Dr David M. Williams
Department of Chemistry
Reader in Chemical Biology
+44 114 222 9502
Full contact details
Department of Chemistry
13 Brook Hill
Dr. Williams obtained a BSc in Chemistry from the University of Liverpool in 1985, which was followed by a PhD from the same institution in 1988. From 1988, he was a Postdoctoral Research Fellow at the Max-Planck Institute for Experimental Medicine in Göttingen and from 1992-1995 at the MRC Laboratory of Molecular Biology in Cambridge.
In 1995 he became a demonstrator at the University of Sheffield. In 1999 he became a lecturer and in 2006 a senior lecturer. In 2014 he was promoted to Reader.
- Research interests
Our main areas of research are in the synthesis of modified nucleosides and nucleotides and their applications.
Currently we are interested in the chemical synthesis of 5'-triphosphates of base-modified, nucleoside analogues that have altered base pairing specificities. We are studying the incorporation of these analogues into DNA by polymerase enzymes in order to gain an insight into the role of base pairing during DNA replication and DNA mutagenesis.
Exposure to alkylating agents can lead to the formation of highly toxic O6-alkylguanine lesions within DNA. We have developed chemical methodology for the preparation of oligodeoxyribonucleotides containing a variety of O6-alkylguanine analogues and these are being used to study DNA recognition and repair by the human protein O6-methylguanine-DNA methyltransferase (MGMT) and the alkyltransferase-like protein Atl1.
Other areas of interest include the use SELEX for the design of nucleic acid-based ligands and catalysts containing chemically synthesised imidazolyl and amino modified nucleotides of dUTP and 7-deazadATP, studying the structural properties of nucleic acids containing modified pyrimidine and purine bases and the design and synthesis of modified oligodeoxyribonucleotides for DNA-DNA and DNA-protein cross-linking.
- Synthesis of polyanionic C5-modified 2'-deoxyuridine and 2'-deoxycytidine-5'-triphosphates and their properties as substrates for DNA polymerases. Molecules, 26(8).
- Synthesis of oligodeoxyribonucleotides containing a tricyclic thio analogue of O6-methylguanine and their recognition by MGMT and Atl1. Nucleosides, Nucleotides & Nucleic Acids. View this article in WRRO
- Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms. Nature, 579(7800), 603-608. View this article in WRRO
- A concise stereoselective synthesis of pterosin B. Tetrahedron Letters, 59(49), 4323-4325. View this article in WRRO
- Bypass of Mutagenic O6-Carboxymethylguanine DNA Adducts by Human Y- and B-Family Polymerases. Chem Res Toxicol, 29(9), 1493-1503. View this article in WRRO
- The use of an artificial nucleotide for polymerase-based recognition of carcinogenic O6-alkylguanine DNA adducts. Nucleic Acids Res, 44(14), 6564-6573. View this article in WRRO
- O⁶-carboxymethylguanine in DNA forms a sequence context-dependent wobble base-pair structure with thymine.. Acta Crystallogr D Biol Crystallogr, 70(Pt 6), 1669-1679.
- Structures of DNA duplexes containing O6-carboxymethylguanine, a lesion associated with gastrointestinal cancer, reveal a mechanism for inducing pyrimidine transition mutations.. Nucleic Acids Res, 41(10), 5524-5532. View this article in WRRO
- The nitrosated bile acid DNA lesion O6-carboxymethylguanine is a substrate for the human DNA repair protein O6-methylguanine-DNA methyltransferase. Nucleic Acids Res, 41(5), 3047-3055.
- Alkyltransferase-like protein (Atl1) distinguishes alkylated guanines for DNA repair using cation-π interactions.. Proc Natl Acad Sci U S A, 109(46), 18755-18760.
- Synthesis of oligodeoxyribonucleotides containing a conformationally-locked anti analogue of O6-methyl-2'-deoxyguanosine and their recognition by MGMT and Atl1.. Chem Commun (Camb), 48(91), 11214-11216.
- Interstrand disulfide crosslinking of DNA bases supports a double nucleotide unpairing mechanism for flap endonucleases.. Chem Commun (Camb), 48(71), 8895-8897.
