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

Psurski, Mateusz; Janczewski, Łukasz; Świtalska, Marta; Gajda, Anna; Goszczyński, Tomasz M.; Oleksyszyn, Józef; Wietrzyk, Joanna; Gajda, Tadeusz

doi:10.1016/j.ejmech.2017.03.028

Cited by 30 publications

(40 citation statements)

References 52 publications

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“…Twoa lternative strategies were applied:t he first was based on aminoalkylphosphine oxides, and the second was based on azidoalkylphosphinates or azidoalkylphosphine oxides as the key intermediates.T hus, (w-isothiocyanatoalkyl)dimethylphosphine oxides 10-13,e thyl (w-isothiocyanatoalkyl)(diethoxymethyl)phosphinates 43-46,a nd methyl and ethyl (w-isothiocyanatoalkyl)(phenyl)phosphonates 64-71 were synthesized via an azide approachu sing the protocol established earlier in our research group. [39,41] In contrast, (w-isothiocyanatoalkyl)diphenylphosphine oxides 29-33 were prepared by an amine approach.The structures of all synthesized compounds wereconfirmedb ym ass spectrometry,I Rs pectroscopy,a nd 1 H, 31 P, and 13 CNMR spectroscopy.…”

Section: Resultsmentioning

confidence: 99%

“…These findings are consistentw ith our previous studies on phosphonates in whichw ep rovedt hat introducing ap hosphonate moiety to the backbone of ITCs potentiate their activity,b ut no clear SAR can be highlighted. [39][40][41] This surprisingl ack of diversification was also observed by others and appearst obe ac ommonf eature of synthetic ITCs. [59,60] The representative phosphine oxides( namely,( 6-isothiocyanatohexyl)diphenylphosphine oxide 33)a nd phosphinates (namely,e thyl (6-isothiocyanatohexyl)(phenyl)phosphinate 71) were used in follow-up studies.…”

Section: In Vitro Biological Studiesmentioning

confidence: 99%

“…At the same time, Balb/3T3, A549, MESSA, and MESSA/Dx-5 cell lines were less sensitive to 71.B ecause the MESSA/Dx-5 doxorubicin-resistance mechanism is similart ot hat observed on LoVo/DX, it is not surprising that the activities of compounds 33 and 71 on these cell lines do not differ significantly from those towardM ESSA. However,u nlike previously reported phosphonates [41] andc ompound 71, (6-isothiocyanatohexyl)diphenylphosphine oxide (33)s howeds ignificantly higher activity on mitoxantrone-resistant HL60 subline, which is characterized by an atypical multidrug resistance mechanism that does not involveP -gp overexpression and is primarily an outcome of decreased levels of a-a nd b-topoisomerase II enzymes. [61,62] These distinguish 33 from previously reported diethyl 6-(isothiocyanato)hexylphosphonate, for which significant signs of resistance were observed (index of resistance = 7.8) when tested on HL60/MX2.…”

Section: In Vitro Biological Studiesmentioning

confidence: 99%

“…[61,62] These distinguish 33 from previously reported diethyl 6-(isothiocyanato)hexylphosphonate, for which significant signs of resistance were observed (index of resistance = 7.8) when tested on HL60/MX2. [41] Next, the influence of ITCs on cell cycle was assessed on LoVoa nd LoVo/DX cell lines after 24 ht reatment ( Figure 2). Neither of the phosphorus-containing ITCs, tested at 15 mm, significantly influenced cell-cycle progression;o nly al imited decreasei nt he percentage of cells in the G 0 /G 1 and Sp hases was observed and was associated with as light increase in G 2 / Mp hase.…”

Section: In Vitro Biological Studiesmentioning

confidence: 99%

“…[37] The resultso fP osner et al [38] inspired us to undertake this study;t heir work has shown that replacement of the methylsulfinyl group in SFN with ad imethylphosphinoyl moiety results in the formation of (4-isothiocyanatobutyl)dimethylphosphine oxide-a potent inducer of QR. Additionally,o ur previously reported dialkyl 1-and 2-isothiocyanatoalkylphosphonates, [39] diphenyl 1-isothiocyanatoalkylphosphonates, [40] and dialkyl and diphenyl w-(isothiocyanato)alkylphosphonates [41] also proved to be at least equallyp otent as SFN. Taking the aforementioned facts into account, the primary goal of this study was to design,s ynthesize, and investigate al ibrary of structurally diverseb ifunctional isothiocyanates, in which the isothiocyanato group and structurally diversep hosphine oxide or phosphinate moieties are connected with unbranched alkyl link-ers of different lengths, for their antiproliferative activity.I na ddition, the analysiso fs tructure-activity relationships (SARs) as well as in vivo anticancer activity for representativeI TCs was undertaken.…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, and Evaluation of ω‐(Isothiocyanato)alkylphosphinates and Phosphine Oxides as Antiproliferative Agents

et al. 2017

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A series of 21 novel, structurally diverse ω‐(isothiocyanato)alkylphosphinates and phosphine oxides (ITCs) were designed and synthesized in moderate to good yields. The synthesized compounds were evaluated for in vitro antiproliferative activity using LoVo and LoVo/DX cancer cell lines. The biological activity of the synthesized compounds was higher than that of natural isothiocyanates such as benzyl isothiocyanate or sulforaphane. The antiproliferative activity of selected ITCs was also tested on selected cancer cell lines: A549, MESSA and MESSA/DX‐5, HL60 and HL60MX2, BALB/3T3, and 4T1. These compounds were assessed for their mechanism of action as inducers of cell‐cycle arrest and apoptosis. Ethyl (6‐isothiocyanatohexyl)(phenyl)phosphinate (71) was tested in vivo on the 4T1 cell line and demonstrated moderate antitumor activity, similar to that benzyl isothiocyanate and cyclophosphamide.

