- Fluorescent cyclic phosphoramide mustards and their cytotoxicity against cancer and cancer stem cells
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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
- Bhattacharyya, Sudipta,Acharya, Sourav,Dey, Suman Kr.,Vipparthi, Kavya,Singh, Sandeep,Mukherjee, Arindam
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- Discovery of phosphorodiamidate mustard-based O2-phosphorylated diazeniumdiolates with potent anticancer activity
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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.
- Zou, Yu,Yan, Chang,Knaus, Edward E.,Zhang, Huibin,Zhang, Yihua,Huang, Zhangjian
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- Further evidence on the favorable role of the anomeric effect on the cleavage of HepDirect and cyclophosphamide prodrugs
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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).
- Sartillo-Piscil, Fernando,Quintero, Leticia,Cruz-Gregorio, Silvano,Espinosa-Aguirre, Javier,Elinos-Baez, Carmen M.,H?pfl, Herbert,Serrano, Abel
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- Synthesis and antitumor activity of novel nitrogen mustard derivatives of 2, 4, 6-trioxo-1, 3, 5, 2-triazaphosphorine
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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.
- Lu, Shui-Ming,Mao, Li-Juan,Xiong, Ye-Rong
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- Synthesis of novel chiral 2-Oxo- And 2-thio-1,3,2-oxazaphospholidines via asymmetric cyclization of L-methionol with (thio)phosphoryl dichlorides
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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.
- Liu, Ling-Yan,Chen, Ru-Yu,Huang, You
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- Synthesis of some amino acid linked nitrogen mustard derivatives
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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.
- McGuigan,Narashiman
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- A simple and convenient protocol for the synthesis of seven- and eight-membered phosphorus heterocycles
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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."
- Kanduluru, Ananda Kumar,Cirandur, Suresh Reddy
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- Decomposition of N-Phosphorylated Nitrogen Mustards: A Mechanistic Investigation
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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.
- Roux, Charlotte le,Modro, Agnes M.,Modro, Tomasz A.
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- An efficient synthesis of 2-hydroxyethyl N,N,N′ ,N′-tetrakis(2-chloroethyl)phosphorodiamidate
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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.
- Herr, R. Jason,Zhichkin, Paul,Hernandez-Abad, Pedro E.,Meckler, Harold,Schow, Steven R.
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- Design, synthesis and evaluation of targeted hypoxia-activated prodrugs applied to chondrosarcoma chemotherapy
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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.
- 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
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supporting information
(2020/04/08)
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- Synthesis and Antitumor Effect of Sophoridine Derivatives Bearing an Acyclic Aryloxy Phosphoramidate Mustard Functionality
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To elevate the potency of sophoridine, phosphoramidate mustard motif was incorporated to D-ring opened sophoridine scaffold. A series of acyclic aryloxy phosphoramidate mustard functionalized sophoridine derivatives were synthesized and screened for cytostatic activity in a range of different tumor cell lines (S180, H22, K562, MCF-7, SMMC-7721, and LoVo). All these compounds were shown to be more sensitive to S180 and H22 cells with IC50 values ranging from 2.10 to 7.21?μM. In addition, all targeted derivatives distinctly are more cytotoxic to cancer cells than normal cell L929. Compounds 8b, 8c, 8d, and 8e displayed moderate tumor suppression without apparent organ toxicity in vivo against mice bearing H22 liver tumors. Their potential binding modes with DNA topoisomerase I complex have also been investigated.
- Dai, Lin-Lin,Li, Dong-Dong,Zhao, Xiu-Mei,Zhi, Shuang,Shen, Hong-Sheng,Yang, Zi-Bo
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p. 417 - 425
(2018/12/05)
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- Process for preparing cyclophosphamide, intermediates, and monohydrate thereof
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The present disclosure provides a process for preparing cyclophosphamide, intermediate, and the monohydrate thereof.
