Novel phosphonate analogs of sulforaphane: Synthesis, in vitro and in vivo anticancer activity.

Eur J Med Chem. 2017 Mar 18;132:63-80. doi: 10.1016/j.ejmech.2017.03.028. [Epub ahead of print]

Psurski M¹, Janczewski Ł², Świtalska M¹, Gajda A², Goszczyński TM¹, Oleksyszyn J³, Wietrzyk J⁴, Gajda T⁵.

Author information

1

Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolf Weigl St., 53-114 Wrocław, Poland.

2

Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, 116 Stefan Żeromski St., 90-924 Łódź, Poland.

3

Division of Medicinal Chemistry and Microbiology, Faculty of Chemistry, Wroclaw University of Technology, 27 Wybrzeże Wyspiańskiego St., 50-370 Wrocław, Poland.

4

Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolf Weigl St., 53-114 Wrocław, Poland. Electronic address: wietrzyk@iitd.pan.wroc.pl.

5

Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, 116 Stefan Żeromski St., 90-924 Łódź, Poland. Electronic address: tadeusz.gajda@p.lodz.pl.

Abstract

A library of over forty, novel, structurally diverse phosphonate analogs of sulforaphane (P-ITCs) were designed, synthesized and fully characterized. All compounds were evaluated for antiproliferative activity in vitro on Lovo and LoVo/DX colon cancer cell lines. All compounds exhibited high antiproliferative activity, comparable or higher to the activity of naturally occurring benzyl isothiocyanate and sulforaphane. Assessment of the mechanisms of action of selected compounds revealed their potential as inducers of G₂/M cell cycle arrest and apoptosis. Further antiproliferative studies for selected compounds with the use of a set of selected cell lines derived from colon, lung, mammary gland and uterus as well as normal murine fibroblasts were performed. In vivo studies of the analyzed phosphonate analogs of sulforaphane showed lower activity in comparison with those of benzyl isothiocyanate. Our studies demonstrated that newly synthesized P-ITCs can be used for as a starting point for the synthesis of novel isothiocyanates with higher anticancer activity in the future.

Copyright © 2017 Elsevier Masson SAS. All rights reserved.

KEYWORDS:

4T1 murine mammary gland cancer; Apoptosis; Cell cycle arrest; IC(50); Isothiocyanates; Isothiocyanatoalkylphosphonates; Tumor growth inhibition

PMID:

28342398

DOI:

10.1016/j.ejmech.2017.03.028