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Section: Resultsmentioning

confidence: 99%

Section: In Vitro Biological Studiesmentioning

confidence: 99%

Section: In Vitro Biological Studiesmentioning

confidence: 99%

Section: In Vitro Biological Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, and Evaluation of ω‐(Isothiocyanato)alkylphosphinates and Phosphine Oxides as Antiproliferative Agents

et al. 2017

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Design and in Vitro Characterization of Tricyclic Benzodiazepine Derivatives as Potent and Selective Antileukemic Agents

Mieczkowski

Frączyk

Psurski

et al. 2020

Chemistry & Biodiversity

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Currently available chemotherapeutic treatments for blood cancers (leukemia) usually have strong side effects. More selective, efficient, and less toxic anticancer agents are needed. We synthesized seven, new, optically pure (12aS)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione derivatives and examined their cytotoxicity towards eight cancer cell lines, including urinary bladder (TCC-SUP, UM-UC-3, KU-19-9), colon (LoVo), and breast (MCF-7, MDA-MB-231) cancer representatives, as well as two leukemic cell lines (MV-4-11, CCRF-CEM) and normal murine fibroblasts (Balb/3T3) as reference cell line. Three of the seven newly-obtained compounds ((12aS)-8-bromo-2-(3-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione, (12aS)-8,9dimethoxy-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione and (12aS)-8-nitro-2-(4phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione, showed enhanced activity and selectivity toward the leukemic MV-4-11 cell lines when compared to our previously reported compounds, with IC 50 values in the range of 2.9-5.6 μM. Additionally, (12aS)-9-nitro-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino [2,1-c][1,4],12(2H,11H)-dione exhibited a strong cytotoxic effect against the leukemic CCRF-CEM (IC 50 = 6.1 μM) and MV-4-11 (IC 50 = 11.0 μM) cell lines, a moderate cytotoxic effect toward other tumor lines (IC 50 = 31.8-55.0 μM) and very weak cytotoxic effect toward the Balb/3T3 reference cell lines. Selected compounds were further evaluated for their potential to induce apoptotic cell death in MV-4-11 cells by measuring caspase-3 activity. We also established the crystal structure of three products and investigated the effect of 22 derivatives of 1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione on the activity of the cancer-associated enzyme autotaxin. All compounds proved to be weak inhibitors of autotaxin, although some (R) and (S) enantiomers had K i values of 10-19 μM. The obtained results showed that the tested compounds exhibited a selective antileukemic effect, which appeared not to be related directly to autotaxin. Molecular targets responsible for this effect remain to be identified. The newly obtained compounds can be used in the search for new, selective anticancer therapies.

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Phosphonic Analogs of Alanine as Acylpeptide Hydrolase Inhibitors

Sieńczyk

Walczak

Chryplewicz

et al. 2021

Chemistry & Biodiversity

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Acylpeptide hydrolase is a serine protease, which, together with prolyl oligopeptidase, dipeptidyl peptidase IV and oligopeptidase B, belongs to the prolyl oligopeptidase family. Its primary function is associated with the removal of N‐acetylated amino acid residues from proteins and peptides. Although the N‐acylation occurs in 50–90 % of eukaryotic proteins, the precise functions of this modification remains unclear. Recent findings have indicated that acylpeptide hydrolase participates in various events including oxidized proteins degradation, amyloid β‐peptide cleavage, and response to DNA damage. Considering the protein degradation cycle cross‐talk between acylpeptide hydrolase and proteasome, inhibition of the first enzyme resulted in down‐regulation of the ubiquitin‐proteasome system and induction of cancer cell apoptosis. Acylpeptide hydrolase has been proposed as an interesting target for the development of new potential anticancer agents. Here, we present the synthesis of simple derivatives of (1‐aminoethyl)phosphonic acid diaryl esters, phosphonic analogs of alanine diversified at the N‐terminus and ester rings, as inhibitors of acylpeptide hydrolase and discuss the ability of the title compounds to induce apoptosis of U937 and MV‐4‐11 tumor cell lines.

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

Cited by 30 publications

References 52 publications

Design, Synthesis, and Evaluation of ω‐(Isothiocyanato)alkylphosphinates and Phosphine Oxides as Antiproliferative Agents

Design, Synthesis, and Evaluation of ω‐(Isothiocyanato)alkylphosphinates and Phosphine Oxides as Antiproliferative Agents

Design and in Vitro Characterization of Tricyclic Benzodiazepine Derivatives as Potent and Selective Antileukemic Agents

Phosphonic Analogs of Alanine as Acylpeptide Hydrolase Inhibitors

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