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Page/Page column 4; 5
(2019/11/28)
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- Novel sophoridine derivatives bearing phosphoramide mustard moiety exhibit potent antitumor activities in vitro and in vivo
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Novel mustard functionalized sophoridine derivatives were synthesized and evaluated for their cytotoxicity against of a panel of various cancer cell lines. They were shown to be more sensitive to S180 and H22 tumor cells with IC50 values ranging from 1.01–3.65 μM, and distinctly were more cytotoxic to cancer cells than normal cell L929. In addition, compounds 7a, 7c, and 7e displayed moderate tumor suppression without apparent organ toxicity in vivo against mice bearing H22 liver tumors. Furthermore, they arrested tumor cells in the G1 phase and induced cellular apoptosis. Their potential binding modes with DNA-Top I complex have also been investigated.
- Li, Dongdong,Dai, Linlin,Zhao, Xiumei,Zhi, Shuang,Shen, Hongsheng,Yang, Zibo
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- Structure-activity relationship study of hypoxia-activated prodrugs for proteoglycan-targeted chemotherapy in chondrosarcoma
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Due to an abundant chondrogenic, poorly vascularized and particularly hypoxic extracellular matrix, chondrosarcoma, a malignant cartilaginous tumour, is chemo- and radio-resistant. Surgical resection with wide margins remains the mainstay of treatment. To address the lack of therapy, our strategy aims to increase anticancer drugs targeting and delivery in the tumour, by leveraging specific chondrosarcoma hallmarks: an extensive cartilaginous extracellular matrix, namely the high negative fixed charge density and severe chronic hypoxia. A dual targeted therapy for chondrosarcoma was investigated by conjugation of a hypoxia-activated prodrug (HAP) to quaternary ammonium (QA) functions which exhibit a high affinity for polyanionic sites of proteoglycans (PGs), the major components of the chondrosarcoma extracellular matrix. Based on preclinical results, an imidazole prodrug, ICF05016, was identified and provided the basis for a lead optimization study. A series of 27 QA-phosphoramide mustard conjugates, differing by the type of QA function and the length of the alkyl linker, was yielded by a common multi-step sequence involving phosphorylation of a key 2-nitroimidazole alcohol. Then, a screening was realized by surface plasmon resonance technology to assess biomolecular interactions between QA derivatives and aggrecan, the most abundant PG in chondrosarcoma. Results revealed that affinity depends more on the type of QA function, than on the linker length. Moreover, the presence of a benzyl group enhanced affinity to aggrecan. Twelve compounds were shortlisted and evaluated for antiproliferative activity (i.e., growth inhibiting concentration 50), under normoxic and hypoxic conditions using the human extraskeletal myeloid chondrosarcoma cell line (HEMC-SS). For all prodrugs, hypoxic selectivity was maintained and even increased, compared with the lead. From this study, compound 31f emerged as the most effective PG-targeted HAPs with a dissociation constant of 2.10 μM in the SPR experiment, a hypoxia cytotoxicity ratio of 24 and an efficient reductive cleavage under chemical and enzymatic conditions.
- Ghedira, Donia,Voissière, Aurélien,Peyrode, Caroline,Kraiem, Jamil,Gerard, Yvain,Maubert, Elise,Vivier, Magali,Miot-Noirault, Elisabeth,Chezal, Jean-Michel,Farhat, Farhat,Weber, Valérie
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- Synthesis, cytotoxicity, topoisomerase I inhibition and molecular docking of novel phosphoramide mustard sophoridinic acid analogues
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A series of novel phosphoramide mustard sophoridinic acid analogues, consisting of nitrogen mustard group and sophoridinic acid scaffold, have been designed, synthesized and evaluated for their topoisomerase inhibitory activity as well as cytotoxicity against six tumor cell lines (SMMC-7721, LoVo, MCF-7, K562, S180 and H22) and a normal cell line (L929). Among the compounds tested, five were found to be potent inhibitors and exhibited potent cytotoxicity against S180 and H22 cell lines with IC50 values of 1–4?μM. Further mechanistic studies showed that this class of compounds acted as novel topoisomerase I (Topo I) catalytic inhibitors by preventing the binding of Topo I to DNA and inhibiting the cleavage of DNA, and molecular docking studies revealed that the binding energy for these compounds was comparable to that for classic Topo I inhibitors CPT and HCPT, indicating that the compounds have an interaction with DNA and Topo I.
