Xiaohua Peng

Xiaohua Peng
University of Wisconsin - Milwaukee | UWM · Department of Chemistry and Biochemistry

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64
Publications
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Introduction
Skills and Expertise

Publications

Publications (64)
Poster
Nitrogen mustard containing compounds are well-known for their high reactivity towards DNA, therefore have been used for the treatment of different types of cancers. This reactivity also introduces a higher risk of off-target effects and lower selectivity. Using the unique oxidative stress environment of tumors to chemically convert boronic acid de...
Poster
Full-text available
Anthracene, a well-known DNA intercalator has interesting features which makes it attractive for DNA cross-linking study. It has large binding constant with DNA bases and can be sensitized by DNA. In addition, anthryl chromophore is photo chemically reactive and has large singlet excited state energy, which is good for initiating photochemical reac...
Article
Full-text available
Triple-negative breast cancer (TNBC) has limited treatment options and the worst prognosis among all types of breast cancer. We describe two prodrugs, namely, CWB-20145 (1) and its methyl analogue FAN-NM-CH3 (2) that reduced the size of TNBC-derived tumors. The DNA cross-linking of nitrogen mustard prodrugs 1 and 2 was superior to that of chlorambu...
Article
Full-text available
Two series of 1,1'‐biphenyl analogues with various leaving groups (L = OAc, OCH 3 , OCHCH=CH 2 , OCH 2 Ph, SPh, SePh, and Ph 3 P + ) were synthesized. Their reactivity towards DNA and the reaction mechanism were investigated by determining DNA interstrand cross‐link (ICL) efficiency, radical and carbocation formation, and the cross‐linking reaction...
Article
We have synthesized and characterized two small libraries of 2-OMe or 2-NO2-benzene analogues 2a-i and 3a-i containing a wide variety of leaving groups. Irradiation of these compounds at 350 nm generated benzyl radicals that were spontaneously oxidized to benzyl cations directly producing DNA interstrand cross-links (ICLs). Compounds with a 2-metho...
Poster
Full-text available
ROS-activated anticancer prodrugs have been sought for some time, however no agents effective in vivo have been discovered. Recently, we have developed a class of arylboronates that are activated in vitro by ROS leading to formation of active nitrogen mustards that alkylate DNA. In this work, we evaluate the in vivo antitumor efficacy and selectivi...
Article
Full-text available
Previous reports showed that consecutive incorporations of triazole-modified 2′-deoxyuridines stabilized DNA·DNA and DNA·RNA duplexes due to additional π-stacking between triazole moieties. In this work, several triazole-modified thymidines (1-3) have been synthesized via Cu-catalyzed azide-alkyne cycloaddition reaction and incorporated into oligod...
Article
We describe several new aromatic nitrogen mustards with various aromatic substituents and boronic ester that can be activated with H2O2 to efficiently cross-link DNA. In vitro studies demonstrated the anticancer potential of these compounds at lower concentrations than clinically used chemotherapeutics such as mephalan and chlorambucil. Especially...
Article
Most recently, alkylation via photo-generated carbocations has been identified as a novel mechanism for photo-induced DNA interstrand cross-link (ICL) formation by bifunctional aryl compounds. However, most compounds showed a low efficiency for DNA cross-linking. Here, we have developed a series of new 1,1’-binaphthalene analogues that efficiently...
Article
Recently, several aryl boronates have been reported to induce DNA interstrand cross-link (ICL) formation via carbocations upon photoirradiation. Herein we synthesized a series of new bifunctional phenyl compounds, in order to test the generality of such a mechanism, and understand how the chemical structure influences carbocation formation and DNA...
Article
Full-text available
Quinone methide (QM) formation induced by endogenously generated H2O2 is attractive for biological and biomedical applications. To overcome current limitations due to low biological activity of H2O2-activated QM precursors, we are introducing herein several new arylboronates with electron donating substituents at different positions of benzene ring...
