Ecotoxicological effects of new C-substituted derivatives of N-phosphonomethylglycine (glyphosate) and their preliminary evaluation towards herbicidal application in agriculture.

In this paper, comparison of ecotoxicological and herbicidal effect of newly synthesized N­[(phosphono)(aryl)methyl]glycines 1a-g (C-substituted glyphosate derivatives) with pure glyphosate (N-phosphonomethylglycine) (2) was demonstrated. All of tested glyphosate derivatives (1a-g) in contrast to glyphosate, were found to be completely safe for oat (Avena sativa) and classified as not harmful for marine bacteria Aliivibrio fischeri. Compounds 1a-g were also found rather harmless to radish (Raphanus sativus) as compared to N-phosphonomethylglycine, but they were moderately toxic against freshwater crustaceans Heterocypris incongruens. One of synthesized compounds, namely N-[(phosphono)(4-hydroxyphenyl)methyl]glycine (1f) was found to possess stronger herbicidal properties against gallant soldier (Galinsoga parviflora) and common sorrel (Rumex acetosa) when compared to pure glyphosate and demonstrated total death of these weeds being ranked 1 in the European Weed Research Council (EWRC) scale. Considering lower phytotoxicity of compound 1f against cultivated plants and tested microorganisms when compared to pure glyphosate, this aminophosphonate may be good candidate for further, more comprehensive study toward its agrochemical application, especially that this active agent demonstrated much stronger herbicidal properties than N-phosphonomethylglycine.

Antagonistic Effects of CAPE (a Component of Propolis) on the Cytotoxicity and Genotoxicity of Irinotecan and SN38 in Human Gastrointestinal Cancer Cells In Vitro.

The incidence of gastrointestinal cancers is increasing every year. Irinotecan (CPT-11), a drug used in the treatment of colorectal cancer and gastric cancer, is metabolized by carboxylesterases to an active metabolite, SN-38, which is more cytotoxic. CAPE (caffeic acid phenethyl ester) is an active component of propolis, which has a high antibacterial, antiviral, and antineoplastic potential. This study analyses the impact of CAPE on the cytotoxic (MTT assay), genotoxic (comet assay) and proapoptotic (caspase-3/7 activity) potential of irinotecan and its metabolite SN-38 in cultures of gastrointestinal neoplastic cells (HCT116, HT29, AGS). Cytotoxicity and genotoxicity activities of these compounds were carried out in comparison with human peripheral blood lymphocytes (PBLs) in vitro. The antioxidant potential of CAPE was investigated in relation H2O2-induced oxidative stress in the both neoplastic cells and PBLs. CAPE expressed cytotoxic, genotoxic, and pro-apoptotic activity against AGS, HCT116, and HT29 tumor cells. CAPE, in the presence of different concentrations of irinotecan or SN38, decreased the cytotoxicity, genotoxicity, and pro-apoptotic activity in these cell lines, but it has no such action on normal human peripheral blood lymphocytes.

The Effect of New Thiophene-Derived Diphenyl Aminophosphonates on Growth of Terrestrial Plants.

The aim of this work was to evaluate the impact of the thiophene-derived aminophosphonates 1-6 on seedling emergence and growth of monocotyledonous oat (Avena sativa) and dicotyledonous radish (Raphanus sativus L.), and phytotoxicity against three persistent and resistant weeds (Galinsoga parviflora Cav., Rumex acetosa L., and Chenopodium album). Aminophosphonates 1-6 have never been described in the literature. The phytotoxicity of tested aminophosphonates toward their potential application as soil-applied herbicides was evaluated according to the OECD (Organization for Economic and Cooperation Development Publishing) 208 Guideline. In addition, their ecotoxicological impact on crustaceans Heterocypris incongruens and bacteria Aliivibrio fischeri was measured using the OSTRACODTOXKITTM and Microtox® tests. Obtained results showed that none of the tested compounds were found sufficiently phytotoxic and none of them have any herbicidal potential. None of the tested compounds showed important toxicity against Aliivibrio fischeri but they should be considered as slightly harmful. Harmful impacts of compounds 1-6 on Heterocypris incongruens were found to be significant.

Hazardous ecotoxicological impact of two commonly used nitrofuran-derived antibacterial drugs: Furazolidone and nitrofurantoin.

