deoxyguanosine (dG) generating 2'-deoxyguanosin- N1 -yl radical (dG(N1-H)) via addition to the nucleobase pi-system and subsequent dehydration. This basic tenet was challenged by an alternative mechanism, in which the major reaction of HO with dG was proposed to involve hydrogen atom abstraction from the N2-amine. The 2'-deoxyguanosin- N2 -yl radical (dG(N2-H)) formed was proposed to rapidly tautomerize to dG(N1-H). We report the first independent generation of dG(N2-H) in high yield via photolysis of 1 . dG(N2-H) is directly observed upon nanosecond laser flash photolysis (LFP) of 1 . The absorption spectrum of dG(N2-H) is corroborated by DFT studies, and anti - and syn -dG(N2-H) are resolved for the first time. The LFP experiments showed no evidence for tautomerization of dG(N2-H) to dG(N1-H) within hundreds of microseconds. This observation suggests that the generation of dG(N1-H) via dG(N2-H) following hydrogen atom abstraction from dG is unlikely to be a major pathway when HO reacts with dG.

    View details for DOI 10.1002/anie.202005300

    View details for PubMedID 32365264

  • Metal-Organic Framework Nanocarriers for Drug Delivery in Biomedical Applications NANO-MICRO LETTERS Sun, Y., Zheng, L., Yang, Y., Qian, X., Fu, T., Li, X., Yang, Z., Yan, H., Cui, C., Tan, W. 2020; 12 (1)
  • Positional Dependence of DNA Hole Transfer Efficiency in Nucleosome Core Particles JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Sun, H., Zheng, L., Yang, K., Greenberg, M. M. 2019; 141 (26): 10154–58

    Abstract

    Electron deficient "holes" migrate over long distances through the π-system in free DNA. Hole transfer efficiency (HTE) is strongly dependent on sequence and π-stacking. However, there is no consensus regarding the effects of nucleosome core particle (NCP) environment on hole migration. We quantitatively determined HTE in free DNA and NCPs by independently generating holes at specific positions in DNA. The relative HTE varied widely with respect to position within the NCP and proximity to tyrosine, which suppresses hole transfer. These data indicate that hole transfer in chromatin will be affected by the DNA sequence and its position with respect to histone proteins within NCPs.

    View details for DOI 10.1021/jacs.9b03686

    View details for Web of Science ID 000474669700005

    View details for PubMedID 31244168

    View details for PubMedCentralID PMC6610759

  • Independent Generation of Reactive Intermediates Leads to an Alternative Mechanism for Strand Damage Induced by Hole Transfer in Poly(dA-T) Sequences JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Sun, H., Zheng, L., Greenberg, M. M. 2018; 140 (36): 11308–16

    Abstract

    Purine radical cations (dA•+ and dG•+) are the primary hole carriers of DNA hole migration due to their favorable oxidation potential. Much less is known about the reactivity of higher energy pyrimidine radical cations. The thymidine radical cation (T•+) was produced at a defined position in DNA from a photochemical precursor for the first time. T•+ initiates hole transfer to dGGG triplets in DNA. Hole localization in a dGGG sequence accounts for ∼26% of T•+ formed under aerobic conditions in 9. Reduction to yield thymidine is also quantified. 5-Formyl-2'-deoxyuridine is formed in low yield in DNA when T•+ is independently generated. This is inconsistent with mechanistic proposals concerning product formation from electron transfer in poly(dA-T) sequences, following hole injection by a photoexcited anthraquinone. Additional evidence that is inconsistent with the original mechanism was obtained using hole injection by a photoexcited anthraquinone in DNA. Instead of requiring the intermediacy of T•+, the strand damage patterns observed in those studies, in which thymidine is oxidized, are reproduced by independent generation of 2'-deoxyadenosin- N6-yl radical (dA•). Tandem lesion formation by dA• provides the basis for an alternative mechanism for thymidine oxidation ascribed to hole migration in poly(dA-T) sequences. Overall, these experiments indicate that the final products formed following DNA hole transfer in poly(dA-T) sequences do not result from deprotonation or hydration of T•+, but rather from deprotonation of the more stable dA•+, to form dA•, which produces tandem lesions in which 5'-flanking thymidines are oxidized.

    View details for DOI 10.1021/jacs.8b05484

    View details for Web of Science ID 000444793400029

    View details for PubMedID 30169029

    View details for PubMedCentralID PMC6135700

  • Traceless Tandem Lesion Formation in DNA from a Nitrogen-Centered Purine Radical JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Zheng, L., Greenberg, M. M. 2018; 140 (20): 6400–6407

    Abstract

    Nitrogen-centered nucleoside radicals are commonly produced reactive intermediates in DNA exposed to γ-radiolysis and oxidants, but their reactivity is not well understood. Examination of the reactivity of independently generated 2'-deoxyadenosin- N6-yl radical (dA•) reveals that it is an initiator of tandem lesions, an important form of DNA damage that is a hallmark of γ-radiolysis. dA• yields O2-dependent tandem lesions by abstracting a hydrogen atom from the C5-methyl group of a 5'-adjacent thymidine to form 5-(2'-deoxyuridinyl)methyl radical (T•). The subsequently formed thymidine peroxyl radical adds to the 5'-adjacent dG, ultimately producing a 5'-OxodGuo-fdU tandem lesion. Importantly, the initial hydrogen abstraction repairs dA• to form dA. Thus, the involvement of dA• in tandem lesion formation is traceless by product analysis. The tandem lesion structure, as well as the proposed mechanism, are supported by LC-MS/MS, isotopic labeling, chemical reactivity experiments, and independent generation of T•. Tandem lesion formation efficiency is dependent on the ease of ionization of the 5'-flanking sequence, and the yields are >27% in the 5'-d(GGGT) flanking sequence. The traceless involvement of dA• in tandem lesion formation may be general for nitrogen-centered radicals in nucleic acids, and presents a new pathway for forming a deleterious form of DNA damage.