Chapter
DNA interstrand cross-links (ICLs) are the sources of the cytotoxicity of many anticancer agents. DNA cross-linking agents are used as anticancer agents, for DNA damage and repair study, for nucleic acid detection, and for construction of DNA nanomaterials. This chapter summarizes various novel methods and chemical reagents recently developed for i...
Article
Coumarin moieties react with thymine and cytosine in DNA via photoinduced [2+2] cycloaddition, which allows quantitative DNA interstrand cross-link (ICL) formation. Here, we report the application of coumarin analogues for DNA photoligation and the rearrangement of coumarin-induced ligation to ICL products. Both DNA sequences and the linker units a...
Article
UV irradiation of several aryl boronates efficiently produced bifunctional benzyl cations that selectively form guanine-cytosine cross-links in DNA. Photoinduced homolysis of the C-Br bond took place with the aryl boronate bromides 3a and 4a, generating free radicals that were oxidized to benzyl cations via electron transfer. However, photoirradiat...
Article
Four novel photo-activated binitroimidazole prodrugs were synthesized. These agents produced the DNA interstrand cross-links (ICL) and direct strand breaks (DSB) upon UV irradiation, while no or very few DNA ICLs and DSBs were observed without UV treatment. Although these four molecules (1-4) contain the same binitroimidazole moiety, they bear four...
Patent
Full-text available
Described herein are compounds that may be selectively activated to produce active anti-cancer agents in tumor cells. Also disclosed are pharmaceutical compositions comprising the compounds, and methods of treating cancer using the compounds.
Article
The coumarin analogues have been widely utilized in medicine, biology, biochemistry, and material sciences. Here, we report a detailed study on the reactivity of coumarins toward DNA. A series of coumarin analogues were synthesized and incorporated into oligodeoxynucleotides. A photoinduced [2+2] cycloaddition occurs between the coumarin moiety and...
Article
A coumarin-modified pyrimidine nucleoside (1) has been synthesized using a Cu(I) -catalyzed click reaction and incorporated into oligodeoxynucleotides (ODNs). Interstrand cross-links are produced upon irradiation of ODNs containing 1 at 350 nm. Cross-linking occurs through a [2+2] cycloaddition reaction with the opposing thymidine, 2'-deoxycytidine...
Article
Three novel H2O2-activated aromatic nitrogen mustard prodrugs (6-8) are reported. These compounds contain a DNA alkylating agent connected to a H2O2-responsive trigger by different electron-withdrawing linkers so that they are inactive towards DNA but can be triggered by H2O2 to release active species. The activity and selectivity of these compound...
Article
Reducing host toxicity is one of the main challenges of cancer chemotherapy. Many tumor cells contain high levels of ROS which makes them distinctively different from normal cells. We report a series of ROS-activated aromatic nitrogen mustards which selectively kill chronic lymphocytic leukemia (CLL) over normal lymphocytes. These agents showed pow...
Article
We evaluated the effects of the benzylic leaving group and core structure of arylboronates on H2O2-induced formation of bisquinone methides for DNA interstrand cross-linking. The mechanism of DNA cross-linking induced by these aryboronates involves generation of phenol intermediates followed by departure of benzylic leaving group leading to QMs whi...
Article
A series of arylboronic esters containing different aromatic substituents and various benzylic leaving groups (Br or N(+) Me3 Br(-) ) have been synthesized. The substituent effects on their reactivity with H2 O2 and formation of quinone methide (QM) have been investigated. NMR spectroscopy and ethyl vinyl ether (EVE) trapping experiments were used...
Article
A novel nonfluorescent alkyne-modified coumarin phosphoramidite was synthesized and successfully incorporated into oligonucleotides, which were then used in highly efficient DNA interstrand cross-linking and ligation reactions via "click" chemistry. The template-directed fluorogenic ligation "click" chemistry reaction was used for single nucleotide...
Article
This review highlights the most recent advances in click chemistry associated with DNA. Cu[I]-catalyzed azides-alkynes Huisgen cycloadditions (CuAAC) and a strain-promoted alkyne-azide cycloaddition (SPAAC) are two popular click reactions that have great impact in DNA science. The simplicity, versatility, orthogonality, and high efficiency of click...
