Design, Synthesis, and Evaluation of ω-(Isothiocyanato)alkylphosphinates and Phosphine Oxides as Antiproliferative Agents (original) (raw)
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Novel phosphonate analogs of sulforaphane: Synthesis, in vitro and in vivo anticancer activity
European Journal of Medicinal Chemistry, 2017
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 G 2 /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.
Journal of Applied Pharmaceutical Science, 2019
The cytotoxic activity of Iso(thio)cyanate derivatives and some new organophosphorus compounds were determined, using MTT assay against human hepatocellular carcinoma (HepG2) and adenocarcinoma breast (MCF-7) in comparison with the reference drug 5-flurouracil. All the selected products have been tested and showed concentration dependent increase in the growth inhibition percentage against HepG2 and MCF-7. Where, the thietane derivatives revealed anticancer activity with IC50 (20, 8.9 µg/ml) against HepG2 and (20, 10.3 µg/ml) against MCF-7; while, thiazinane compounds showed IC50 (12.7, 32.5 µg/ml) against HepG2 and (20 and 20 µg/ml) against MCF-7. The newly synthesized azetidines showed anticancer activity with IC50 (13.5 and 32.5 µg/ml) against HepG2 and IC 50 (10 and 25.9 µg/ml) against MCF-7 cancer. Moreover, azetidinedione compound exhibited more potent activity than the azetidinone with both types of cancer cell lines. In addition, the cytotoxic activity of the iso(thio) cyanates, and malonamic acid methyl ester compound were also investigated. 4-Methoxyphenyl isothiocyanate and methylisothiocyanate, with IC 50 (25.9, 12.3 and 40, 20 µg/ml), respectively, against HepG2 and MCF-7 cancer cells. 1, 2-Dichloro-4-isocyanato-benzene was similar in potency to the known anticancer drug 5-flurouracil with IC 50 (5.3 µg/ml) versus 5 µg/ml for 5-flurouracil against MCF-7. While, malonamic acid methyl ester compound had no effect on both types of cancer cell lines.
Journal of Inorganic Biochemistry, 2010
a b s t r a c t Compounds of the type [(AuPPh 3 ) 2 (xspa)]; H 2 xspa [x: p = 3-phenyl-, f = 3-(2-furyl)-, t = 3-(2-thienyl)-, -o-py = 3-(2-pyridyl)-, Clp = 3-(2-chlorophenyl)-, -o-mp = 3-(2-methoxyphenyl)-, -p-mp = 3-(4-methoxyphenyl)-, -o-hp = 3-(2-hydroxyphenyl)-, -p-hp = 3-(4-hydroxyphenyl)-, -diBr-o-hp = 3-(3,5-dibromo-2hydroxyphenyl)-; spa = 2-sulfanyl propenoato] were synthesized and characterized by IR and NMR ( 1 H, 13 C and 31 P) spectroscopy and by FAB mass spectrometry. The structures of [(AuPPh 3 ) 2 (Clpspa)], [(AuPPh 3 ) 2 (o-hpspa)], [(AuPPh 3 ) 2 (p-hpspa)]ÁMeOH and [(AuPPh 3 ) 2 (diBr-o-hpspa)]Á2Me 2 CO show the dinuclear nature of the complexes with the two gold atoms, one of which is also O-bonded to an O atom of the carboxylate group, bonded to the S atom. The in vitro antitumor activities against the HeLa-229, A2780
Bioorganic & medicinal chemistry letters, 2018
A series of phosphonates, phosphinates and phosphine oxides isothiocyanate-derived mercapturic acids were synthesized. A temperature dependence dynamic proton decoupled P NMR studies indicated that in most cases the compounds were obtained as a mixture of rotamers. Moreover, biologically relevant reversibility of mercapturic acids synthesis from the parental isothiocyanates was confirmed. All compounds were evaluated ashighly 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.
2 3 Antineoplastic activity of fused nitrogen- phosphorus heterocycles and derived phosphonates
A variety of derivatives incorporating substituted heterocycle-phosphor motifs is described. Substituted N,P-heterocycles and derived phosphonates were produced efficiently in a tandem operation without intermediate isolation. The synthesis methodology is based on the reaction of dialkyl phosphites with Schiff base Kabachnik-Fields intermediates, which are generated in situ from 2-amino-4,6-di-tert-butylphenol and substituted benzaldehydes in dry THF/FeCl 3 (10 %) solution, to yield fused oxazole-2-phosphonates in moderate yield (&55 %). The latter products could be also obtained in excellent yield (C76 %) by directly applying the same P(III) reagents to the parent Schiff bases. On the other hand, oxazaphosphinine-2-amines were isolated in high yields (&77 %) when the Schiff bases were allowed to react with hexaalkyltriamidophosphites at rt. More P-heterocycles and the derived phosphonates were also obtained when the same reagents were applied to another imino derivative derived from the aminophenol, 2-hydroxybenzaldehyde oxime. The synthesized scaffolds were biologically evaluated and found to possess potent anticancer activities. On the basis of bioassay data, the produced N,P-heterocycles exhibit remarkable antitumor activity against 17 tested human tumor cell lines, representing breast and prostate cancer and melanoma. Several phosphonates were found to possess specific anti-breast cancer activity (especially MDA-MB-435 cell lines) while others possess specific effects against melanoma (MI4 and SK-MEL-2 cancer cell lines). These findings form a foundation for further investigation in our continuing efforts to develop selective anticancer agents.
