Faculty / Research

Francis Johnson, PhD

Professor 

 

Ph.D., Glasgow University, Scotland

Postdoctoral, Boston University

631-632-8866  francis.johnson@stonybrook.edu
Effects of Chemical Carcinogens on DNA : Drug Design and Development - Anti-aging drug substances and Antibiotics.

Francis Johnson was born in Bristol, England but was educated in Scotland. He obtained a B.Sc. and Ph.D. degrees from Glasgow University then moved to the U.S.A. for post-doctoral training at Boston University in the laboratory of Walter Gensler. Thereafter he joined the Eastern Research Laboratory (Director, Dr. F.W. McLafferty)  of The Dow Chemical Company where he rose rapidly to the top-rank position of Research Scientist.  In November 1973, He joined the faculty of the Department of Pharmacological Sciences at Stony Brook as Professor of Pharmacological Sciences, with a joint appointment in the Department of Chemistry.

The more significant scientific contributions of Francis Johnson have been in four areas, namely stereochemistry, the structure and synthesis of natural products, the chemistry of DNA damage and repair and more recently the chemistry of  diseases of aging.

In the field of molecular structure, Dr. Johnson advanced a theory of conformational behavior of unsaturated compounds called  “Allylic Strain”, that covers many areas of chemistry and biology. The principal review article describing these ideas is one of the most quoted papers in the history of organic chemistry. In area of natural products, Dr. Johnson is best known for his work on the glutarimide antibiotics such as cycloheximide, the antitumor anthracyclines, the antibiotic thermorubin,  avenaciolide, the prostaglandins and bleomycin. In the course of this work two new reactions were discovered, one involving the anionic rearrangement of aryl acetylenic ethers and the other, a new type of condensation reaction between alkyl benzoates and benzyl cyanides, substances that have been known for more than 150 years---new chemistry from ancient compounds.

However, DNA damage and its repair have occupied much of the time that he has spent at Stony Brook. In this area his efforts have been devoted mainly to the synthesis of abnormal DNA nucleosides (xenonucleosides) that represent either xenobiotic, oxidative, or radiation damage. He first introduced the now popular “tetrahydrofuran” as a stable abasic site model and demonstrated the use of the “carba” nucleosides as non-hydrolysable  substrates for DNA repair enzymes especially those associated with oxidative damage. Dr. Johnson was also the first to devise general totally synthetic methods for the site-specific introduction  into DNA, of the damage caused by a) the unsaturated aldehydes such as acrolein, b) the carcinogenic amines including the food mutagen PhIP, and c) the polyaromatic hydrocarbons(PAHs), specifically the most carcinogenic metabolites of benzo[a] pyrene –the principle  pro-carcinogen in tobacco smoke.

More recently his research has focused on the highly nephrotoxic and carcinogenic Aristolochic  Acids (AAs). These are naturally-occurring plant substances, found in many herbal products that have been in use for thousands of years. Recently it has been recognized that  their chronic use leads to death by kidney failure and/or cancer development. Both of the DNA adducts formed by AAII have been synthesized in his laboratory and introduced into oligomeric DNA, for biological studies by other team members. In addition, a general and practical, totally-synthetic route to the aristolochic acids ,their congeners and their metabolic products was published recently. Structure-activity studies  are now possible  and should  aid markedly in understanding the etiology of both the nephrotoxicity and the carcinogenicity of this class of substance. 

The past seven years  has seen the development of new areas of interest mainly concerning drug discovery. At present Dr. Johnson is involved in five different drug development  projects where he provides the basic design and synthesizes the molecules involved. These include a) an HDAC inhibitor competitive with Vorinostat but less toxic and with a much better half- life, b) new derivatives of cantharidin that are PP2a inhibitors and useful as anti-tumor compounds in combination with cytoxic drugs, c) Phospho- NSAIDs which are highly effective anti-inflammatory agent  but which have very little effect on the gastric chamber, give high blood levels and are very effective for osteo-arthritis and against prostate and colon cancers, d) new derivatives of the non –toxic potent antibiotic Thermorubin that are highly effective against  all resistant  MRSAs and VREs and most importantly, e) new derivatives of curcumin III (not curcumin I)  that are “resolvins” and that prevent collagen loss in diseases of aging.  Most diseases of the elderly are associated in some way with the loss of collagen mediated by MMPs the key catalytic operator being a zinc atom . Using the idea of constructing a better zinc binding agent  as a basis, a  series of substances have been synthesized and the most active of these has been screened in models of diseases  popularly associated with older people such as osteo-arthritis, periodontitis, heart failure and cancer. In all cases the lead drug substance, which appears to have no toxicity, was found to be highly effective in inhibiting the enzymes and cytokines that are associated with both the natural and the unnatural loss of collagen  . In particular  the lead compound has been found to be highly successful  i) in preventing  bone and soft-tissue loss in rats suffering from periodontitis and ii) in  regulating collagen debriding and restoration during chronic wound-healing (diabetic lesions) again in a diabetic  rat study. Further research is continuing in this area because it appears that the prevention of collagen- loss  likely will delay aging .

             Dr. Johnson is the author or co-author of more than three -hundred publications in peer-reviewed journals including about sixty patents.

 He is the co- founder (with Dr. Ramesh Gupta) and president, of  Chem-Master International Inc., a company that (a)  serves the synthetic  interests of pharmaceutical companies and scientists who work at the interfaces  of Chemistry, Biology and Medicine and (b) is involved in several collaborative  drug development programs as noted above,  with other faculty members at Stony Brook University   

Johnson, F., Huang, C-Y., and Yu, P-L. (1994). Synthetic and oxidative studies of 8-arylamino-2'-deoxyguanosine and -guanosine derivatives. Environ. Health Perspec. 102: 143-149.