Article
Full-text available
The clean crossed code: Two nitroimidazole-modified thymidines 1 a and 1 b were synthesized and incorporated into DNA oligomers. The 350 nm photolysis of 1 a and 1 b generated a 5-(2'-deoxyuridinyl)methyl radical that induced DNA interstrand cross-links (ICL; see scheme). A higher ICL yield was observed under hypoxic conditions than under aerobic c...
Article
Targeting tumor cells is an important strategy to improve the selectivity of cancer therapies. With the advanced studies in cancer biology, we know that cancer cells are usually under increased oxidative stress. The high level of reactive oxygen species in cancer cells has been exploited for developing novel therapeutic strategies to preferentially...
Article
Down at the crossed code: Novel arylboronic ester and biarylboronic ester derivatives were synthesized. Compound 1 can be activated by hydrogen peroxide to release 2,5-bis(trimethylammonium) benzyl-1,4-diol (2), which leads to interstrand cross-link formation and DNA alkylation. Compound 1 provides a novel building block for the development of H(2)...
Article
The major concern for anticancer chemotherapeutic agents is the host toxicity. The development of anticancer prodrugs targeting the unique biochemical alterations in cancer cells is an attractive approach to achieve therapeutic activity and selectivity. We designed and synthesized a new type of nitrogen mustard prodrug that can be activated by high...
Article
A library consisting of a series of O,O′-diaryzoyl-L-(-)-tartaric acids (2) was designed and synthesized. The substituent on the aromatic ring of 2 significantly affects the diastereomeric excess and efficiency of the resolution of racemic albuterol (1). Excellent resolving reagent 2a was selected for the resolution of rac-1 via the parallel approa...
Article
The first nucleic acid-directed catalytic photochemical reaction that is induced by nontoxic red light was developed. This reaction is fast, high yielding, sequence specific, and enables one to functionalize an oligonucleotide.
Article
A highly efficient chemical ligation was developed for quantitative conjugation of PNA with DNA (PNA or peptide) using the copper-catalyzed azide-alkyne cycloaddition reaction. While PNAs with an alkyne at the C-terminus and an azide at the N-terminus have been used, an efficient click-click reaction occurs. The PNA click ligation is sequence-speci...
Article
The DNA radical resulting from formal abstraction of a hydrogen atom from the thymidine methyl group, 5-(2'-deoxyuridinyl)methyl radical, forms interstrand cross-links with the opposing 2'-deoxyadenosine. This is the first chemically characterized, radical-mediated cross-link between two opposing nucleotides. In addition, cross-linking between oppo...
Article
Full-text available
The replication terminator protein Tus of Escherichia coli promotes polar fork arrest at sequence-specific replication termini (Ter) by antagonizing DNA unwinding by the replicative helicase DnaB. Here, we report that Tus is also a polar antitranslocase. We have used this activity as a tool to uncouple helicase arrest at a Tus–Ter complex from DNA...
Article
Oxidative DNA damage is important in aging and a variety of diseases. Significant advances have been made in our understanding of the chemistry of radical mediated DNA damage. These studies have been carried out on DNA in the absence of proteins. However, in cells DNA is typically bound by proteins such as in chromatin and transiently by proteins t...
Article
DNA interstrand cross-links have important biological consequences and are useful biotechnology tools. Phenylselenyl substituted derivatives of thymidine (1) and 5-methyl-2'-deoxycytidine (5) produce interstrand cross-links in duplex DNA when oxidized by NaIO4. The mechanism involves a [2,3]-sigmatropic rearrangement of the respective selenoxides t...
Article
Full-text available
A facile, sensitive method for detecting specific sequences of oligonucleotides was developed. Detection of DNA sequences with single nucleotide discrimination is achieved by combining the selectivity of hybridization with an efficient cross-linking reaction. Readily synthesized bifunctional oligonucleotide probes containing a modified pyrimidine t...