This paper discusses the impact of two nitrofuran-derived drugs, namely furazolidone and nitrofurantoin on growth of oat and common radish as well as their impact on bacteria Allivibrio fischeri and crustaceans Heterocypris incongruens. Results indicated that both compounds were highly phytotoxic for radish (R. sativus) being simultaneously nearly not harmful for oat (A. sativa). Growing inhibition of shoots, roots, fresh matter and photosynthetic pigments is correlated with growing concentration of drugs in soil. Ecotoxicological impact of both compounds on model luminescence bacteria Aliivibrio fischeri and freshwater crustaceans Heterocypris incongruens as a representative organisms of two different level of food chain, is also reported herein, and the obtained data show significant toxicity against these two organisms. Basing on obtained results, it was concluded that both nitrofuran drugs in case of distribution through environment, by improper utilisation after use or unplanned environmental intoxication with unused drugs may cause serious environmental problems and therefore both should be handled with a reasonable care at any step of their production or utilisation.

Cytotoxic Action of N-aryl, Furan-derived Aminophosphonates against HT29 and HCT116 Cancer Cell Lines.

BACKGROUND: The anticancer activity of aminophosphonic derivatives has been described extensively, some recent papers included furan-derived aminophosphonates and their cytostatic action against various cancer cells. OBJECTIVE: A series of twelve furan-derived dibenzyl and diphenyl aminophosphonates 2a-f and 3a-f was synthesized and tested in aspect of their cytotoxic action on two cell lines of colorectal cancer: HT29 and HCT116. Seven of them are new compounds, while the rest five have already been published by us, together with their cytotoxic action against squamous esophageal cancer cells. METHODS: To estimate the cytotoxicity effect of tested compounds MTT test was used. Pro-apoptotic activity of five selected compounds was evaluated using APC Annexin V Apoptosis Detection Kit on a flow cytometer. Quantification of caspases 3/7 activity was performed using Caspase-Glo® 3/7 Assay Kit. RESULTS: Five of these aminophosphonates showed significant cytotoxicity higher than those of cisplatin. Simultaneous evaluation of their cytotoxicity against PBLs revealed that these compounds are rather not harmful for regular human lymphocytes. Tests on apoptosis vs. their necrotic actions on cells were performed with selected compounds showing the most significant cytotoxicity against cancer cells and all tested compounds did not induce significant increase of necrosis in cells, whereas they showed moderate-to-strong proapoptotic actions even at the lowest applied concentration. Caspase 3/7 activity results confirmed proapoptotic properties of tested aminophosphonates. CONCLUSION: From among studied compounds, dibenzyl N-phenyl substituted amino(2-furyl)methylphsophonates were found to be more potent compounds in aspect of their antiproliferative action than the corresponding diphenyl derivatives.

Effect of New Thiophene-Derived Aminophosphonic Derivatives on Growth of Terrestrial Plants. Part 2. Their Ecotoxicological Impact and Phytotoxicity Test Toward Herbicidal Application in Agriculture.

Background: The aim of this work was to evaluate phytotoxicity of the thiophene derivatives against three persistent weeds of a high degree of resistance (Galinsoga parviflora Cav., Rumex acetosa L., and Chenopodium album) as well as their ecotoxicological impact on Heterocypris incongruens. In addition, Aliivibrio fischeri was measured. Two of eight described aminophosphonates, namely dimethyl N-(2-methoxyphenyl)amino(2-thienyl)methylphosphonate (2d) and dimethyl N-(tert-butyl)- (2-thienyl)methylphosphonate (2h), have never been reported before. Methods: The phytotoxicity of tested aminophosphonates toward their potential application as soil-applied herbicides was evaluated according to the OECD 208 Guideline. Ecotoxicological properties of investigated compounds were made using the OSTRACODTOXKITTM and Microtox® tests. Results: Obtained results showed that four aminophosphonates have interesting herbicidal properties and N-(2-methylphenyl)amino- (2-thienyl)methylphosphonate (2a) was found to kill efficiently the most resistant plant Chenopodium album. None of the tested compounds showed important toxicity against Aliivibrio fischeri. However, their toxic impact on Heterocypris incongruens was significantly elevated. Conclusions: The aminophosphonate 2a showed herbicidal potential and it is not toxic against tested bacteria (EC50 over 1000 mg/L). It was found to be moderately toxic against ostracods [mortality 48% at 10 mg/kg of soil dry weight (s.d.w.)] and this problem should be solved by the use of the controlled release from a polymeric carrier.

