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

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 .

Looking back on my career, initially as a chemist and later a pharmacologist, I have always tackled problems that have had some significance to these areas of science and in a number of cases of direct relevance to human health problems. In character I am a problem-solver and in almost all of my publications there are elements of originality. An outstanding  contribution was the devising of two theorems that solved immediately the stereochemical behavior of  almost all unsaturated systems in the field of organic chemistry, where only disarray existed previously.

This now constitutes the fourth leg of all molecular stereochemical behavior. Other accomplishments include (1) the first method that allowed the introduction of the most carcinogenic benzopyrene metabolite into dG and dA and the subsequent  incorporation of the xeno-base into oligomeric DNA and (2) a similar scenario in which the redox lesion (DNA damage) commonly known as FaPy was synthesized and again introduced into oligomeric DNA at any position required.  Other accomplishments include the total syntheses of Cycloheximide, Avenaciolide, Prostaglandin F2a  and the Aristolochic Acids. More recently I have sortied into drug development and of the four drug substances that I have invented, one, namely LB100, which is a checkpoint inhibitor, has passed through clinical trials successfully and the company shepherding it, will likely be listed on the NASDAQ. The other, CMC 2.24 a pleiotropic substance, is currently being licensed to a French veterinary company for use to prevent or halt both periodontitis and osteoarthritis in companion animals. Because it has no demonstrable side-effects at high dosing (Diabetic-1 rats: 1000mg/kg body weight) we believe that it assuredly will find a place in human therapy.

These are some of the unvarnished highlights of the nearly 400 papers and patents etc., that I have published.

RECENT

Chemically-modified curcumin 2.24: a novel systemic therapy for natural periodontitis in dogs. Deng J; Golub LM Lee H-M; Lin MC; Bhatt HD; Hong H-L; Johnson F; Scaduto J; Zimmerman T; Gu Y. Journal of Experimental Pharmacology (2020), 12, 47-60, PMID: 32104105

Enhanced efficacy of chemically modified curcumin in experimental periodontitis: systemic implications. Wang HH; Lee H-M; Raja V; Hou W; Iacono VJ; Scaduto J; Johnson F; Golub LM; Gu Y. Journal of Experimental Pharmacology (2019), 11, 1-14, PMID: 30774454

Targeted and Untargeted Detection of DNA Adducts of Aromatic Amine Carcinogens in Human Bladder by Ultra-Performance Liquid Chromatography-High-Resolution Mass Spectrometry. Guo J; Villalta PW; Weight CJ; Bonala R; Johnson F; Rosenquist TA; Turesky RJ. Chemical Research in Toxicology (2018), 31(12), 1382-1397, PMID: 30387604

A Chemically Modified Curcumin (CMC 2.24) Inhibits Nuclear Factor κB Activation and Inflammatory Bone Loss in Murine Models of LPS-Induced Experimental Periodontitis and Diabetes-Associated Natural Periodontitis. Elburki MS; Rossa C Jr; Guimaraes-Stabili MR; Lee H-M; Curylofo-Zotti FA; Johnson F; Golub LM. Inflammation (2017), 40(4), 1436-144, PMID: 28534138

Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial. Chung V; Mansfield AS; Braiteh F; Richards D; Durivage H; Ungerleider RS.; Johnson F; Kovach JS. Cancer Research (2017), 23(13), 3277-3284, PMID: 28039265

A novel chemically modified curcumin "normalizes" wound-​healing in rats with experimentally induced type I diabetes: initial studies. Zhang Y; McClain SA; Lee H-M; Elburki MS; Yu H; Gu Y; Zhang Y; Wolff M; Johnson F; Golub LM. Journal of Diabetes Research (2016), 5782904/1-5782904/11, PMID: 27190999

Total Synthesis of the Aristolochic Acids, Their Major Metabolites, and Related Compounds. Attaluri S; Iden CR; Bonala Radha R; Johnson F. Chemical Research in Toxicology (2014), 27(7), 1236-1242, PMID: 24877584

Prostate cancer stem cell-targeted efficacy of a new-generation taxoid, SBT-1214 and novel polyenolic zinc-binding curcuminoid, CMC2.24. Botchkina GI; Zuniga ES; Rowehl RH; Park R; Bhalla R; Bialkowska AB; Johnson F; Golub LM; Zhang Y; Ojima I; et al. PloS one (2013), 8(9), e69884, PMID: 24086245

Design, synthesis and biological activity of new polyenolic inhibitors of matrix metalloproteinases: a focus on chemically-modified curcumins. Zhang Y; Gu Y; Lee H-M; Hambardjieva E; Vrankova Ka; Golub, Lorne M.; Johnson, Francis. Current Medicinal Chemistry (2012), 19(25), 4348-4358, PMID: 22830350

The Antibiotic Thermorubin Inhibits Protein Synthesis by Binding to Inter-Subunit Bridge B2a of the Ribosome. Bulkley D; Johnson F; Steitz TA. Journal of Molecular Biology (2012), 416(4), 571-578, PMID: 22240456

 

EARLIER

Novel post-synthetic generation, isomeric resolution, and characterization of Fapy-dG within oligodeoxynucleotides: differential anomeric impacts on DNA duplex properties. Lukin M; Minetti CASA; Remeta DP; Attaluri S; Johnson F; Breslauer KJ; de los Santos C. Nucleic Acids Research (2011), 39(13), 5776-5789, PMID: 21415012

Structure-activity relationship study of novel anticancer aspirin-based compounds. Joseph S; Nie T; Huang L; Zhou H; Atmakur K; Gupta RC; Johnson F; Rigas, B. Molecular Medicine Reports (2011), 4(5), 891-899, PMID: 21805049

Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms. Lu J; Kovach JS; Johnson F; Chiang J; Hodes R; Lonser R; Zhuang Z. Proceedings of the National Academy of Sciences, USA (2009), 106(28), 11697-11702, PMID: 19564615

3-demethoxy-3-glycosylaminothiocolchicines: Synthesis of a new class of putative muscle relaxant compounds. Gelmi ML; Pocar D; Pontremoli G; Pellegrino S; Bombardelli E; Fontana G; Riva A; Balduini W; Carloni S; Cimino M; et al. Journal of medicinal chemistry (2006), 49(18), 5571-7, PMID: 16942030

Inhibition of the Bacterial Enoyl Reductase FabI by Triclosan: A Structure-​Reactivity Analysis of FabI Inhibition by Triclosan Analogues. Sivaraman S; Sullivan, TJ; Johnson F; Novichenok P; Cui G; Simmerling C; Tonge PJ. Journal of Medicinal Chemistry (2004), 47(3), 509-518, PMID: 14736233

Application of vicarious nucleophilic substitution to the total synthesis of dl-physostigmine. Rege PD; Johnson F. The Journal of organic chemistry (2003), 68(16), 6133-9, PMID: 12895041

Efficient synthesis of the benzo[a]pyrene metabolic adducts of 2'-deoxyguanosine and 2'-deoxyadenosine and their direct incorporation into DNA. Johnson F; Bonala R; Tawde D; Torres MC; Iden CR. Chemical research in toxicology (2002), 15(12), 1489-94, PMID: 12482230

A New Method for the Postsynthetic Generation of Abasic Sites in Oligomeric DNA. Shishkina IG; Johnson, F. Chemical Research in Toxicology (2000), 13(9), 907-912, PMID: 10995264