Article
The title compound, 2,4-diamino-5-bromo-7-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, C(11)H(13)BrFN(5)O(3), shows two conformations of the exocyclic C4'-C5' bond, with the torsion angle gamma (O5'-C5'-C4'-C3') being 170.1 (3) degrees for conformer 1 (occupancy 0.69) and 60.7 (7) degrees for conformer 2 (occupancy 0.31)....
Article
In the title compound [systematic name: 7-(2-de­oxy-β-d-erythro-pentofuranos­yl)-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-2-amine], C11H13FN4O3, the conformation of the N-glycosylic bond is between anti and high-anti [χ = −110.2 (3)°]. The 2′-deoxy­ribofuranosyl unit adopts the N-type sugar pucker (4T3), with P = 40.3° and τm = 39.2°. The orientation of...
Article
The effect of tautomerism on the mismatch discrimination was studied on 7-deazapurine and 8-aza-7-deazapurine analogues of isoguanosine. 7-Halogenated 7-deaza-2'-deoxyisoguanosines show better base pair discrimination than 2'-deoxyisoguanosine due to the more favored keto tautomer formation. 8-Aza-7-deazaisoguanosine and its 7-halogeno derivatives...
Article
The glycosylation reaction performed with 7-halogenated 7-deazapurines employing commercially available 1-O-acetyl-2,3,5-tri-O-benzoyl-D- or L-ribofuranoses is described.
Article
This review reports on the synthesis of 7-deazapurine ribonucleosides, including C-nucleosides, 2'-C-methyl derivatives and L-enantiomers. It covers the various aspects of convergent nucleoside synthesis such as the Schiff base procedure, the fusion reaction, the metal salt procedures, the Silyl-Hilbert-Johnson reaction, and the nucleobase anion gl...
Article
In 4-chloro-7-(2-deoxy-beta-D-erythro-pentofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine, C11H14ClN5O3, the conformation of the N-glycosylic bond is between anti and high-anti [chi = -102.5 (6) degrees]. The 2'-deoxyribofuranosyl unit adopts the C3'-endo-C4'-exo (3T4) sugar pucker (N-type) with P = 19.6 degrees and taum = 32.9 degrees [termino...
Article
The manuscript reports on the syntheses of modified 2′-deoxy-ribonucleosides containing pyrrolo[2,3-d]pyrimidines (7-deazapurines), pyrrolo[3,2-d]pyrimidines (9-deazapurines), pyrazolo[3,4-d]pyrimidines (8-aza-7-deazapurines), and 6-azauridines as nucleobases. Some of them are additionally modified at the sugar moiety with 2′-fluoro substituents in...
Article
The synthesis and properties of 7-deazapurine β-L-nucleosides are described. The stereoselective glycosylation of the anions of 2-amino-6-chloro-7-deazapurines 9a , 9b or 6-chloro-7-deazapurines 13a , 13d with 3,5-di- O -(4-methylbenzoyl)-2-deoxy-α-L- erythro -pentofuranosyl chloride ( 8 ) furnished the β-L-2'-deoxyribonucleosides 1 - 4 . The synth...
Article
The binding of actinomycin D (C1, 1) and its analog actinomin (2) was studied on base-modified oligonucleotide duplexes with parallel chain orientation (ps) and with anti-parallel chains (aps) for comparison. Actinomycin D binds not only to aps duplexes containing guanine-cytosine base pairs but also to those incorporating modified bases such as 7-...
Article
Full-text available
Oligonucleotides incorporating 2′-deoxytubercidin (1a), its 2-amino derivative 2a and related 2-, or 7-substituted analogs (1d, 2b–d, 3 and 4) are synthesized. For this purpose, a series of novel phosphoramidites are prepared and employed in solid-phase synthesis. Hybridization experiments performed with 12mer duplexes indicate that 7-halogenated n...
Article
[reaction: see text] The Silyl-Hilbert-Johnson reaction as well as the nucleobase-anion glycosylation of a series of 7-deazapurines has been investigated, and the 7-functionalized 7-deazapurine ribonucleosides were prepared. Glycosylation of the 7-halogenated 6-chloro-2-pivaloylamino-7-deazapurines 9b-d with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofur...
