Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl Phosphorus-containing isothiocyanate-derived mercapturic acids as a useful alternative for parental isothiocyanates in experimental oncology Mateusz Psurski a, ⁎ ,e , Łukasz Janczewski b,e , Marta Świtalska a,e , Anna Gajda b , Tomasz M. Goszczyński a , Jarosław Ciekot a , Łukasz Winiarski c , Józef Oleksyszyn c , Joanna Wietrzyk a , Tadeusz Gajda b a Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Weigla St., 53-114 Wrocław, Poland b Institute of Organic Chemistry, Faculty of Chemistry, Technical University of Lodz, 116 Żeromskiego St., 90-924 Łódź, Poland c Division of Medicinal Chemistry and Microbiology, Faculty of Chemistry, Wrocław University of Science and Technology, 27 Wybrzeże Wyspiańskiego St., 50-370 Wrocław, Poland ARTICLE INFO Keywords: Isothiocyanate Mercapturic acid Antiproliferative activity Synthesis Cytostatic activity Proapoptotic activity ABSTRACT A series of phosphonates, phosphinates and phosphine oxides isothiocyanate-derived mercapturic acids were synthesized. A temperature dependence dynamic proton decoupled 31 P NMR studies indicated that in most cases the compounds were obtained as a mixture of rotamers. Moreover, biologically relevant reversibility of mer- capturic acids synthesis from the parental isothiocyanates was confirmed. All compounds were evaluated as highly active antiproliferative agents in vitro in human colon cancer cell lines (LoVo and its doxorubicin- resistant subline LoVo/DX). The cell cycle progression and caspase-3 activity analyses revealed compounds moderate activity as apoptosis inducers and their poor influence on cell cycle progression in the LoVo cells. Our results confirm that isothiocyanate-derived mercapturic acids present a reasonable alternative for the parental compounds, and can replace them in the future studies on isothiocyanates potential as anticancer agents. Naturally occurring isothiocyanates (ITCs) have been extensively studied for their potential as anticancer agents. Since the discovery of sulforaphane (SFN) as a potent inducer of phase II detoxification en- zymes, 1 numerous studies provided evidences for isothiocyanates use- fulness in experimental oncology, and their multi-targeted mode of action as chemopreventive and cytotoxic agents. 2 A list of iso- thiocyanates potential molecular targets comprises almost 30 proteins, which activity plays an important role at different stages of carcino- genesis. 3 This includes, but is not limited to, a modulation of cyto- chrome P450 enzymes activity, 4 inhibition of NF-κB, 5 proteasome, 6 and histone deacetylases (HDAC). 7 The last one represents particularly in- teresting target, since HDAC enzymatic activity is known to be modu- lated by a mercapturic acid, not by the parental isothiocyanate. 7 Moreover, mercapturic acids are substrates for multidrug-resistance pumps and their potential inhibitors. 8 These observations indicate that the mercapturic acids are not only a final stage of isothiocyanates in- tracellular metabolism, but also play an important (if not crucial) role in their biological activity, themselves being able to exhibit antiproliferative potential. The use of isothiocyanate-derived mercapturic acids in lieu of the parental isothiocyanates as anticancer agents presents several im- portant advantages. A significantly higher solubility in water and crystalline form simplifies drug handling and applications. Additionally, under physiological conditions mercapturic acid extra- cellular decomposition is a necessary step for its biological activity. Thus, it can be considered as isothiocyanate prodrug form with lowered unspecific, off-target activities. Despite these potential advantages, mercapturic acids are rarely used in experimental oncology. Thronalley et al. evaluated the antiproliferative activity of several phenethyli- sothiocyanate-derived mercapturic acids, including N-acetyl-S-(N-phe- nylethylthiocarbamoyl)cysteine, as well as some derivatives of benzyl and phenylpropyl isothiocyanates on the HL60 cell line. 9 Zhang group tested benzyl and allyl isothiocyanates-derived mercapturic acids on several bladder cancer cell lines, both in vitro and in vivo. 10,11 In all cases, the mercapturic acids and parental isothiocyanates exhibited a comparable antiproliferative potential, and the liberation of a cognate https://doi.org/10.1016/j.bmcl.2018.06.042 Received 22 May 2018; Received in revised form 14 June 2018; Accepted 19 June 2018 ⁎ Corresponding author. e MP, ŁJ and MŚ share equal contribution. E-mail address: mateusz.psurski@iitd.pan.wroc.pl (M. Psurski). Abbreviations: BITC, benzyl isothiocyanate; CDDP, cisplatin; Doxo, doxorubicin; HDAC, histone deacetylases; ITC, isothiocyanate; MITO, mitoxantrone; NAC, N-acetylcysteine; SFN, sulforaphane; SRB, sulforhodamine B Bioorganic & Medicinal Chemistry Letters xxx (xxxx) xxx–xxx 0960-894X/ © 2018 Published by Elsevier Ltd. Please cite this article as: Psurski, M., Bioorganic & Medicinal Chemistry Letters (2018), https://doi.org/10.1016/j.bmcl.2018.06.042