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Preparation, Properties and Crystal Structure of syn-Isomer of 2,6-Dichlorophenyl-cyanoxime, H(2,6-diCl-PhCO): Potent Carbonyl Reductase Inhibitor

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Abstract

The oximino(2,6-dichlorophenyl)acetonitrile, H(2,6-diCl-PhCO) has been synthesized in a reasonably high yield of 60%, and characterized using a variety of physical, electrochemical, spectroscopic methods and X-ray analysis. This compound belongs to the family of cyanoximes; a new subclass of oximes with the general formula NC–C(=N–OH)–R (where R is an electron-withdrawing group) which recently emerged as new biologically active compounds. This cyanoxime represents a disubstituted arylcyanoxime that was found to be a powerful inhibitor of the Carbonyl Reductase enzyme involved in the developing of resistance to anticancer treatment, and the making of cardiotoxic derivatives of anthracyclines that are currently used in medicine. The oximino(2,6-dichlorophenyl)acetonitrile, H(2,6-diCl-PhCO) is a weak acid with pKa = 6.17 and does not dissociate in organic polar protic and aprotic solvents. The cyanoxime was obtained as a microcrystalline mixture of two diastereomers (anti- and syn-) and deprotonates in solutions with the formation of yellow anions which exhibit solvatochromic behavior. However, one specific diastereomer—syn—was isolated in crystalline form from a solvent system as colorless blocks overlayed with pentane ether solution in a monoclinic system in a P2/c (#13) space group with unit cell parameters: a = 8.1720(2), b = 8.8013(3), c = 13.0146(4) and β = 102.546(3); Z = 4. A single crystal was studied using filtered CuKa radiation, providing Rint value of 0.0348 from a full-sphere of reflections. A crystal structure was solved using direct methods, and well refined to R1 = 0.0459, wR2 = 0.1268 and GOF = 1.107. The studied specimen of oximino(2,6-dichlorophenyl)acetonitrile, H(2,6-diCl-PhCO), represents a highly non-planar, rare syn-diastereomer in which the oxime fragment is positioned towards the chlorinated phenyl group. In the crystal, the compound forms a columnar structure extended along the c-direction by using slipped π–π stacking interactions. Columns are interconnected via H-bonding between the oxime OH-group and N atom of the nitrile group with the following parameters: N–H = 1.841 Å, and 169.20° N···H–O angle. No thermal interconversion of syn- into anti- diastereomer was observed upon heating of crystals of one isomer under flow of Ar.

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Acknowledgements

NG is grateful to Mr. Leon Goeden for his pioneering work on the project, Dr. Svitlana Silchenko (Absorption Systems, Inc.) for pK determination and Ms. Victoria Barry for technical help. A financial support from the ACS PRF Award # 39079-B3 and the Cottrell Research Corporation Award # CC6598 is highly appreciated. NG is also very grateful to the College of Natural and Applied Sciences for the continuous support of the X-ray analysis facility.

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Authors and Affiliations

  1. Department of Chemistry, Missouri State University, Temple Hall 456, Springfield, MO, 65897, USA

    Seth Adu Amankrah & Nikolay Gerasimchuk

  2. Department of Chemistry, Middle Tennessee State University, Davis Science Building, Office 113, Murfreesboro, TN, 37132, USA

    Oleksandr Hietsoi

  3. Center for Drug Discovery, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, USA

    Sergiy Tyukhtenko

  4. Department of Chemistry & Biochemistry, Boise State University, 1910 University Drive SCNC 153, Boise, ID, 83725, USA

    Henry Charlier

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Amankrah, S.A., Hietsoi, O., Tyukhtenko, S. et al. Preparation, Properties and Crystal Structure of syn-Isomer of 2,6-Dichlorophenyl-cyanoxime, H(2,6-diCl-PhCO): Potent Carbonyl Reductase Inhibitor. J Chem Crystallogr 52, 194–204 (2022). https://doi.org/10.1007/s10870-021-00905-1

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