Novel phosphonate analogs of sulforaphane: Synthesis, in vitro and in vivo anticancer activity.
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.
Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolf Weigl St., 53-114 Wrocław, Poland.
Mateusz
M
Psurski
Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, 116 Stefan Żeromski St., 90-924 Łódź, Poland.
Łukasz
Ł
Janczewski
Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolf Weigl St., 53-114 Wrocław, Poland.
Marta
M
Świtalska
Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, 116 Stefan Żeromski St., 90-924 Łódź, Poland.
Anna
A
Gajda
Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolf Weigl St., 53-114 Wrocław, Poland.
Tomasz M
TM
Goszczyński
Division of Medicinal Chemistry and Microbiology, Faculty of Chemistry, Wroclaw University of Technology, 27 Wybrzeże Wyspiańskiego St., 50-370 Wrocław, Poland.
Józef
J
Oleksyszyn
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.
Joanna
J
Wietrzyk
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.
Tadeusz
T
Gajda
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D017879:Isothiocyanates / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D063065:Organophosphonates / Q000737:chemistry* / Q000494:pharmacology; D013454:Sulfoxides
D000970:Antineoplastic Agents; D017879:Isothiocyanates; D063065:Organophosphonates; D013454:Sulfoxides; C016766:sulforaphane
4T1 murine mammary gland cancer; Apoptosis; Cell cycle arrest; IC(50); Isothiocyanates; Isothiocyanatoalkylphosphonates; Tumor growth inhibition