- Liu, Kai,Li, Dong-Dong,Zhao, Xiu-Mei,Dai, Lin-Lin,Zhang, Ting,Tao, Zun-Wei
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- Amido phosphate bis-curcumin ester compound, preparation method and application
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The invention discloses an amido phosphate bis-curcumin ester compound, a preparation method and application, and belongs to the field of medicinal chemistry. The compound has the structural formula as follows (referring to the description). The R1 and R2 in the formula (I) can form a saturated nitrogen heterocyclic ring structure as follows through cyclization (referring to the description). The preparation method of the compound comprises the following steps: firstly, preparing amino phosphoryl chloride or thio amino phosphoryl chloride; then reacting with curcumin to obtain the compound. The amido phosphate bis-curcumin ester compound provided by the invention has relatively good antineoplastic activity, the toxicity of the compound is smaller than that of cisplatin, and the compound can be used for preparing medicine for resisting lung cancer, stomach cancer, leukemia, breast cancer and inflammation.
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Paragraph 0188
(2016/10/07)
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- Matrine derivative having antitumor performance
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The invention relates to a matrine derivative, and provides a matrine derivative with characteristics of high activity, low toxicity and good antitumor performance, and uses of the matrine derivative in preparation of antitumor drugs.
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Paragraph 0062; 0063; 0064
(2016/10/08)
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- A convenient synthesis of chrysin-7-yl aryl N-bis(2-chloroethyl) phosphoramidate
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A series of novel chrysin-7-yl aryl N-bis(2-chloroethyl) phosphoramidates have been synthesised in good yield via phosphorylation reactions and their structures were elucidated by IR, NMR and elemental analysis.
- Chen, Xiaolan,Yuan, Jinwei,Wang, Junliang,Qu, Lingbo,Yu, Zhangqi,Zhao, Yufen
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experimental part
p. 407 - 409
(2010/12/19)
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- 2-ethyl N,N-bis(2-chloroethyl)phosphorodiamidates
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2-{[2-(Substituted amino)ethyl]sulfonyl}ethyl N,N-bis(2-chloroethyl)phosphorodiamidates and their salts, their preparation and intermediates in their preparation, pharmaceutical compositions containing them, and methods of treatment using them. The compounds are useful for treating cancer and autoimmune diseases, alone and in combination with other therapies.
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(2009/07/03)
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- A convenient synthesis of novel phosphoramide mustard analogues of 2-arylquinolone
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A series of novel phosphoramide mustard analogues of 2-arylquinolones are synthesized through a convenient and facile phosphorylated reaction, and their structures are elucidated by NMR, IR, and HR MS. The amino acid esters and phosphoryl nitrogen mustard are linked to 2-arylquinolone to improve their undesirable physicochemical and biological properties.
- Yuan, Jinwei,Chen, Xiaolan,Qu, Lingbo,Zhang, Shouren,Lu, Jiansha,Zhao, Yufen
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experimental part
p. 2936 - 2944
(2010/04/05)
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- Design, synthesis, and biological evaluation of phosphoramide derivatives as urease inhibitors
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The design, synthesis, and biological evaluation of phosphoramide derivatives as urease inhibitors to reduce the loss of ammonia has been carried out. Forty phosphorus derivatives were synthesized and their inhibitory activities evaluated against that of jack bean urease. In addition, in vivo assays have been carried out. All of the compounds were characterized by IR, 1H NMR, MS, and elemental microanalysis. In some cases, detailed molecular modeling studies were carried out, and these highlighted the interaction between the enzyme active center and the compounds and also the characteristics related to their activity as urease inhibitors. According to the IC50 values for in vitro inhibitory activity, 12 compounds showed values below 1 μM and 8 of them represent improvements of activity in comparison to the commercial urease inhibitor N-n-butylthiophosphorictriamide (NBPT) (100 nM) (AGROTAIN). On the basis of the activity results and the conclusions of the molecular modeling study, a structural model for new potential inhibitors has been defined.