Research Square (Research Square), 2024
Based on the wide range of pharmacological aspects related to organophosphates, a novel type of compound, containing chalcones-phosphonates derivative was synthesized by the reaction of dialkyl phosphite and substituted chalcones using anhydrous Mg(ClO 4) 2 at 80 °C under solvent-free conditions. All the obtained structures were con rmed by IR, 1 H NMR 13 C NMR, and HRMS techniques. The synthesized compounds were tested in vitro against a panel of three human cancer cell lines against MCF7, HeLa, and A549 cell lines. As compared to the reference drug Doxorubicin (IC 50 = 4.17, 3.31, 6.61 µM against MCF7, HeLa, and A549 cell lines, respectively), most of the synthesized derivatives exhibited moderate to good antiproliferative activity. The structure-activity relationship of synthesized compounds is discussed. To speculate on the mechanism of anticancer activity, a molecular docking study was carried out. The molecular docking investigation indicates that all of the synthesized derivatives have good binding ability in the active site of the Vaccinia H1-related (VHR) phosphatase (PDB: 3F81), PI3-kinase (PDB: 3R7Q), androgen receptor (PDB: 3V49) and VEGFR2 kinase (PDB: 3VHE). Furthermore, all compounds were screened for in silico drug-likeness, and all were found to have drug-like properties, following the Lipinski rule of 5, with no PAINS alarms. Thus, the in vitro inhibitory activity and in silico molecular studies con rmed the potency of the chalcone-phosphonate derivatives for anti-proliferative activity.
Antineoplastic activity of fused nitrogen-phosphorus heterocycles and derived phosphonates
A variety of derivatives incorporating substituted heterocycle-phosphor motifs is described. Substituted N,P-heterocycles and derived phosphonates were produced efficiently in a tandem operation without intermediate isolation. The synthesis methodology is based on the reaction of dialkyl phosphites with Schiff base Kabachnik-Fields intermediates, which are generated in situ from 2-amino-4,6-di-tert-butylphenol and substituted benzaldehydes in dry THF/FeCl 3 (10 %) solution, to yield fused oxazole-2-phosphonates in moderate yield (&55 %). The latter products could be also obtained in excellent yield (C76 %) by directly applying the same P(III) reagents to the parent Schiff bases. On the other hand, oxazaphosphinine-2-amines were isolated in high yields (&77 %) when the Schiff bases were allowed to react with hexaalkyltriamidophosphites at rt. More P-heterocycles and the derived phosphonates were also obtained when the same reagents were applied to another imino derivative derived from the aminophenol, 2-hydroxybenzaldehyde oxime. The synthesized scaffolds were biologically evaluated and found to possess potent anticancer activities. On the basis of bioassay data, the produced N,P-heterocycles exhibit remarkable antitumor activity against 17 tested human tumor cell lines, representing breast and prostate cancer and melanoma. Several phosphonates were found to possess specific anti-breast cancer activity (especially MDA-MB-435 cell lines) while others possess specific effects against melanoma (MI4 and SK-MEL-2 cancer cell lines). These findings form a foundation for further investigation in our continuing efforts to develop selective anticancer agents.
Zeitschrift für Naturforschung C, 2012
The Schiff bases N-furfurylidene-p-toluidine and N-(4-dimethylaminobenzilidene)p-toluidine, and the recently synthesized aminophosphonic acid diesters p-[N-methyl-(diethoxyphosphonyl)-(2-furyl)]toluidine and p-[N-methyl(diethoxyphosphonyl)-(4-dimethylaminophenyl)]toluidine were tested for in vitro antitumour activity on six human epithelial cancer cell lines. The genotoxicity and antiproliferative activity of these compounds were tested in mice. The aminophosphonates showed high in vitro antitumour activity towards the breast cancer-derived cell lines (MCF-7 and MDA-MB-231), the cervical carcinoma cell line (HeLa), and the human colon adenocarcinoma cell line . In addition, the Schiff base N-furfurylidene-p-toluidine signifi cantly inhibited the growth of bladder carcinoma cells (647-V) and the hepatocellular carcinoma line HepG2, and U-shaped dose-response curves were observed after treatment of 647-V and MCF-7 cells. All studied compounds had a moderate genotoxic and antiproliferative activity in vivo.
Pharmaceutical Chemistry Journal, 2021
Condensation of 4-chloroacetophenone 1 with phenyl hydrazine 2 afforded hydrazone 3. Further reaction of 3 with Vilsmeier reagent yielded the pyrazolaldehyde 4 in excellent yield. A one-pot, three-component reaction between aldehyde 4, triphenylphosphite 5, and appropriate amines in the presence of lithium perchlorate as Lewis acid catalyst gave the corresponding-amino phosphonates 7-12(a-d) in good yields. The chemical structures of all new compounds were established by IR, 1 H NMR, and mass spectroscopy analysis. The anti-proliferative activity of the synthesized compounds against HCT-116, HepG2 and MCF-7 human cancer cells using the MTT assay was evaluated, and revealed higher anticancer activity when compared with reference drug doxorubicin. Among the tested compounds, pyrazole derivatives 4 and 9 exhibited the highest anticancer activity against breast (MCF-7), and colon (HCT-116) cancer cell lines with IC 50 = 2.7 and 3.3 M, respectively.