- Atl1 Regulates Choice between Global Genome and Transcription-Coupled Repair of O 6-Alkylguanines. Molecular Cell, 47(1), 50-60. View this article in WRRO
- Flap endonucleases pass 5'-flaps through a flexible arch using a disorder-thread-order mechanism to confer specificity for free 5'-ends.. Nucleic Acids Res, 40(10), 4507-4519. View this article in WRRO
- Convenient and efficient syntheses of oligodeoxyribonucleotides containing O6-(carboxymethyl)guanine and O6-(4-oxo-4-(3-pyridyl)butyl)guanine.. Nucleosides Nucleotides Nucleic Acids, 31(4), 328-338.
- Insights into the DNA stabilizing contributions of a bicyclic cytosine analogue: crystal structures of DNA duplexes containing 7,8-dihydropyrido [2,3-d]pyrimidin-2-one.. Nucleic Acids Res, 38(19), 6737-6745.
- Application of the Ugi reaction for the one-pot synthesis of uracil polyoxin C analogues.. J Org Chem, 74(13), 4870-4873.
- Flipping of alkylated DNA damage bridges base and nucleotide excision repair. NATURE, 459(7248), 808-813.
- Stereoselective synthesis of novel uracil polyoxin C conjugates as substrate analogues of chitin synthase.. J Org Chem, 73(10), 3714-3724.
- Crystal structures of DNA duplexes stabilized by bicyclic-C residues(52), 127-128.
- Novel post DNA synthesis chemistry and biological evaluation of O-6-alkylguanine-containing oligodeoxyribonucleotides. CHEMISTRY OF NUCLEIC ACID COMPONENTS, 10, 133-136.
- The synthesis and properties of tricyclic analogues of S6-methylthioguanine and O6-methylguanine.. Nucleosides Nucleotides Nucleic Acids, 26(8-9), 1099-1102.
- 7,8-Dihydropyrido[2,3-d]pyrimidin-2-one; a bicyclic cytosine analogue capable of enhanced stabilisation of DNA duplexes.. Chem Commun (Camb)(33), 3516-3518.
- The syntheses and properties of tricyclic pyrrolo[2,3-d]pyrimidine analogues of S6-methylthioguanine and O6-methylguanine.. Org Biomol Chem, 4(9), 1723-1729.
- X-Ray analyses of DNA duplexes stabilized by bicyclic-C residues(50), 213-214.
- A novel DNA damage recognition protein in Schizosaccharomyces pombe. NUCLEIC ACIDS RES, 34(8), 2347-2354.
- Novel synthesis of O6-alkylguanine containing oligodeoxyribonucleotides as substrates for the human DNA repair protein, O6-methylguanine DNA methyltransferase (MGMT).. Nucleic Acids Res, 34(6), 1884-1891.
- Novel post DNA synthesis chemistry for preparing oligonucleotides containing O6-modified purines.. Nucleic Acids Symp Ser (Oxf)(49), 23-24.
- Amino-functionalized DNA: the properties of C5-amino-alkyl substituted 2'-deoxyuridines and their application in DNA triplex formation.. Nucleic Acids Res, 33(4), 1362-1371.
- The synthesis and properties of oligoribonucleotide-spermine conjugates.. Org Biomol Chem, 2(14), 2103-2112.
- Sequence-specific cleavage of RNA in the absence of divalent metal ions by a DNAzyme incorporating imidazolyl and amino functionalities.. Nucleic Acids Res, 32(4), 1591-1601.
- The syntheses of tricyclic analogues of O6-methylguanine.. Org Biomol Chem, 1(23), 4166-4172.
- Recognition of base-pairing by DNA polymerases during nucleotide incorporation: the properties of the mutagenic nucleotide dPTP alphaS.. Org Biomol Chem, 1(12), 2070-2074.
- The effect of tautomeric constant on the specificity of nucleotide incorporation during DNA replication: support for the rare tautomer hypothesis of substitution mutagenesis.. J Mol Biol, 326(5), 1389-1401.
- Synthesis and applications of a tricyclic analogue of N-6-methoxy-2,6-diamino-2 '-deoxyriboside. CHEMISTRY OF NUCLEIC ACID COMPONENTS, 5, 328-331.
- DNA replication with the mutagenic nucleotide dPTP; Effects of tautomerism on nucleotide incorporation. CHEMISTRY OF NUCLEIC ACID COMPONENTS, 5, 215-220.
