The polyamine-biosynthetic pathway represents an inviting target for the development of agents inhibiting carcinogenesis and tumor growth. Polyamines play an essential role in the proliferation and development of mammalian cells. Deranged polyamine metabolism may be an important factor in carcinogenesis. Depletion of polyamines inhibits growth of neoplastic cells in vitro and in animal models. Several different classes of other anticancer agents may under some conditions exert enhanced effects when polyamine levels are depleted. Some suitable inhibitors of polyamine production are currently available and other promising compounds are presently being tested. It should soon prove possible to block polyamine biosynthesis at every step in the pathway. The use of these inhibitors alone and combined either with each other or with other antitumor agents will enable a full examination of the potential of this approach.

https://cancerres.aacrjournals.org/content/canres/48/4/759.full.pdf

Polyamine Metabolism and Its Importance in Neoplastic Growth and as a Target for Chemotherapy

Polyamines are ubiquitous organic cations of low molecular weight. The content of these amines is closely regulated by the cell according to the state of growth. The reactions responsible for the biosynthesis and interconversion of the polyamines and their precursor putrescine are described and the means by which polyamine content can be varied in response to exogenous stimuli are discussed. The role of polyamines in the cell cycle, cell division, tissue growth, and differentiation is considered. Recent studies using highly specific inhibitors of polyamine biosynthesis such as alpha-difluoromethylornithine to prevent accumulation of polyamines have indicated that the synthesis of polyamines is intimately associated with these processes. Such inhibitors have great potential for investigation of the cellular role of polyamines.

https://www.physiology.org/doi/pdf/10.1152/ajpcell.1982.243.5.C212

Polyamine metabolism and function.

/pdf/recent-advances-in-the-biochemistry-of-polyamines-in-382j7cp9ea.pdf

Recent advances in the biochemistry of polyamines in eukaryotes.

Described is a bioorthogonal reaction that proceeds with unusually fast reaction rates without need for catalysis: the cycloaddition of s-tetrazine and trans-cyclooctene derivatives. The reactions tolerate a broad range of functionality and proceed in high yield in organic solvents, water, cell media, or cell lysate. The rate of the ligation between trans-cyclooctene and 3,6-di-(2-pyridyl)-s-tetrazine is very rapid (k2 2000 M−1 s−1). This fast reactivity enables protein modification at low concentration.

/pdf/tetrazine-ligation-fast-bioconjugation-based-on-inverse-2fu21l5iai.pdf

Tetrazine ligation: fast bioconjugation based on inverse-electron-demand Diels-Alder reactivity.

