Chemoselective fluorination and chemoinformatic analysis of griseofulvin: Natural vs fluorinated fungal metabolites.

Griseofulvin is a fungal metabolite and antifungal drug used for the treatment of dermatophytosis in both humans and animals. Recently, griseofulvin and its analogues have attracted renewed attention due to reports of their potential anticancer effects. In this study griseofulvin (1) and related analogues (2-6, with 4 being new to literature) were isolated from Xylaria cubensis. Six fluorinated analogues (7-12) were synthesized, each in a single step using the isolated natural products and Selectflour, so as to examine the effects of fluorine incorporation on the bioactivities of this structural class. The isolated and synthesized compounds were screened for activity against a panel of cancer cell lines (MDA-MB-435, MDA-MB-231, OVCAR3, and Huh7.5.1) and for antifungal activity against Microsporum gypseum. A comparison of the chemical space occupied by the natural and fluorinated analogues was carried out by using principal component analysis, documenting that the isolated and fluorinated analogues occupy complementary regions of chemical space. However, the most active compounds, including two fluorinated derivatives, were centered around the chemical space that was occupied by the parent compound, griseofulvin, suggesting that modifications must preserve certain attributes of griseofulvin to conserve its activity.

[1]  H. Goldschmidt,et al.  GF-15, a novel inhibitor of centrosomal clustering, suppresses tumor cell growth in vitro and in vivo. , 2012, Cancer research.

[2]  T. C. White,et al.  Sequenced dermatophyte strains: growth rate, conidiation, drug susceptibilities, and virulence in an invertebrate model. , 2011, Fungal genetics and biology : FG & B.

[3]  H. Raistrick,et al.  Studies in the biochemistry of micro-organisms: Griseofulvin, C(17)H(17)O(6)Cl, a metabolic product of Penicillium griseo-fulvum Dierckx. , 1939, The Biochemical journal.

[4]  Alan L Harvey,et al.  Current strategies for drug discovery through natural products , 2010, Expert opinion on drug discovery.

[5]  Ralph A. Cacho,et al.  Identification of the viridicatumtoxin and griseofulvin gene clusters from Penicillium aethiopicum. , 2010, Chemistry & biology.

[6]  P. V. Balaji,et al.  Griseofulvin stabilizes microtubule dynamics, activates p53 and inhibits the proliferation of MCF-7 cells synergistically with vinblastine , 2010, BMC Cancer.

[7]  Nicholas H Oberlies,et al.  Fungal Identification Using Molecular Tools: A Primer for the Natural Products Research Community , 2017, Journal of natural products.

[8]  A. Cousson,et al.  Efficient oxidative ipso -fluorination of para -substituted phenols using pyridinium polyhydrogen fluoride in combination with hypervalent iodine(III) reagents , 2004 .

[9]  D. Taub,et al.  Synthesis in the Griseofulvin Series. II. 7-Fluoro-7-dechlorogriseofulvin, an Active Analog1 , 1963 .

[10]  K. Zomorodian,et al.  The effect of griseofulvin on the gene regulation of β-tubulin in the dermatophyte pathogen Trichophyton rubrum , 2007, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy.

[11]  Tsuyoshi Fukuhara,et al.  Novel Fluorination Reagent: IF5 / Et3N–3HF , 2001 .

[12]  José L Medina-Franco,et al.  Chemoinformatic expedition of the chemical space of fungal products. , 2016, Future medicinal chemistry.

[13]  M. Zupan,et al.  Efficient Synthesis of 4-Fluorocyclohexa-2,5-dienone Derivatives Using N-Fluoro-1,4-diazoniabicyclo[2.2.2]octane Salt Analogues , 1999 .

[14]  Jean‐Cyrille Hierso.  Indirect nonbonded nuclear spin-spin coupling: a guide for the recognition and understanding of "through-space" NMR J constants in small organic, organometallic, and coordination compounds. , 2014, Chemical reviews.

[15]  D. Barton,et al.  Organic reactions of fluoro-oxy-compounds. Fluorination of griseofulvin. , 1972, Journal of the Chemical Society. Perkin transactions 1.

[16]  D. Newman,et al.  Natural Products as Sources of New Drugs from 1981 to 2014. , 2016, Journal of natural products.

[17]  N. Klaus.  Influence of chlorine substituents on biological activity of chemicals: a review. , 2000 .

[18]  Wei Zhu,et al.  Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II-III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas. , 2016, Chemical reviews.

[19]  V. N. Kovtonyuk,et al.  Interaction of pentafluorophenol with lead tetraacetate in acids , 1985 .

[20]  M. Balouiri,et al.  Methods for in vitro evaluating antimicrobial activity: A review☆ , 2015, Journal of pharmaceutical analysis.

[21]  C. Dumontet,et al.  Microtubule-binding agents: a dynamic field of cancer therapeutics , 2010, Nature Reviews Drug Discovery.

[22]  A. Krämer,et al.  Disparate SAR data of griseofulvin analogues for the dermatophytes Trichophyton mentagrophytes, T. rubrum, and MDA-MB-231 cancer cells. , 2012, Journal of medicinal chemistry.

[23]  José L Medina-Franco,et al.  Activity Cliffs: Facts or Artifacts? , 2013, Chemical biology & drug design.

[24]  David J Newman,et al.  Natural products as sources of new drugs over the 30 years from 1981 to 2010. , 2012, Journal of natural products.

[25]  S. Tyring,et al.  Therapy of common superficial fungal infections , 2004, Dermatologic therapy.