    View details for DOI 10.1021/jacs.8b02828

    View details for Web of Science ID 000433404000031

    View details for PubMedID 29738242

    View details for PubMedCentralID PMC5966344

  • DNA Damage Emanating From a Neutral Purine Radical Reveals the Sequence Dependent Convergence of the Direct and Indirect Effects of gamma-Radiolysis JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Zheng, L., Greenberg, M. M. 2017; 139 (49): 17751–54

    Abstract

    Nucleobase radicals are the major intermediates generated by the direct (e.g., dA•+) and indirect (e.g., dA•) effects of γ-radiolysis. dA• was independently generated in DNA for the first time. The dA•+/dA• equilibrium, and consequently the reactivity in DNA, is significantly shifted toward the radical cation by a flanking dA. Tandem lesions emanating from dA• are the major products when the reactive intermediate is flanked by a 5'-dGT. In contrast, when dA• is flanked by dA, the increased dA•+ pKa results in DNA damage arising from hole transfer. This is the first demonstration that sequence effects lead to the intersection of the direct and indirect effects of ionizing radiation.

    View details for DOI 10.1021/jacs.7b10942

    View details for Web of Science ID 000418204600013

    View details for PubMedID 29190086

    View details for PubMedCentralID PMC5729073

  • Independent Photochemical Generation and Reactivity of Nitrogen-Centered Purine Nucleoside Radicals from Hydrazines ORGANIC LETTERS Zheng, L., Lin, L., Qu, K., Adhikary, A., Sevilla, M. D., Greenberg, M. M. 2017; 19 (23): 6444–47

    Abstract

    Photochemical precursors that produce dA• and dG(N2-H)• are needed to investigate their reactivity. The synthesis of two 1,1-diphenylhydrazines (1, 2) and their use as photochemical sources of dA• and dG(N2-H)• is presented. Trapping studies indicate production of these radicals with good fidelity, and 1 was incorporated into an oligonucleotide via solid-phase synthesis. Cyclic voltammetric studies show that reduction potentials of 1 and 2 are lower than those of widely used "hole sinks", e.g., 8-oxodGuo and 7-deazadGuo, to investigate DNA-hole transfer processes. These molecules could be useful (a) as sources of dA• and dG(N2-H)• at specific sites in oligonucleotides and (b) as "hole sinks" for the study of DNA-hole transfer processes.

    View details for DOI 10.1021/acs.orglett.7b03368

    View details for Web of Science ID 000417229000046

    View details for PubMedID 29125775

    View details for PubMedCentralID PMC5711525

  • Independent generation of neutral purine radicals involved in DNA damage Zheng, L., Greenberg, M. AMER CHEMICAL SOC. 2017
  • Independent generation of 2 '-deoxyadenosine-N6-yl radical and its reactivity in DNA Zheng, L., Griesser, M., Pratt, D., Greenberg, M. AMER CHEMICAL SOC. 2017
  • Aminyl Radical Generation via Tandem Norrish Type I Photocleavage, beta-Fragmentation: Independent Generation and Reactivity of the 2 '-Deoxyadenosin- N6-yl Radical JOURNAL OF ORGANIC CHEMISTRY Zheng, L., Griesser, M., Pratt, D. A., Greenberg, M. M. 2017; 82 (7): 3571–80

    Abstract

    Formal hydrogen atom abstraction from the nitrogen-hydrogen bonds in purine nucleosides produces reactive intermediates that are important in nucleic acid oxidation. Herein we describe an approach for the independent generation of the purine radical resulting from hydrogen atom abstraction from the N6-amine of 2'-deoxyadenosine (dA•). The method involves sequential Norrish Type I photocleavage of a ketone (7b) and β-fragmentation of the initially formed alkyl radical (8b) to form dA• and acetone. The formation of dA• was followed by laser flash photolysis, which yields a transient with λmax ≈ 340 nm and a broader weaker absorption centered at ∼560 nm. This transient grows in at ≥2 × 105 s-1; however, computations and reactivity data suggest that β-fragmentation occurs much faster, implying the consumption of dA• as it is formed. Continuous photolysis of 7b in the presence of ferrous ion or thiophenol produces good yields of dA, whereas less reactive thiols afford lower yields presumably due to a polarity mismatch. This tandem photochemical, β-fragmentation method promises to be useful for site-specific production of dA• in nucleic acid oligomers and/or polymers and also for the production of aminyl radicals, in general.

    View details for DOI 10.1021/acs.joc.7b00093

    View details for Web of Science ID 000398986000021

    View details for PubMedID 28318253

    View details for PubMedCentralID PMC5494259

  • Nickel-Catalyzed Heck-Type Alkenylation of Secondary and Tertiary a-Carbonyl Alkyl Bromides ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Liu, C., Tang, S., Liu, D., Yuan, J., Zheng, L., Meng, L., Lei, A. 2012; 51 (15): 3638–41

    View details for DOI 10.1002/anie.201108350

    View details for Web of Science ID 000302348200022

    View details for PubMedID 22383291

  • Covalently Bound Benzyl Ligand Promotes Selective Palladium-Catalyzed Oxidative Esterification of Aldehydes with Alcohols ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Liu, C., Tang, S., Zheng, L., Liu, D., Zhang, H., Lei, A. 2012; 51 (23): 5662–66

    View details for DOI 10.1002/anie.201201960

    View details for Web of Science ID 000304814000025

    View details for PubMedID 22539112