- Synthesis and applications of C5-amino modified 2 '-deoxyuridines. CHEMISTRY OF NUCLEIC ACID COMPONENTS, 5, 221-224.
- Enhancing the catalytic repertoire of nucleic acids. II. Simultaneous incorporation of amino and imidazolyl functionalities by two modified triphosphates during PCR.. Nucleic Acids Res, 29(9), 1898-1905.
- Enhancing the catalytic repertoire of nucleic acids: a systematic study of linker length and rigidity.. Nucleic Acids Res, 29(7), 1565-1573.
- Selection of novel ligands from a whole-molecule randomly mutated C5a library.. Protein Eng, 14(3), 189-193.
- Analysis of receptor/ligand interactions using whole-molecule randomly-mutated ligand libraries.. J Immunol Methods, 245(1-2), 139-145.
- A new and versatile synthesis of 5-substituted pyrrolo[2,3-d]pyrimidines. TETRAHEDRON LETT, 41(44), 8581-8585.
- Novel syntheses of (Z)-alkene and alkane base-modified nucleosides. TETRAHEDRON LETT, 41(2), 267-270.
- The synthesis of modified 5-(aminoalkyl)- and 5-(aminoalkenyl)uridine 5 '-triphosphates. CHEMISTRY OF NUCLEIC ACID COMPONENTS, 2, 35-38.
- Studying the function of methyltransferases using nucleotide analogue based random mutagenesis. CHEMISTRY OF NUCLEIC ACID COMPONENTS, 2, 209-212.
- Synthesis and polymerase incorporation properties of a tricyclic pyrrolopyrimidine related to N-6-hydroxy-2 '-deoxyadenosine. NUCLEOSIDES & NUCLEOTIDES, 18(4-5), 573-574.
- Highly potent bisphosphonate ligands for phosphoglycerate kinase and protein binding studies. PHOSPHORUS SULFUR AND SILICON AND THE RELATED ELEMENTS, 146, 533-536.
- Synthesis and binding of stable bisubstrate ligands for phosphoglycerate kinase.. Bioorg Med Chem Lett, 8(18), 2603-2608.
- A bisubstrate analog induces unexpected conformational changes in phosphoglycerate kinase from Trypanosoma brucei. J MOL BIOL, 279(5), 1137-1148.
- Properties of mutagenic pyrimidine analogue, P(39), 245-246.
- Comparative mutagenicities of N6-methoxy-2,6-diaminopurine and N6-methoxyaminopurine 2'-deoxyribonucleosides and their 5'-triphosphates. Nucleic Acids Research, 26(5), 1144-1149.
- Synthesis of a hydrogen-bond-degenerate tricyclic pyrrolopyrimidine nucleoside and of its 5′-triphosphate. Journal of the Chemical Society - Perkin Transactions 1(21), 3565-3570.
- The synthesis of a tricyclic pyrrolopyrimidine related to N6-hydroxyadenine. Journal of the Chemical Society - Perkin Transactions 1(8), 1171-1178.
- The mechanism of mutation induction by a hydrogen bond ambivalent, bicyclic N4-oxy-2'-deoxycytidine in Escherichia coli. Nucleic Acids Research, 25(8), 1548-1552.
- An approach to random mutagenesis of DNA using mixtures of triphosphate derivatives of nucleoside analogues. Journal of Molecular Biology, 255(4), 589-603.
- Synthesis and kinetic studies of bisubstrate analogues of phosphoglycerate kinase. COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS, 61, S88-S91.
- SOME PYRROLOPYRIMIDINE CHEMISTRY DIRECTED TO THE SYNTHESIS OF TRICYCLIC PURINE ANALOGS. Cheminform1522-2667(10), 1225-1231.
- Mechanism of mutagenesis induced by cytosine analogs bearing N(4)-substitutions. Nucleic Acids Symposium Series(34), 231-232.
- Translation of 2'-modified mRNA in vitro and in vivo.. Nucleic Acids Research, 22(23), 4963-4968.
- Conformationally restrained degenerate base analogues. Collection of Czechoslovak Chemical Communications, 58(s1), 41-43.
- 2'-Fluoro- and 2'-amino-2'-deoxynucleoside 5'-triphosphates as substrates for T7 RNA polymerase.. Biochemistry, 31(40), 9636-9641.