[26]  D. Burton,et al.  Robust hepatitis C virus infection in vitro. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[27]  C. Pearce,et al.  Cytotoxic epipolythiodioxopiperazine alkaloids from filamentous fungi of the Bionectriaceae , 2012, The Journal of Antibiotics.

[28]  M. D. Hill,et al.  Applications of Fluorine in Medicinal Chemistry. , 2015, Journal of medicinal chemistry.

[29]  H. Raja,et al.  Biosynthetically Distinct Cytotoxic Polyketides from Setophoma terrestris. , 2015, European journal of organic chemistry.

[30]  Gianni Chessari,et al.  Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design. , 2010, Journal of medicinal chemistry.

[31]  Hong Liu,et al.  Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011). , 2014, Chemical reviews.

[32]  A. Kinghorn,et al.  Chemical Diversity of Metabolites from Fungi, Cyanobacteria, and Plants Relative to FDA-Approved Anticancer Agents. , 2012, ACS medicinal chemistry letters.

[33]  A. Krämer,et al.  Identification of griseofulvin as an inhibitor of centrosomal clustering in a phenotype-based screen. , 2007, Cancer research.

[34]  Peng Zhou,et al.  Fluorine Bonding - How Does It Work In Protein-Ligand Interactions? , 2009, J. Chem. Inf. Model..

[35]  J. Passchier,et al.  Metal-free oxidative fluorination of phenols with [18F]fluoride. , 2012, Angewandte Chemie.

[36]  S. Polyak,et al.  Identification of hepatoprotective flavonolignans from silymarin , 2010, Proceedings of the National Academy of Sciences.

[37]  S. Matthew,et al.  Resorcylic acid lactones with cytotoxic and NF-κB inhibitory activities and their structure-activity relationships. , 2011, Journal of natural products.

[38]  B. E. Evans,et al.  Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists. , 1988, Journal of Medicinal Chemistry.

[39]  Nicholas H Oberlies,et al.  Isolation, semisynthesis, covalent docking and transforming growth factor beta-activated kinase 1 (TAK1)-inhibitory activities of (5Z)-7-oxozeaenol analogues. , 2015, Bioorganic & medicinal chemistry.

[40]  R. Singh,et al.  Recent highlights in electrophilic fluorination with 1-chloromethyl-4-fluoro- 1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate). , 2004, Accounts of chemical research.

[41]  Tsuyoshi Fukuhara,et al.  Effective synthesis of difluorocyclohexadienones by electrochemical oxidation of phenols , 2002 .

[42]  G. Mauer,et al.  New routes to hexafluorocyclopentadiene and related compounds , 1985 .

[43]  C. J. Singh.  Extracellular protease expression in Microsporum gypseum complex, its regulation and keratinolytic potential , 2011, Mycoses.

[44]  F. Moy,et al.  qNMR for profiling the production of fungal secondary metabolites , 2017, Magnetic resonance in chemistry : MRC.

[45]  Natural products as antifungal agents against clinically relevant pathogens , 2010 .

[46]  John D. Roberts,et al.  ^(13)C nuclear magnetic resonance spectroscopy. Determination of carbon-fluorine couplings , 1971 .

[47]  M. Ghannoum,et al.  Agar-Based Disk Diffusion Assay for Susceptibility Testing of Dermatophytes , 2010, Journal of Clinical Microbiology.

[48]  Jen-kun Lin,et al.  Griseofulvin potentiates antitumorigenesis effects of nocodazole through induction of apoptosis and G2/M cell cycle arrest in human colorectal cancer cells , 2000 .

[49]  James W. MacDonald,et al.  Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling. , 2015, Journal of natural products.

[50]  D. O'Hagan,et al.  Fluorine in medicinal chemistry: A review of anti-cancer agents , 2006 .

[51]  A. Ganesan.  The impact of natural products upon modern drug discovery. , 2008, Current opinion in chemical biology.

[52]  Helen J. Mitchell,et al.  Natural Product-like Combinatorial Libraries Based on Privileged Structures. 1. General Principles and Solid-Phase Synthesis of Benzopyrans , 2000 .

[53]  T. Lectka,et al.  The close interaction of a C F bond with a carbonyl π–system: Attractive, repulsive, or both? , 2016 .

[54]  D. Czerucka,et al.  The anti-mitotic drug griseofulvin induces apoptosis of human germ cell tumor cells through a connexin 43-dependent molecular mechanism , 2013, Apoptosis.

[55]  Chi‐Huey Wong,et al.  Selectfluor: mechanistic insight and applications. , 2004, Angewandte Chemie.

[56]  E. Pasquier,et al.  Microtubules: A dynamic target in cancer therapy , 2008, IUBMB life.

[57]  Dulal Panda,et al.  Microtubule assembly dynamics: An attractive target for anticancer drugs , 2008, IUBMB life.

[58]  Thomas Sander,et al.  DataWarrior: An Open-Source Program For Chemistry Aware Data Visualization And Analysis , 2015, J. Chem. Inf. Model..

[59]  A. Kaur,et al.  New diketopiperazine dimer from a filamentous fungal isolate of Aspergillus sydowii , 2015, Magnetic resonance in chemistry : MRC.

[60]  D. Barton,et al.  Organic reactions of fluoroxy-compounds: electrophilic fluorination of activated olefins , 1968 .

[61]  T. O. Larsen,et al.  The chemistry of griseofulvin. , 2014, Chemical reviews.

[62]  J. Gentles.  Experimental Ringworm in Guinea Pigs: Oral Treatment with Griseofulvin , 1958, Nature.