Novel (5-nitrofurfuryl)-substituted esters of phosphonoglycine - Their synthesis and phyto- and ecotoxicological properties.

Since aminophosphonate-based herbicides like glyphosate are currently one of the most popular and widely applied active agent in agrochemistry, there is an urgent need for searching new compounds among this family with potential herbicidal activity, but exhibiting low toxicity against surrounding environment. Six new (5-nitrofurfuryl)-derived aminophosphonates were synthesized for the first time and apart from the only one example of N-benzylamino(5-nitrofuryl)-methylphosphonic acid, it was the first time in the history, when this class of compounds was prepared. Their prospective and real biological properties have been followed up by evaluation of their preliminary ecotoxicology. They have been then investigated in aspect of their phytotoxicity against oat (A. sativa) and common radish (R. sativus) exhibiting moderate-to-severe toxicity for these plants. The significant selectivity towards radish (up to 3 times greater toxicity against radish) was observed in some cases. Title compounds were also tested in terms of their toxicity for freshwater crustaceans H. incongruens (ostracods) and marine luminescent bacteria A. fischeri. Although their harmful action on ostracods was not too much elevated, they were found to be highly toxic for bacteria. Various aspects of their ecotoxicity are discussed in this paper.

Novel N-Arylaminophosphonates Bearing a Pyrrole Moiety and Their Ecotoxicological Properties.

A wide range of biological activities of aminophosphonates predisposes them to find applications as anticancer, antiviral, antimicrobial, antifungal, or herbicidal agents. Despite a number of positive aspects of the use of aminophosphonates, their applications may cause a risk to the environment, which is well exemplified by the case of glyphosate. Therefore, scientists see a pressing need to rate ecotoxicity of aminophosphonates. Nowadays, it is recommended to use comprehensive tools to carry out appropriate and effective risk assessments of toxic substances. For these purposes, tests based on the acute toxicity of the luminescent bacteria Aliivibrio fischeri, as well as the measurement of sub-chronic toxicity of the crustacean Heterocypris incongruens seem to be the most convenient. A series of five diphenyl N-arylamino(pyrrole-2-yl)methylphosphonates was synthesized and preliminary evaluation of their ecotoxicological properties was performed. In order to carry out such investigations, we applied the two biotests mentioned above. Results showed that the N-(4-nitrophenyl) derivative was the most toxic for bacteria in comparison to other tested compounds. As for crustaceans, N-phenyl and N-naphthyl derivatives were found to be the most harmful, simultaneously being relatively harmless for bacteria. Such a phenomenon are discussed in correlation with the literature, while its reason is discussed with respect to the aspect of structure of the tested compounds.

Evaluation of ecotoxicological impact of new pyrrole-derived aminophosphonates using selected bioassay battery.

Six new dimethyl N-arylamino(2-pyrrolyl)methylphosphonates 2a-f were synthesized by the modified aza-Pudovik reaction. Their ecotoxicological impact using battery of bioassay was assessed using Microtox and Ostracodtoxit tests as well as phytotoxicity towards two plants, dicotyledonous radish (Raphanus sativus) and monocotyledonous oat (Avena sativa) following the OECD 208 Guideline. Ecotoxicological properties of compounds 2a-f in aspect of acute and chronic toxicity were evaluated using Heterocypris incongruens and Aliivibrio fisheri tests. The obtained results showed that tested aminophosphonates 2a-f have moderate-to-high phyto- and ecotoxicological impact. They are toxic for both plants but more toxic against dicotyledonous. The investigated compounds showed important ecotoxicity against Heterocypris incongruens crustaceans and Aliivibrio fisheri bacteria. It was found that the substituents of the phenyl ring plays a key role in the degree of toxicity. Results showed that investigated compounds are ecologically toxic and that any of their application should be implemented with care.

Synthesis, fluorescence properties and the promising cytotoxicity of pyrene-derived aminophosphonates.