- Dominguez, Maria J.,Sanmartin, Carmen,Font, Maria,Palop, Juan A.,San Francisco, Sara,Urrutia, Oscar,Houdusse, Fabrice,Garcia-Mina, Jose M.
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experimental part
p. 3721 - 3731
(2010/03/05)
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- A convenient method for the synthesis of cyclophosphamide analogues
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Several new 2-[bis(2-chloroethyl)amino)]-7-methoxyl-3-alkyl-4-methyl-1,3,2- benzoxazaphosphorin-2-oxides(3a-e) have been synthesized by cyclic condensation of bis(2-chloroethyl)amino phosphoryl dichloride and 2-(1-alkylamino) ethyl-4-methoxylphenol. The title compounds are characterized by NMR, ESI-Q-TOF, and ESI-MS. Copyright Taylor & Francis Group, LLC.
- Liuji, Zhang,Lingbo, Qu,Baojun, Zhang,Xiaolan, Chen,Yufen, Zhao
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experimental part
p. 799 - 803
(2009/04/06)
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- Prodrugs activated by targeted catalytic proteins
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Prodrugs that are activated by and conjugated to a catalytic antibody conjugated to a moiety that binds to a tumor cell population are provided.
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- Chemistry of N-phosphorylated nitrogen mustards: The effect of a second nitrogen substituent at phosphorus on the stability of the system
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Methyl N,N-diethyl-N′N′-bis(2-chloroethyl)phosphoramidate was prepared as a precursor for the corresponding phosphordiamidate anion, a model for the phosphoramidate mustard, biologically active degradation product of cyclophosphamide drug. Demethylation of the precursor led to a highly unstable ion which underwent spontaneous fragmentation. In the absence of an external nucleophile, the ion decomposed yielding metaphosphoramidate and N-substituted ethyleneimine as primary intermediates. In the presence of pyridine, bis-alkylation of two pyridines took place yielding bis [2-(N-pyridinio)ethyl]amine dication, in addition to some 1,3,2-oxazaphospholidine derivative, formed via the competitive 1,5-cyclization of the demethylated anion. Incubation of the precursor in the presence of thiophenol/triethylamine resulted in two parallel nucleophilic displacements: (i) the O-demethylation followed by bisalkylation of two molecules of thiophenol, together with some 1,5-cyclization; (ii) initial direct displacement of the chlorine at the β-carbon of the precursor, followed by the fragmentation of the system. It is concluded that the electron-rich ionic phosphoramidate substituent, -O(R2N)P(O), highly activates the N-(2-chloroethyl) functional group in alkylation reactions.
- Wan, Huijie,Modro, Tomasz A.
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p. 155 - 168
(2007/10/03)
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- SYNTHESIS AND PROPERTIES OF NOVEL NITROGEN MUSTARD LINKED PHOSPHORYL DIAMIDE DERIVATIVES
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Two series of novel phosphoryl diamide derivatives (3, 4) containing the nitrogen mustard group were synthesized, and the effects of substituents on the reactivity and the spectral properties are discussed.All the compounds prepared were confirmed by 1H NMR, IR, MS, 31P NMR and elemental analysis.Preliminary bioassays indicate that compounds 3 have good antitumor activities, and some of compounds 4 display high inhibitory activities against the tobacco mosaic virus (TMV).Key words: Antitumor; antivirus; phosphoryl diamide; nitrogen mustard.