Article
7-Substituted 7-deazapurine (pyrrolo[2,3-d]pyrimidine) 2'-deoxyribonucleosides are synthesized by stereoselective nucleobase anion glycosylation. The introduction of a halogen at C7 is performed regioselectively either on the nucleobase or on the nucleoside. The pK(a) values of a series of 7-deazapurine 2'-deoxyribonucleosides are provided, and flu...
Article
Oligonucleotides containing 2'-deoxyisoguanosine (1, iG(d)), 7-deaza-2'-deoxyisoguanosine (2, c(7)iG(d)), and its 7-halogenated derivatives 3 and 4 were synthesized on solid phase using the phosphoramidite building blocks 5-7. The hybridization properties of oligonucleotides were studied on duplexes with parallel and antiparallel chain orientation....
Article
Phosphoramidites are first synthesized from suitably protected 7-deazapurine 2'-deoxyribonuclosides that have halogen or alkynyl subsituents at the 7 position. Oligonucleotides containing 7-deazapurines (pyrrolo[2,3-d]pyrimidines) in place of the canonical nucleobases are then prepared by solid-phase synthesis. These oligonucleotides are subsequent...
Article
The synthesis of 7-substituted 7-deazaguanine and 7-deazaadenine ribonucleosides 1-2, the incorporation of 3a-d into oligonucleotides, and the stability of the corresponding duplexes and base discrimination are described. The pKa values of 3-4 are determined.
Article
The fluorescence quenching of ethidium bromide in base-modified parallel-stranded DNA was studied. Parallel stranded (ps) duplexes were constructed by incorporating 7-deaza-2′-deoxyisoguanosine (1a) or its 7-halogenated analogs 1b,c in place of 2′-deoxyisoguanosine. UV and T m analyses prove the high affinity of ethidium bromide (EB) to these modif...
Article
The stereoselective syntheses of 5-halogenated 7-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine nucleosides 3b–d, 4a–c as well as 7-deaza-2′-deoxyisoguanosine 2 are described. Nucleobase anion glycosylation of 2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5) with 3,5-di-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl bromide (6...
Article
The syntheses of 7-halogenated derivatives 3b-e of 2-amino-7-deaza-2'-deoxyadenosine as well as 7-bromo and 7-chloro-7-deaza-2'-deoxyisoguanosines 4b-c are described. Nucleobase anion glycosylation was employed for the convergent nucleoside synthesis. The regioselective 7-halogenation was performed either on the nucleoside precursor 7 or on the nuc...
Article
The regioselective synthesis of 4-nitroindazole N1- and N2-(beta-D-ribonucleosides) (8, 9, 1b and 2b) is described. The N1-regioisomers are formed under thermodynamic control of the glycosylation reaction [fusion reaction or Silyl Hilbert-Johnson glycosylation for 48 h (66%)], while the kinetic control (Silyl Hilbert-Johnson glycosylation for 5 h)...
Article
The structures of the isomeric nucleosides 4-nitro-1-(beta-D-ribofuranosyl)-1H-indazole, C(12)H(13)N(3)O(6), (I), and 4-nitro-2-(beta-D-ribofuranosyl)-2H-indazole, C(12)H(13)N(3)O(6), (II), have been determined. For compound (I), the conformation of the glycosylic bond is anti [chi = -93.6 (6) degrees ] and the sugar puckering is C2'-exo-C3'-endo....
Article
An effective resolving agent, (2S, 3S)-di-O-(p-toluoyl) tartaric acid(4), was screened using a 'family' approach to yield direct resolution of (R)-terbutaline (1) with high optical purity and yield. Molecular recognition was studied by X-ray crystallographic analyses of the single crystals of the pair of diastereomeric salts. The more-soluble salt...
Article
An effective resolving agent, (2S,3S)-di-O-(p-toluoyl) tartaric acid (4), was screened using a ‘family’ approach to yield direct resolution of (R)-terbutaline (1) with high optical purity and yield. Molecular recognition was studied by X-ray crystallographic analyses of the single crystals of the pair of diastereomeric salts. The more-soluble salt...

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