A large series of variously substituted amino(pyren-1-yl)methylphosphonic acid derivatives was synthesized using a modified aza-Pudovik reaction in 20-97% yields. The fluorescence properties of the obtained compounds were investigated revealing that N-alkylamino(pyren-1-yl)methylphosphonic derivatives are stronger emissive compounds than the corresponding N-aryl derivatives. N-Benzylamino(pyren-1-yl)methylphosphonic acid displayed strong fluorescence (ΦF = 0.68) in phosphate-buffered saline (PBS). The influence of a series of derivatives on two colon cancer cell lines HT29 and HCT116 was also investigated. The most promising results were obtained for N-(4-methoxyphenyl)amino(pyren-1-yl)methylphosphonate, which was found to be cytotoxic for the HCT116 cancer cell line (IC50 = 20.8 µM), simultaneously showing weak toxicity towards normal lymphocytes (IC50 = 230.8 µM).

Synthesis, Spectral Characterization of Several Novel Pyrene-Derived Aminophosphonates and Their Ecotoxicological Evaluation Using Heterocypris incongruens and Vibrio fisheri Tests.

Four diphenyl pyrene-derived aminophosphonates were synthesized. Attempts were made to synthesize diphenyl N-(R)-α-methylbenzylamino(pyren-1-yl)methylphosphonate (3e) in order to obtain the chiral aminophosphonate bearing a pyrene moiety. Because these attempts failed, dimethyl and dibenzyl N-(R)-α-methylbenzyl substituted aminophosphonates 4 and 5 were synthesized and the predominant diastereoisomer of dimethyl aminophosphonate 4 was isolated. The resolution of the diastereomeric mixture of 5 failed. Aminophosphonates 3a-d and the predominant diastereoisomer of 4 were investigated in terms of their ecotoxicity using tests performed on the ostracode Heterocypris incongruens and the fluorescent bacterium Vibrio fisheri. The tests confirmed the moderate-to-high ecotoxicity of aminophosphonates 3a-d and 4, but no evident correlation between the structure and toxicity has been found.

The Effect of New Thiophene-Derived Aminophosphonic Derivatives on Growth of Terrestrial Plants: A Seedling Emergence and Growth Test.

The aim of this work was to synthesize selected thiophene-derived aminophosphonic systems and evaluate the phytotoxicity of newly obtained products according to the OECD 208 Guideline. Seven new thiophene-derived N-substituted dimethyl aminomethylphosphonic acid esters 2a-h were synthesized by the addition of an appropriate phosphite to azomethine bond of starting Schiff bases 1a-h, and NMR spectroscopic properties of aminophosphonates were investigated. These eight compounds were analyzed in regard to their phytotoxicity towards two plants, radish (Raphanus sativus) and oat (Avena sativa). On the basis of the obtained results, it was found that tested aminophosphonates 2a-h showed an ecotoxicological impact against selected plants, albeit to various degrees.

Phytotoxicity of new furan-derived aminophosphonic acids, N-aryl furaldimines and 5-nitrofuraldimine.

The aim of this work was to synthesize selected furaldimines and their aminophosphonic derivatives and evaluation the phytotoxicity of new obtained products according to OECD 208 Guideline. Four Schiff bases, N-furfurylidene-p-anisidine (1a), N-furfurylidene-p-toluidine (1b), N-furfurylidene-benzhydrylamine (1c), and N-(2-nitrofurfurylidene)-p-toluidine (1d) were synthesized and three new furan-derived N-substituted aminomethylphosphonic acids, namely: 2-furyl N-(p-methoxyphenyl)-aminomethylphosphonic acid (2a), 2-furyl N-(p-methylphenyl)-aminomethylphosphonic acid (2b) and 2-furyl N-(diphenylmethyl)-aminomethylphosphonic acid (2c) were synthesized by the addition of in situ generated bis-(trimethylsilyl) phosphite to azomethine bond of corresponding Schiff bases 1a-c. Three Schiff bases 1a-b and 1d as well as all three aminophosphonic acids 2a-c were analyzed in regard with their phytotoxicity toward two plants, radish (Raphanus sativus) and oat (Avena sativa). It has been found that tested N-furfurylidene-p-anisidine (1a), N-(2-nitrofurfurylidene)-p-toluidine (1d) and aminophosphonic acids 2a-c are toxic for selected plants. N-furfurylidene-p-toluidine (1b) did not show any ecotoxicological impact in used plant growth test.