- Synthesis of Suitably-Protected Phosphoramidites of 2′-Fluoro-2′-Deoxyguanosine and 2′-Amino-2′-Deoxyguanosine for Incorporation Into Oligoribonucleotides. Nucleosides and Nucleotides, 11(7), 1333-1351.
- Function of specific 2'-hydroxyl groups of guanosines in a hammerhead ribozyme probed by 2' modifications.. Proc Natl Acad Sci U S A, 89(3), 918-921.
- Properties of 2'-fluorothymidine-containing oligonucleotides: interaction with restriction endonuclease EcoRV.. Biochemistry, 30(16), 4001-4009.
- INFLUENCE OF 2'-MODIFICATIONS ON THE STRUCTURE AND FUNCTION OF HAMMERHEAD RIBOZYMES, 372(9), 731-731.
- Structure-function relationship of hammerhead ribozymes as probed by 2'-modifications.. Nucleic Acids Symp Ser(24), 51-53.
- Molecular recognition in the minor groove of the DNA helix. Studies on the synthesis of oligonucleotides and polynucleotides containing 3-deaza-2'-deoxyadenosine. Interaction of the oligonucleotides with the restriction endonuclease EcoRV.. Nucleic Acids Res, 18(16), 4771-4778.
- Interaction of the EcoRV Restriction Endonuclease with the Deoxyadenosine and Thymidine Bases in Its Recognition Hexamer d(GATATC). Biochemistry, 29(42), 9902-9910.
- Incorporation of a Complete Set of Deoxyadenosine and Thymidine Analogues Suitable for the Study of Protein Nucleic Acid Interactions into Oligodeoxynucleotides. Application to the EcoRV Restriction Endonuclease and Modification Methylase. Biochemistry, 29(42), 9891-9901.
- An approach to the stereoselective synthesis of Sp-dinucleoside phosphorothioates using phosphotriester chemistry.. Nucleic Acids Res, 15(23), 9921-9932.
- Nucleotides and nucleic acids, Organophosphorus Chemistry (pp. 196-264). Royal Society of Chemistry
Conference proceedings papers
- The Nitrosated Bile Acid DNA Lesion, O-6-carboxymethylguanine, Is a Substrate for Human O-6-alkylguanine DNA Alkyltransferase. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Vol. 53 (pp S36-S36)
- Impact of a novel conjugation method on the efficiency of CD40mAb-antigen conjugate vaccines in vivo. IMMUNOLOGY, Vol. 137 (pp 763-763)
- Damaged guanine residue relevant to gastrointestinal cancer allows thymine residue to be flexible between Watson–Crick type pairing and large wobbling. Acta Crystallographica Section A Foundations of Crystallography, Vol. 68(a1) (pp s166-s166)
- Crystal structures of DNA containing X relevant to gastro-intestinal cancer. Acta Crystallographica Section A Foundations of Crystallography, Vol. 67(a1) (pp C286-C287)
- X-ray analyses of DNA duplexes stabilized by bicyclic-C residues. Acta Crystallographica Section A Foundations of Crystallography, Vol. 64(a1) (pp C298-C298)
- Teaching interests
- Teaching activities
Undergraduate and postgraduate taught modules
- Chemistry and the World Around Us (Level 1): Magic Medicines
This course aims to develop an appreciation of some of the types of medicines that are available, how they were discovered and how they work to control diseases.
- Aromatic chemistry (Level 2)
This module reviews the concept of aromaticity and the mechanisms of reactions of aromatic systems, particularly benzene and its derivatives.
- Introduction to Organic Synthesis 1 (Level 2)
This module revises the reactions of carbonyl compounds with nucleophiles, introduces conjugate addition reactions (electrophilic alkenes), and discusses the acid and base-catalysed reactions of carbonyl compounds at the α-carbon via enols and enolates. Methods for the synthesis of amines are also discussed.
- Heterocyclic Chemistry (Level 3)
This lecture course introduces aromatic and non-aromatic heterocyclic compounds.
- Tutorials: Level 2 Organic Chemistry.
- Level 2 Organic Laboratories
- Level 4 Research Project
- Chemistry and the World Around Us (Level 1): Magic Medicines