127-88-8Relevant articles and documents
Fluorescent cyclic phosphoramide mustards and their cytotoxicity against cancer and cancer stem cells
Bhattacharyya, Sudipta,Acharya, Sourav,Dey, Suman Kr.,Vipparthi, Kavya,Singh, Sandeep,Mukherjee, Arindam
, p. 205 - 215 (2019)
Two fluorescent cyclic phosphoramides, 1,3-dihydronaphtho[1,8-cd][1,2,6]phosphdiazine-2-oxide-(2-bis(2-chloroethyl)amide) (1) and 2,3-dihydro-2-oxo-1H-anthra[1,2-d][1,3,2]diazaphosphole-6,11-dione-2[N,N-bis(2-chloroethyl)]amide (2) were synthesized and ch
Discovery of phosphorodiamidate mustard-based O2-phosphorylated diazeniumdiolates with potent anticancer activity
Zou, Yu,Yan, Chang,Knaus, Edward E.,Zhang, Huibin,Zhang, Yihua,Huang, Zhangjian
, p. 18893 - 18899 (2017)
Nitric oxide (NO) has recently joined the clinical arena of cancer therapy because high levels of NO could not only induce cytotoxicity and apoptosis of cancer cells, but also sensitize the cells to chemo- and radio-therapies. Diazeniumdiolates are an important class of NO donors, and the O2-alkylation, arylation and sulfonylation of diazeniumdiolates result in more stable and potent anticancer agents. However, O2-phosphorylation has so far not been reported yet. Herein, we describe the design, synthesis and biological evaluation of a group of phosphorodiamidate mustard-based O2-phosphorylated diazeniumdiolates, 6-9. The most active compound, 7, was comparable, or even more potent, than a known anticancer agent, O2-2,4-dinitrobenzene diazeniumdiolate JS-K, against six cancer cell lines. Furthermore, 7 released larger amounts of NO, caused more significant DNA damage and cancer cell apoptosis than JS-K in the cancer cells. Our findings suggest that this new type of O2-substituted diazeniumdiolate could be potentially applied in the fight against cancer.
Further evidence on the favorable role of the anomeric effect on the cleavage of HepDirect and cyclophosphamide prodrugs
Sartillo-Piscil, Fernando,Quintero, Leticia,Cruz-Gregorio, Silvano,Espinosa-Aguirre, Javier,Elinos-Baez, Carmen M.,H?pfl, Herbert,Serrano, Abel
, p. 9647 - 9654 (2014)
On the basis of previous conformational and configurational studies of 4-aryl-substituted cyclophosph(on)ates derived from D-xylofuranose derivatives, wherein it was proposed that the anomeric effect is involved in the spontaneous isomerization of the P atom and the C4 carbon, and consequently, this unusual behavior was associated with the cleavage of the HepDirect prodrugs. We synthesized an analogous series of 2-amino-2-oxo-1,3,2-dioxaphosphorinanes and performed a conformational and configurational analysis in solution and the solid state followed by an examination of their mutagenic activity. The results showed that the 2-amino-2-oxo-1,3,2-dioxaphosphorinanes with the largest mutagenic activity contain either a 4-methoxyphenyl or 4-fluorophenyl group at C4 carbon and presented a major chair conformation, which is prone to weaken the C4 - O3 bond via the anomeric effect and facilitates the cleavage for the release of the biologically active metabolite. (Chemical Equation Presented).
Synthesis and antitumor activity of novel nitrogen mustard derivatives of 2, 4, 6-trioxo-1, 3, 5, 2-triazaphosphorine
Lu, Shui-Ming,Mao, Li-Juan,Xiong, Ye-Rong
, p. 91 - 97 (2000)
A series of novel nitrogen mustard derivatives of 2, 4, 6-trioxo-1, 3, 5, 2-triazaphosphorine have been synthesized by the cyclization reactions of N, N-bis(2-chloroethyl)amino phosphonyl diisocyanate with amines. The structures of the products were confirmed by 1H NMR, IR, MS and elemental analysis. The preliminary bioassay indicated that some of the compounds significantly inhibited the growth of Leukemia L1210 cell in vitro.
Synthesis of novel chiral 2-Oxo- And 2-thio-1,3,2-oxazaphospholidines via asymmetric cyclization of L-methionol with (thio)phosphoryl dichlorides
Liu, Ling-Yan,Chen, Ru-Yu,Huang, You
, p. 33 - 38 (2005)
In order to search for novel antitumor and antiviral agents with high activity and low toxicity, a series of chiral 2-thio(oxo)-1,3,2- oxazaphospholidines were synthesized via the reaction of L-methionol with all kinds of (thio)phosphoryl dichlorides in THF in the presence of triethylamine at room temperature. The structures of all of the new compounds were confirmed by elemental analyses, 1H, 31P NMR, and 1R spectra.
Synthesis of some amino acid linked nitrogen mustard derivatives
McGuigan,Narashiman
, p. 311 - 314 (1993)
Dichlorophosphoramide is readily prepared by the reaction of bis(β-chloroethyl)amine hydrochloride with phosphoryl chloride at elevated temperature. The crude product is pure without need for troublesome vacuum distillation. However, this reagent reacts only poorly with ethanol, propanol, and the methyl ester of valine. Thus, an alternative route was sought to amino acid linked derivatives of nitrogen mustards. This involved the synthesis of the appropriate alkyl phosphorodichloridate, and its reaction with bis(β-chloroethyl)amine, followed by condensation with an amino acid carboxyl ester. Reactions proceed in high yield, under mild conditions. In all but the case of glycine derivatives, the presence of multiple chiral centres in the final product leads to the generation of diastereoisomers, which can be observed by spectroscopic and analytical (HPLC) methods.