Introduction Chapter 1 "Unique Properties of Fluorine and Their Relevance to Medicinal Chemistry and Chemical Biology" by Takashi Yamazaki, Takeo Taguchi and Iwao Ojima Medicinal Chemistry Chapter 2 "Fluorinated Prostanoids: Development of Tafluprost, a New Anti-glaucoma Agent" by Yasushi Matsumura Chapter 3 "Fluorinated conformationally restricted glutamate analogs for CNS drug discovery and development" by Atsuro Nakazato Chapter 4 "Fluorinated Inhibitors of Matrix Metalloproteinases" by Roberta Sinisi, Monika Jagodzinska, Gabriele Candiani, Florent Huguenot, Monica Sani, Alessandro Volonterio, Raffaella Maffezzoni and Matteo Zanda Chapter 5 "Fluoro-Taxoid Anticancer Agents" by Antonella Pepe, Larisa Kuznetsova, Liang Sun and Iwao Ojima Chapter 6 "Antimalarial Fluoroartemisinins: Increased Metabolic and Chemical Stability"by Jean-Pierre Begue, Daniele Bonnet-Delpon Chapter 7 "Synthesis and Biological Activity of Fluorinated Nucleosides" by Tokumi Maruyama, Masahiro Ikejiri, Kunisuke Izawa and Tomoyuki Onishi Synthetic methods for medicinal chemistry and chemical biology Chapter 8 "Synthesis of gem -Difluoromethylenated Nucleosides via gem -Difluoromethylene-Containing Building Blocks" by Wei-Dong Meng and Feng-Ling Qing Chapter 9 "Recent Advances in the Syntheses of Fluorinated Amino Acids" by Kenji Uneyama Chapter 10 "Fluorinated Moieties for Replacement of Amide and Peptide Bonds" by Takeo Taguchi and Hikaru Yanai Chapter 11 "Perfluorinated Heteroaromatic Systems as Scaffolds for Drug Discovery" by David Armstrong, Matthew W. Cartwright, Emma L. Parks, Graham Pattison, Graham Sandford, Rachel Slater, John A. Christopher, David D. Miller, Paul W. Smith and Antonio Vong Chapter 12 " gem -Difluorocyclopropanes as key building blocks for novel biologically active molecules" by Toshiyuki Itoh Chapter 13 "Fluorous Mixture Synthesis (FMS) of Drug-Like Molecules and Enantiomers, Stereoisomers, and Analogs of Natural Products" by Wei Zhang Chapter 14 "Fluorine-18 Radiopharmaceuticals" by Michael R. Kilbourn and Xia Shao Applications of fluorinated amino acids and peptides to chemical biology and pharmacology Chapter 15 "Application of Artificial Model Systems to Study the Interactions of Fluorinated Amino Acids within the Native Environment of Coiled Coil Proteins" by Mario Salwiczek, Toni Vagt and Beate Koksch Chapter 16 "Fluorinated Amino Acids and Biomolecules in Protein Design and Chemical Biology" by He Meng, Ginevra A. Clark , and Krishna Kumar Chapter 17 "Effects of Fluorination on the Bioorganic Properties of Methionine" by John F. Honek Chapter 18 "Structure analysis of membrane-active peptides using 19 F-labeled amino acids and solid state NMR" by Parvesh Wadhwani and Erik Strandberg Chapter 19 "Metabolism of Fluorine-containing Drugs using in vivo Magnetic Resonance Spectroscopy" by Erika Schneider Appendix "FDA-Approved Active Pharmaceutical Ingredients Containing Fluorine" by Elizabeth Pollina-Cormier, Manisha Das, and Iwao Ojima

Fluorine in medicinal chemistry and chemical biology

Catalytic irreversible inhibition of mammalian ornithine decarboxylase (E.C.4.1.1.17) by substrate and product analogs

Anti-proliferative properties of DL-α-difluoromethyl ornithine in cultured cells. A consequence of the irreversible inhibition of ornithine decarboxylase

A biphasic increase of putrescine concentration occurs in rat hepatoma tissue culture cells induced to proliferate. DL-alpha-Methyl ornithine, a competitive inhibitor of ornithine decarboxylase ( L-ornithine carboxylyase, EC 4.1.1.7) of hepatoma tissue culture cells, blocks the usual increases of putrescine and spermidine concentrations in these cells, and causes a rapid fall in the levels of putrescine which is followed by a striking decrease of spermidine.In parallel with the depletion of these amines, incorporation of [3H]thymidine into DNA and cell proliferation are inhibited. Addition of putrescine, spermidine, or spermine results in an immediate resumption of cell proliferation. Cell proliferation is also restored by L-ornithine presumably due to in situ competitive inhibition of ornithine decarboxylase. These findings of hepatoma tissue culture cells support the concept that polyamines play an essential function in the cell division processes.

Philippe Bey

Papers

Catalytic irreversible inhibition of mammalian ornithine decarboxylase (E.C.4.1.1.17) by substrate and product analogs

Anti-proliferative properties of DL-α-difluoromethyl ornithine in cultured cells. A consequence of the irreversible inhibition of ornithine decarboxylase

Alpha-methyl ornithine, a potent competitive inhibitor of ornithine decarboxylase, blocks proliferation of rat hepatoma cells in culture

N-2,3-Butadienyl-1,4-butanediamine derivatives: potent irreversible inactivators of mammalian polyamine oxidase.

Direct synthesis of .alpha.-halogenomethyl-.alpha.-amino acids from the parent .alpha.-amino acids