Mustard, derivatives

According to a hypothesis launched by Larionov et al in the 1960s, some new nitrogen mustard derivatives were developed. They contain metabolites and heterocyclic structures as carriers of the cytotoxic chloroethylamine groups. By this way the synthesis of aliylating metabolites started melphalan (sarcolysine) as L- or DL-phenylalanine derivative prospidine with a tricyclic piperazine moiety and chlorambucil as butyric acid derivative. It was proven that each alkylating metabolite has its own spectrum of selective antitumor activity. 

Rubefacients Produce redness Allyl isothiocyanate 0.5-5% Ammonia water 1 -2.5% Musterole Extra Made by dilution of concentrated solution with water Mustard derivative Pungent odor Avoid inhalation More concentrated solutions are highly caustic Avoid inhalation... 

Bi- and poly-thioethers with aliphatic backbones are produced by attack of RS on the appropriate haloalkane. This is the method of choice for RS(CH2)raSR (R = Me or Ph),26 MeC(CH2SR)3,27,28 MeS(CH2)raS(CH2)raSMe (n = 2 or 3) and MeS(CH2)raS(CH2) S(CH2) SMe.28,29 [Caution Some of these syntheses involve sulfur mustard derivatives as intermediates - these are very powerful vesicants and should be handled only with extreme care.] The other tridentates RS(CH2)3S(CH2)3SR (R = Et, Pr or Ph) may be obtained from nucleophilic attack by RS on the ditosylate TsO(CH2)3S(CH2)3OTs.30 Tetra-dentate thioethers involving o-phenylene interdonor linkages are also known.31 More recently the preparation and coordination chemistry of the silicon-apex derivative MeSi(CH2SMe)3 has been described.32... 

Despite the fact that alkylating agents exhibit a common mechanism of action, their clinical use varies depending on differences in pharmacokinetics, metabolism, hpid solubility, ability to penetrate membranes, and toxicity. They can be classified as nitrogen-containing mustard derivatives (mechorethamine, chlorambucil, melfalan, cyclophosphamide, ifos-famide), derivatives of ethylenimine (thiotepa), nitrosoureas (carmustine, lomustine, strep-tozocin), alkylsulfonates (busulfan), and derivatives of platinum (cwplatin, carboplatin). 

Direct electrolytic dechlorination of 9-chloroanthracene at a mercury electrode occurs at about -1.65 V (see) in a layer of adsorbed cetyltrimethylammonium bromide on the electrode surface233. Similarly, electrochemical degradation of trichloroethylene in acetonitrile resulted in quantitative conversion to chloroacetylene, which was reduced further to acetylene at a more negative reduction potential (-2.8 V) in 96% yield234. Reductive destruction of 1,3,5-trichlorobenzene in the cathode compartment could be observed235. Electrochemical methods presumably can be used for decontamination of chemical warfare agents such as mustard derivatives as an alternative to the chemical methods such as base-catalyzed dehydrohalogenation236. 

The Mannich reaction of various 3(2Jy)-pyridazinones with 2,2 -dichlorodiethylamine was investigated. In few cases the expected nitrogen-mustard derivatives were obtained, but in most cases iV -hydroxymethyl derivatives were isolated. With other amines the corresponding N-Mannich bases were formed in good yields. Reaction with 4(l I)-pyridazinones was also investigated. 

Cyclophosphamide is an alkylating nitrogen mustard derivative mainly used in oncology patients (1) or in conditioning regimens for bone marrow transplantation. Its immunosuppressant properties have been used in organ transplantation and more often in chronic inflammatory disorders or autoimmune diseases. 

Chlorambucil acts most slowly and is the lea.st toxic i any nitrogen mustard derivative in use. It is indicated es x cially in treatment of CLL and primary maeroglobuliiKiuu... 

The LAT system has been used for the transport of various compounds to the brain. Variations in the cerebellum to plasma ratio at late times in 6-[18F]fluoro-L-DOPA studies are consistent with competitive binding of large neutral amino acids (LNAAs) for the LAT at the BBB (117). In addition, it was shown that oral administration of phenylalanine inhibited the uptake of an artificial amino acid [(1 lC)-aminocyclohexanecarboxylate] in human brain (118). Melphalan, a nitrogen mustard derivative of the neutral amino acid L-phenylalanine, was transported to the brain via the LAT system at the rat BBB. In addition, it was shown that melphalan competed with phenylalanine for the LAT system (119). 

Krentzkamp, N., and Cordes, G., Carbonyl- and cyanophosphonic acid esters. Part 6. a-Substimted benzylphosphonic acid and its derivatives. Arch. Pharm. Ber. Dtsch Pharm. Ges., 295, 276, 1962. Schulze, W., WiUitzer, H., and Fritzsche, H., Nitrogen mustard derivatives by the reaction of N,N-iiw(P-chloroethyl)-p-(tricyanovinyl)aniline with the sodium salts of OH, NH, PH, and SH acidic compounds, Chem. Ber., 100, 2640, 1967,... 

Cyclophosphamide and ifosfamide are nitrogen mustard derivatives, and are widely used alkylating agents (Table 124—14). They are closely related in structure, clinical use, and toxicity. Neither agent is active in its parent form and must be activated by mixed hepatic oxidase enzymes. The active metabolite of cyclophosphamide is phosphoramide mustard. Another metabolite, 4-hydroxycyclophos-phamide is cytotoxic, but is not an alkylating agent. Ifosfamide is hepaticaUy activated to ifosfamide mustard. Acrolein, a metabolite of both cyclophosphamide and ifosfamide, has little antitumor activity, but is responsible for some of their toxicity. ... 

Nitrogen mustard derivative forms interstrand DNA cross-links selective cytotoxicity for lymphocytes... 

Alkylating agent nitrogen mustard derivative cross-links DNA-DNAor DNA-protein inhibits DNA synthesis activated by hepatic microsomal (CYP450) mixed function oxidases acrolein metabolite (no antitumor activity) associated with hemorrhagic cystitis... 

Chlorobenzo[b][l,8]phenanthroline 109 (X = H) was later used by Creech et al. (72JMC739) to prepare nitrogen mustard derivatives 111 of benzo[h][l,8]phenanthroline as antitumor agents, and by Sanchez et al. (90H2003) to prepare a series of 7-anilino derivatives of benzo[b][l,8]phe-nanthroline 114. These anilino derivatives 114 were also prepared to cyclization of 2-(isoquinoline-5 -yl)benzanilides 113 with POCI3 (Scheme 21)... 

Although aziridine derivatives and nitrogen mustard derivatives differ in structural respects, they presumably act in the same way. Nitrogen mustards readily form a cyclic aziridinium ion which reacts in the subsequent rate-controlling step in an S 2 process with an available nucleophilic Y. This process is repeated with a second chloroethyl group and a second nucleophilic Z (Bartlett el al., 1947 Montgomery el al., 1970). 

A nitrogen mustard derivative of barbituric acid has been reported without antitumour data [206]. 5-Diazobarbituric anhydride (XLVI) has been found to be amoebicidal at 0-001 mg/ml vs. Endamoeba histolytica [207]. The inhibition is reversed by nucleotides, but not by the bases or nucleosides. It had previously been found that (XLVI) is a cytosine antagonist in the yeasts, Torula utilis and Saccharomyces cerevisiae Hansen [208]. This compound is prepared by the action of nitrous and nitric acids on 5-aminouracil-6-sulphonic acid [209], and as a cyclic derivative of a barbituric acid, it has quite different properties from the pyrimidinetriones. 

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