- Chen, Ru-Yu,Mao, Li-Juan,Wang, Hui-Lin,Zhou, Jia
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- Synthesis and Antitumor Properties of Activated Cyclophosphamide Analogues
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A series of 5- and 6-substituted cyclophosphamide analogues has been prepared, and their 31P NMR kinetics of phosphoramide mustard (PDA) release and in vitro and in vivo cytotoxicity have been evaluated. cis-4-Hydroxy-5-methoxycyclophosphamide equilibrated very slowly and to a minor extent with the ring-opened aldophosphamide analogues in aqueous buffer; release of PDA was observed to a minor extent and only at high (1 M) buffer concentrations.This analogue was essentially inactive in vitro against L1210 and P388 leukemia cells. 6-Phenylcyclophosphamide and its 4-hydroperoxy derivative were potent inhibitors of blood acetylcholinesterase and were lethal at therapeutic doses in mice.In contrast, 4-hydroperoxy-6-(4-pyridyl)cyclophosphamide did not inhibit acetylcholinesterase and showed significant antitumor activity in vitro and in vivo against both wild-type and cyclophosphamide-resistant L1210 leukemia.The 4-hydroperoxy-6-arylcyclophosphamides were generally active in vitro against both wild-type and cyclophosphamide-resistant L1210 and P388 cells, and several analogues showed significant activity in vivo.Suprisingly, there was no correlation between antitumor activity in vitro and the rate of PDA release in aqueous buffer.Several compounds that showed essentially no release of PDA in aqueous buffer over several hours were highly cytotoxic to leukemia following a 1-h exposure in vitro.These results show that activated cyclophosphamide analogues substituted at the 6-position are not-cross-resistant in these leukemia cell lines, and that a specific intracellular activation mechanism may be catalyzing PDA release in these analogues.
- Borch, Richard F.,Canute, Gregory W.
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p. 3044 - 3052
(2007/10/02)
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- New Dihydrazido and Oxyamido Derivatives of Phosphoric and Thiophosphoric Acid with Bis(2-chloroethyl)amido Substituents
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(Cl-CH2CH2)2N-P(=X)Cl2, X = O, reacts with 1,2-dimethylhydrazine in the presence of triethylamine to give the dihydrazide.Hexahydropyridazine as "cyclic hydrazine" leads to a tetracyclic side product formed by HCl elimination from the reactive 2-chloroethyl groups and active β-NH protons of the hexahydropyridazinyl substituents.The corresponding thio-compound, X = S, yields the monosubstitution product (Cl-CH2CH2)2N-P(=S)(N(CH3)-N(CH3)H)Cl.O-Benzylhydroxyamine hydrochloride substitutes both Cl-atoms at P to form (Cl-CH2CH2)2N-P(=S)(NH-O-CH2-C6H5)2.The corresponding phenylesters C6H5O-P(=X)(NH-O-CH2-C6H5)2, X = O, S, are prepared in a similar reaction. - Keywords: N-Lost Derivatives, O-Benzyloxyamido Derivatives
- Giersdorf, Konrad,Diefenbach, Ursula,Engelhardt, Udo
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p. 1545 - 1549
(2007/10/02)
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- Derivatives of N,N-(2-chloro-ethyl)-phosphoric acid amide
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The invention concerns derivatives of N,N-bis(2-chloroethyl)-phosphoric acid amide of general formula I STR1 wherein X and Y are the same or different and signify oxygen or NR3, R1 and R2 are the same or different and R1 signifies the radical CH2 (OR4)--CH2 --CH2 --, CH2 (OR4)--CH(CH3)--CH2 -- or CH2 (OR4)--CH(OR5)--CH2 -- and, when X is an NR3 group, can also be hydrogen, R2 possesses one of the meanings of R1 or is ethyl, propyl, allyl, propenyl, chloroethyl, methyl or benzyl, R3 is hydrogen, methyl, ethyl, propyl or allyl and wherein the radicals R4 and R5 are the same or different and represent an alkyl radical R or an acyl radical --COR, whereby R signifies a straight-chained or branched, saturated or unsaturated alkyl group with 1 to 25 carbon atoms, or an aralkyl radical with 1 to 25 carbon atoms in the alkyl chain, and one of the radicals can also be a hydrogen atom, as well as processes for their preparation. The compounds according to the invention display an outstanding antitumour action comparable with the action of cyclophosphamide.
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