Abstract
Optically active helicene derivatives inhibit the activity on histamine N-methyl transferase (HNMT). Specifically, methyl (P)-1,12-dimethylbenzo[c]phenanthrene-8-carboxylate with 6-iodo and 5-trifluoromethanesulfonyloxy groups inhibits HNMT activity on the μM order of IC50. Chirality is important, and (M)-isomers exhibits substantially reduced activity. The 6-iodo group is also essential, which suggests the involvement of halogen bonds in protein binding. Substituents on the sulfonate moiety also affect the inhibitory activity.
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References
Alberts B, et al. Molecular biology of the cell. 6th ed. New York, NY, USA: Garland Science; 2014.
Shen Y, Chen C-F. Helicenes: synthesis and applications. Chem Rev. 2012;112:1463–535.
Gingras M. One hundred years of helicene chemistry. Part 1: non-stereoselective syntheses of carbohelicenes. Chem Soc Rev. 2013;42:968–1006.
Gingras M, Félix G, Peresutti R. One hundred years of helicene chemistry. Part 2: stereoselective syntheses and chiral separations of carbohelicenes. Chem Soc Rev. 2013;42:1007–50.
Gingras M. One hundred years of helicene chemistry. Part 3: applications and properties of carbohelicenes. Chem Soc Rev. 2013;42:1051–95.
Yamaguchi M, Shigeno M, Saito N, Yamamoto K. Synthesis, double-helix formation, and higher-assembly formation of chiral polycyclic aromatic compounds: conceptual development of polyketide aldol synthesis. Chem Rec. 2014;14:15–27.
Saito N, Yamaguchi M. Synthesis and self-assembly of chiral cylindrical molecular complexes: functional heterogeneous liquid-solid materials formed by helicene oligomers. Molecules. 2018;23:277.
Hasan M, Borovkov V. Helicene-based chiral auxiliaries and chirogenesis. Symmetry. 2018;10:10.
Honzawa H, et al. Chiral recognition in the binding of helicenediamine to double strand DNA: interactions between low molecular weight helical compounds and a helical polymer. Bioorg Med Chem. 2002;10:3213–8.
Xu Y, et al. (P)-Helicene displays chiral selection in binding to Z-DNA. J Am Chem Soc. 2004;126:6566–7.
Shinohara K, et al. A chiral wedge molecule inhibits telomerase activity. J Am Chem Soc. 2010;132:3778–82.
Kawara K, Tsuji G, Taniguchi Y, Sasaki S. Synchronized chiral induction between [5]helicene-spermine ligand and B-Z DNA transition. Chem Eur J. 2017;23:1763–9.
Kel O, et al. Chiral selectivity in the binding of [4]helicene derivatives to double-stranded DNA. Chem Eur J. 2013;19:7173–80.
Passeri R, et al. Photophysical properties of N-alkylated azahelicene derivatives as DNA intercalators: counterion effect. Photochem Photobiol Sci. 2009;8:1574–82.
Bauer C, et al. Specific labelling of mitochondria of Chlamydomonas with cationic helicene fluorophores. Org Biomol Chem. 2018;16:919–23.
Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev. 2008;88:1183–241.
Haas H, Panula P. The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci. 2003;4:121–30.
Alraksinen MS, et al. Histamine neurons in human hypothalamus: anatomy in normal and alzheimer diseased brains. Neuroscience. 1991;44:465–81.
Szakacs Z, et al. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16:200–7.
Naganuma F, et al. Histamine N-methyltransferase regulates aggression and the sleep-wake cycle. Sci Rep. 2017;7:15899.
Saito N, Terakawa R, Yamaguchi M. Synthesis, π‐face‐selective aggregation, and π‐face chiral recognition of configurationally stable C 3‐symmetric propeller‐chiral molecules with a π‐core. Chem Eur J. 2014;20:5601–7.
Wang L, Zhou X, Fredimoses M, Liao S, Liu Y. Naturally occurring organoiodines. RSC Adv. 2014;4:57350–76.
Wilcken R, Zimmermann MO, Lange A, Joerger AC, Boeckler FM. Principles and applications of halogen bonding in medicinal chemistry and chemical biology. J Med Chem. 2013;56:1363–88.
Bott G, Field LD, Sternhell S. Steric effects. A study of a rationally designed system. J Am Che Soc. 1980;102:5618–26.
Minkwitz R, et al. Synthesis and characterization of the first examples of perfluoroalkyl-substituted trialkyloxonium salts, [(CH3)2OCF3]+[Sb2F11]- and [(CH3)2OCF(CF3)2]+[Sb2F11]-. Inorg Chem. 2001;40:4404–8.
Horton JR, Sawada K, Nishibori M, Zhang X, Cheng X. Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons. Structure. 2001;9:837–49.
Horton JR, Sawada K, Nishibori M, Cheng X. Structural basis for inhibition of histamine N-methyltransferase by diverse drugs. J Mol Biol. 2005;353:334–44.
Yoshikawa T, et al. Molecular mechanism of histamine clearance by primary human astrocytes. Glia. 2013;61:905–16.
Acknowledgements
This work was financially supported by Grants-in-Aid for Scientific Research (nos. 17H03050 and 17H08203) from the Japan Society for the Promotion of Science (JSPS), and Platform Project for Supporting Drug Discovery and Life Science Research from AMED under Grant Number JP18am0101100. TS thanks JSPS for a Research Fellowship for Young Scientists (no. 17J02496).
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Dedication Dedicated to Professor Samuel Danishefsky for his contribution in synthetic chemistry.
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Ichinose, W., Sawato, T., Kitano, H. et al. Optically active iodohelicene derivatives exhibit histamine N-methyl transferase inhibitory activity. J Antibiot 72, 476–481 (2019). https://doi.org/10.1038/s41429-018-0118-z
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DOI: https://doi.org/10.1038/s41429-018-0118-z
