Ph.D. Glasgow University, 1954 Postdoctoral Fellow, Boston University, 1954-1957

Organic Chemistry - Medical Chemistry The major research interests of this laboratory are concerned with a) chemical aspects of genetic toxicology and b) a program of synthesis aimed at rationally designed drugs to inhibit viral enzymes associated with HIV-1 (AIDS), c) new methods of synthesis involving organo-alkali chemistry.

Our approach to studies in genetic toxicology involves the synthesis (automated) of DNA having chemical lesions that arise physiologically from carcinogenic substances or radiation. The chief objective is to examine the mutation spectrum associated with these lesions. This is investigated both by in vitro and in vivo studies with DNA polymerases and repair enzymes. Our work so far has examined lesions associated with acrolein, carcinogenic amines, and oxidation products of both deoxyguanosine and deoxyadenosine, products that are associated with both radiation damage and asbestos-mediated transformations. In the course of this work the oxidation chemistry of the carcinogenic amine adducts has shown that at physiological pH a slow oxygen-induced degradation takes place, producing an array of intermediates derived from the initial adduct. The role of these secondary lesions in carcinogenesis is under investigation. In addition, new protecting groups for the synthesis of DNA containing these lesions have had to be designed to accommodate the extreme sensitivity of a number of these adducts to the normal chemistry of DNA synthesis.

In the area of AIDS research, we have been successful in designing new substances that interfere with the reverse transcriptase responsible for the viral DNA/RNA replication. These substances constitute a new class of anti-viral agents in that they inhibit the viral reverse transcriptase at the active site and appear to be irreversible in action. They are active against a range of other viruses, but do not inhibit the cellular DNA synthetases of mammalian cells.

The third area of research concerns new synthetic methods. Here, we have discovered a new type of directed ortho-metalation cyclization that allows the easy synthesis of a wide variety of indenediones. Previously, synthetic methods for the preparation of this class of compound were limited to the simplest members of the group. Some of the new compounds are now being tested for anticoagulant and antibiotic activity.

Genotoxic mechanism for the major acrolein-derived deoxyguanosine adduct in human cells Yang IY, Johnson F, Grollman AP, Moriya M CHEMICAL RESEARCH IN TOXICOLOGY 15 (2): 160-164 FEB 2002 Preparation of oligodeoxynucleotides containing a diastereoisomer of alpha-(N-2-2 '-deoxyguanosinyl)tamoxifen by phosphoramidite chemical synthesis, Laxmi YRS, Suzuki N, Dasaradhi L, Johnson F, Shibutani S CHEMICAL RESEARCH IN TOXICOLOGY 15 (2): 218-225 FEB 2002 Regioisomeric synthesis and characteristics of the alpha-hydroxy-1,N-2-propanodeoxyguanosine Huang Y, Johnson F, CHEMICAL RESEARCH IN TOXICOLOGY 15 (2): 236-239 FEB 2002 A spin-labeled abasic DNA substrate for AP endonuclease, Kolaczkowski SV, Perry A, Mckenzie A, Johnson F, Budil DE, Strauss PR, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 288 (3): 722-726 NOV 2 2001 Site-specifically located 8-amino-2 '-deoxyguanosine: thermodynamic stability and mutagenic properties in Escherichia coli Venkatarangan L, Sivaprasad A, Johnson F, Basu AK NUCLEIC ACIDS RESEARCH 29 (7): 1458-1463 APR 1 2001 Influence of flanking sequence context on the mutagenicity of acetylaminofluorene-derived DNA adducts in mammalian cells, Shibutani S, Suzuki N, Tan XZ, Johnson F, Grollman AP BIOCHEMISTRY 40 (12): 3717-3722 MAR 27 2001 Responses to the major acrolein-derived deoxyguanosine adduct in Escherichia coli Yang IY, Hossain M, Miller H, Khullar S, Johnson F, Grollman A, Moriya M JOURNAL OF BIOLOGICAL CHEMISTRY 276 (12): 9071-9076 MAR 23 2001 NMR characterization of a DNA duplex containing the major acrolein-derived deoxyguanosine adduct gamma-OH-1,N-2-propano-2 '-deoxyguanosine, de los Santos C, Zaliznyak T, Johnson F, JOURNAL OF BIOLOGICAL CHEMISTRY 276 (12): 9077-9082 MAR 23 2001 Bulge-specific DNA binding of spirocyclic NCS-chrom analogs. Jones G, Qabaja G, Goldberg I, Xi Z, Johnson F, ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 219: 677-ORGN Part 2 MAR 26 2000 Synthesis of biologically active N-2-amine adducts of 2 '-deoxyguanosine, Bonala RR, Shishkina IG, Johnson F TETRAHEDRON LETTERS 41 (38): 7281-7284 SEP 16 2000 A new method for the postsynthetic generation of abasic sites in oligomeric DNA Shishkina IG, Johnson F, CHEMICAL RESEARCH IN TOXICOLOGY 13 (9): 907-912 SEP 2000 Enolate ions as beta-activators of ortho-metalation: Direct synthesis of 3-aminoindenones Kayaleh NE, Gupta RC, Johnson F, JOURNAL OF ORGANIC CHEMISTRY 65 (15): 4515-4522 JUL 28 2000 Structure of an 11-mer DNA duplex containing the carbocyclic nucleotide analog: 2 '-deoxyaristeromycin, Smirnov S, Johnson F, Marumoto R, de los Santos C JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS 17 (6): 981-991 JUN 2000 Solution structure of an 11-mer duplex containing the 3,N-4-ethenocytosine adduct opposite 2 '-deoxycytidine: Implications for the recognition of exocyclic lesions by DNA glycosylases Cullinan D, Johnson F, de los Santos C, JOURNAL OF MOLECULAR BIOLOGY 296 (3): 851-861 FEB 25 2000 Chemical synthesis of cross-linked purine nucleosides, De Riccardis F, Johnson F ORGANIC LETTERS 2 (3): 293-295 FEB 10 2000 Synthesis and DNA binding of spirocyclic model compounds related to the neocarzinostatin chromophore, Xi Z, Jones GB, Qabaja G, Wright J, Johnson F, Goldberg IH, ORGANIC LETTERS 1 (9): 1375-1377 NOV 4 1999 8-OxodGTP incorporation by DNA polymerase beta is modified by active-site residue Asn279 Miller H, Prasad R, Wilson SH, Johnson F, Grollman AP BIOCHEMISTRY 39 (5): 1029-1033 FEB 8 2000

Dynamics and ordering in a spin-labeled oligonucleotide observed by 220 GHz electron paramagnetic resonance, Budil DE, Kolaczkowski SV, Perry A, Varaprasad C, Johnson F, Strauss PR BIOPHYSICAL JOURNAL 78 (1): 430-438 Part 1 JAN 2000