A simple and convenient protocol for the synthesis of seven- and eight-membered phosphorus heterocycles
Kanduluru, Ananda Kumar,Cirandur, Suresh Reddy
, p. 719 - 722 (2016)
A simple procedure for the synthesis of eight-membered 6-(2-chloroethyl)/bis(2-chloroethyl)-amino-12-oxo-dibenzo[d,g][1,3,2]dioxaphosphocin 6-oxides (3a-b) and seven-membered 6-(2-chloroethyl)/bis-(2-chloroethyl)aminodibenzo[d,f][1,3,2]dioxaphosphepin 6-oxides (5a-b) from cyclocondensation of equimolar ratios of 2,2'-dihydroxybenzophenone (1) and 2,2'-dihydroxybiphenol (4), respectively with 2-chloroethylphosphonicdichloride (2a) and bis(2-chloroethyl)phosphoramidic dichloride (2b) in dry toluene in the presence of triethylamine at 45-50 °C is described. All synthesized compounds possessed significant growth inhibition for their antibacteria against Bacillus subtilis and Klebsiella pneumonia and antifungi activity on "Curvularia lunata" and "Aspergillus Niger."
Decomposition of N-Phosphorylated Nitrogen Mustards: A Mechanistic Investigation
Roux, Charlotte le,Modro, Agnes M.,Modro, Tomasz A.
, p. 3832 - 3839 (1995)
Lithium methyl N-(2-chloroethyl)phosphoramidate (2b) and lithium methyl N,N-bis(2-chloroethyl)phosphoramidate (2c) were prepared as models of N-phosphorylated mustards used in cancer chemotherapy.The decomposition of those substrates in D2O and in D2O-pyridine-d5 was studied to elucidate the mechanism of their alkylating reactivity.The products of the decomposition and the variation of the proportions of the products with time were determined, and the results led to the following conclusions.Decomposition of substrates of the type 2 can follow three independent pathways: (i) 1,5-cyclization to a 1,3,2-oxazaphospholidine derivative, followed by fast ring opening via the pH-dependent P-O or P-N bond cleavage; (ii) 1,3-cyclization to a N-phosphorylated aziridinium derivative, followed by the nucleophilic opening of the aziridine ring; (iii) fragmentation to metaphosphate and aziridine species, followed by rapid reactions of those intermediates with nucleophiles.The first pathway deactivates the substrate with respect to the alkylating reactivity.Relative contributions of individual pathways to the decomposition are highly sensitive to the detailed structure of the substrate and to the nucleophilic composition of the reaction medium.
An efficient synthesis of 2-hydroxyethyl N,N,N′ ,N′-tetrakis(2-chloroethyl)phosphorodiamidate
Herr, R. Jason,Zhichkin, Paul,Hernandez-Abad, Pedro E.,Meckler, Harold,Schow, Steven R.
, p. 442 - 444 (2001)
A process for the multikilogram preparation of 2-hydroxyethyl N,N,N′ ,N′-tetrakis(2-chloroethyl)phosphorodiamidate has been achieved in substantially pure form by a short synthetic sequence starting from phosphorus oxychloride and 2 equiv of bis(2-chloroethyl)amine. This process involves a two-step preparation of the intermediate mustard chloride in one pot, followed by the base-catalyzed reaction with excess ethylene glycol. This method has been carried out to provide 2.9 kg of this key drug substance intermediate in 52% overall yield.
Design, synthesis and evaluation of targeted hypoxia-activated prodrugs applied to chondrosarcoma chemotherapy
Canitrot, Damien,Chezal, Jean-Michel,Galmier, Marie-Josephe,Gaumet, Vincent,Gerard, Yvain,Ghedira, Donia,Maubert, Elise,Miot-Noirault, Elisabeth,Peyrode, Caroline,Tarrit, Sebastien,Voissière, Aurélien,Weber, Valérie
supporting information, (2020/04/08)
The tumor microenvironment in chondrosarcoma (CHS), a chemo- and radio-resistant cancer provides unique hallmarks for developing a chondrosarcoma targeted drug‐delivery system. Tumor targeting could be achieved using a quaternary ammonium function (QA) as a ligand for aggrecan, the main high negative charged proteoglycan of the extracellular matrix of CHS, and a 2-nitroimidazole as trigger that enables hypoxia‐responsive drug release. In a previous work, ICF05016 was identified as efficient proteoglycan-targeting hypoxia-activated prodrug in a human extraskeletal myxoid chondrosarcoma model in mice and a first study of the structure-activity relationship of the QA function and the alkyl linker length was conducted. Here, we report the second part of the study, namely the modification of the nitro-aromatic trigger and the position of the proteoglycan-targeting ligand at the aromatic ring as well as the nature of the alkylating mustard. Synthetic approaches have been established to functionalize the 2-nitroimidazole ring at the N-1 and C-4 positions with a terminal tertiary alkyl amine, and to perform the phosphorylation step namely through the use of an amine borane complex, leading to phosphoramide and isophosphoramide mustards and also to a phosphoramide mustard bearing four 2-chloroethyl chains. In a preliminary study using a reductive chemical activation, QA-conjugates, except the 4-nitrobenzyl one, were showed to undergo efficient cleavage with release of the corresponding mustard. However N,N,N-trimethylpropylaminium tethered to the N-1 or C-4 positions of the imidazole seemed to hamper the enzymatic reduction of the prodrugs and all tested compounds featured moderate selectivity toward hypoxic cells, likely not sufficient for application as hypoxia-activated prodrugs.