Tchou, J., Bodehupi, V., Shibutani, S., Antoshechkin, I., Miller, J., Grollman, A.P., and Johnson, F. (1994). Substrate specificity of Fpg protein. Recognition and cleavage of oxidatively damaged DNA. J. Biol. Chem. 269: 15318-15324.

Gandolfi, C.A., Beggiolin, C, Menta, E., Palumbo, M., Sissi, C., and Johnson, F. (l995). Chromophore-modified anti-tumor anthracenediones: synthesis, DNA binding, and cytotoxic activity of 1,4-Bis [(aminoalkyl) amino]benzzo [g]phthalazine-5-1 0,diones. J. Med. Chem. 38: 526-536.

Zhang, W., Rieger, R., Iden, C., and Johnson, F. (1995). Synthesis of 3,N4-etheno, 3,N4-ethano, and 3-(2-hydroxyethyl) derivatives of -2'-deoxycytidine and their incorporation into oligomeric DNA. Chem. Res. Toxicol. 8: 148-156.

Maruenda, H. and Johnson, F. (1995). Design and synthesis of novel inhibitors of HIV-1 reverse transcriptase. J. Med. Chem. 38: 2145-2151.

Gelfand, C.A., Plum G.E., Grollman, A.P., Johnson, F. and Breslauer K.J. (1996) The impact of a bistrand abasic lesion on DNA duplex properties. Biopolymers 38, 439-445.

Bulychev, N.V., Varaprasad, C.V., Dorman, G., Miller, J.H., Eisenberg, M., Grollman, A.P., and Johnson, F. (1996) Substrate specificity of Escherichia coli MutY protein. Biochemistry 35, 13147-13156.

Cullinan, D., Johnson, F., Grollman, A.P., Eisenberg, M., and de los Santos C. (1997) Solution structure of a DNA duplex containing the exocyclic lesion 3,N4-etheno-2'-deoxycytidine opposite 2'-deoxyguanosine. Biochemistry 36, 11933-11943.

Johnson, F., Dorman, G., Rieger, R.A., Marumoto, R., Iden, C.R., and Bonala, R. (1998) Synthesis of enzymatically noncleavable carbocyclic nucleosides for DNA-N-glycosylase studies. Chemical Research in Toxicology 11, 193-202.

Gelfand, C.A., Plum, G.E., Grollman, A.P., Johnson, F., and Breslauer K.J. (1998) Thermodynamic consequences of an abasic lesion in duplex DNA are strongly dependent on base sequence. Biochemistry 37, 7321-7327.

Gelfand, C.A., Plum, G.E., Grollman, A.P., Johnson, F., and Breslauer K.J. (1998) The impact of an exocyclic cytosine adduct on DNA duplex properties: significant thermodynamic consequences despite modest lesion-induced structural alterations. Biochemistry 37, 12507-12512.

Khullar, S., Varaprasad, C.V. and Johnson, F. (1999) Postsynthetic generation of a major acrolein adduct of 2'-deoxyguanosine in oligomeric DNA. J. Med. Chem. 42, 947-950.

Rieger, R.A., Iden, C.R., Gonikberg, E., and Johnson, F. (1999) 8-Amino-2'-deoxyguanosine incorporation into oligomeric DNA. Nucleosides & Nucleotides 18, 73-88.

Torres, M.C., Varaprasad, C.V., Johnson, F., and Iden, C.R. (1999) Formation of s-triazines during aerial oxidation of 8-oxo-7,8-dihydro-2'-deoxyguanosine in concentrated ammonia. Carcinogenesis 20, 167-172.

Shibutani, S., Fernandes, A., Suzuki, N., Zhou, L., Johnson, F., and Grollman A.P. (1999) Mutagenesis of the N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine DNA adduct in mammalian cells. Sequence context effects. J. Biol. Chem. 274, 27433-27438.

Tan, X., Suzuki, N., Johnson, F., Grollman, A.P., and Shibutani S. (1999) Mutagenic properties of the 8-amino-2'-deoxyguanosine DNA adduct in mammalian cells. Nucleic Acids Research 27, 2310-2314.

Bonala, R.R., Rieger, R.A., Shibutani, S., Grollman, A.P., Iden, C.R., and Johnson F. (1999) 3,N(4)-ethano-2'-deoxycytidine: chemistry of incorporation into oligomeric DNA and reassessment of miscoding potential. Nucleic Acids Research 27, 4725-4733.

Moriya, M., Pandya, G.A., Johnson, F., and Grollman, A.P. (1999) Cellular response to exocyclic DNA adducts. IARC Scientific Publications (Lyon). (150):263-270.

Miller, H., Prasad, R., Wilson, S.H., Johnson, F., and Grollman, A.P. (2000) 8-oxodGTP incorporation by DNA polymerase beta is modified by active-site residue Asn279. Biochemistry 39, 1029-1033.

Budil, D.E., Kolaczkowski, S.V., Perry, A., Varaprasad, C., Johnson, F., and Strauss, P.R. (2000) Dynamics and ordering in a spin-labeled oligonucleotide observed by 220 GHz electron paramagnetic resonance. Biophysical Journal 78, 430-438.

Cullinan, D., Johnson, F., and de los Santos, C. (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. J. Molec. Biol. 296, 851-861.

De Riccardis, F. and Johnson, F. (2000) Chemical synthesis of cross-linked purine nucleosides. Organic Letters 2, 293-295.