Alkaline Hydrolytic Pathway of the Antitumor Drug,Cyclophosphamide

Abstract

In an attempt to clarify the alkaline hydrolytic pathway of the antitumor agent, cyclophosphamide (CP), the time course of its degradation was monitored by ³¹P NMR in 0.5 M KOH solution. After 16 hr at 25°C. 70% of CP is hydrolyzed (t_½ 9 hr) leading to a mixture of 8 phosphorated compounds. among them only 4 represented more than 5% of the initial CP. The chemical shifts and the intensities of these compounds were as follows: 1 1 .1 ppm. 30% of the initial CP (compound 1); 9.5 ppm, 12% (compound 2); 6.4 ppm, 9% (unknown) and 4.8 ppm, 9% (compound 3). The structures of compounds 1–3 were identified by NMR (13C and IH) and mass spectrometry after their isolation. The major degradation compound formed, the nine-membered ring compound I, was also observed during CP hydrolysis at neutral or moderately acid pHsill and was detected in urine of patients treated with CP[2] Compounds 2 and 3 were also formed during the hydrolysis of compound I in 0.5 M KOH solution. Based on the formation in time of the 31P NMR signals in KOH solutions of CP and compound I, the following scheme was established for the major degradation alkaline pathway of CP.     

Alkaline Hydrolysis of the Cytostatic Drug,Ifosfamide, and its N-Dechloroethylated Metabolites

Abstract

I fosfamide (IF) is an alkylating antitumor agent used in the treatment of solid tumors. Up to 50% of IF administered to patients undergoes an oxidative N-dealkylation reaction resulting in the loss or one, other or both chloroethyl side chain(s) to produce 2- or 3-dechloioethylIF (ZDCIF, 3DCIF) or 2,3-didechloroethyllF (DDCIF). The hydrolytic pathway of these four oxazaphosphorines has been studied earlier but only at acidic and neutral pHs^[l] In the present work, we monitored their time courses of hydrolysis at basic pHs using phosphorus-3 1 NMR. The structures of the compounds formed were determined by NMR (13C and 1H) and mass spectrometry. The results are reported in the following scheme.     

High‐performance liquid chromatographic method for the quantification of Mitragyna inermis alkaloids in order to perform pharmacokinetic studies

In Africa, Mitragyna inermis (Willd.) O. Kuntze (Rubiaceae) is commonly used in traditional medicine to treat malaria. Antimalarial activity is mostly due to the hydromethanolic extract of M. inermis leaves and especially to the main alkaloids, uncarine D and isorhynchophilline. In the present study, we describe for the first time an HPLC method for the simultaneous quantification of uncarine D and isorhynchophylline in biological matrices. SPE was used to extract the components and the internal standard naphthalene from human and pig plasma samples. Chromatographic separation was performed on a C‐18 reversed column at a flow rate of 1 mL/min, using methanol–phosphate buffer (10:90, pH 7), as a mobile phase. Good linearity was observed over the concentration ranges of 0.0662–3.31 μg/mL for uncarine D and 0.0476–2.38 μg/mL for isorynchophylline. The precision was less than 12% and the accuracy was from 86 to 107% without any discrepancy between the two species. Uncarine D and isorhynchophylline recoveries were over 80%. These results allowed the quantification of both uncarine D and isorhynchophylline in pig plasma after intravenous administration of M. inermis extract.     

A new friedelane triterpenoid and saponin with moderate antimicrobial activity from the stems of Drypetes laciniata

A new friedelane-type triterpene named 3β-hydroxyfriedelane-7,12,22-trione,as well as nine known compounds were isolated from the whole stems of Drypetes laciniata Hutch.(Euphorbiaceae).Their structures were established on the basis of spectroscopic methods.The new triterpene derivative and a known saponin were tested for antimicrobial and antifungal activities and they appeared to be moderate active.     

Synthesis of poly(2‐oxazoline)s with side chain methyl ester functionalities: Detailed understanding of living copolymerization behavior of methyl ester containing monomers with 2‐alkyl‐2‐oxazolines

Poly(2‐oxazoline)s with methyl ester functionalized side chains are interesting as they can undergo a direct amidation reaction or can be hydrolyzed to the carboxylic acid, making them versatile functional polymers for conjugation. In this work, detailed studies on the homo‐ and copolymerization kinetics of two methyl ester functionalized 2‐oxazoline monomers with 2‐methyl‐2‐oxazoline, 2‐ethyl‐2‐oxazoline, and 2‐n‐propyl‐2‐oxazoline are reported. The homopolymerization of the methyl ester functionalized monomers is found to be faster compared to the alkyl monomers, while copolymerization unexpectedly reveals that the methyl ester containing monomers significantly accelerate the polymerization. A computational study confirms that methyl ester groups increase the electrophilicity of the living chain end, even if they are not directly attached to the terminal residue. Moreover, the electrophilicity of the living chain end is found to be more important than the nucleophilicity of the monomer in determining the rate of propagation. However, the monomer nucleophilicity can be correlated with the different rates of incorporation when two monomers compete for the same chain end, that is, in copolymerizations. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2649–2661     

Interaction between p-tetraphenyl tetrahomodioxacalix[4]arene amide derivatives and alkali and alkaline-earth metal cations

The binding properties of four amido derivatives of p-tetraphenyl tetrahomodioxacalix[4]arene towards alkali and alkaline-earth metal cations using UV-absorption spectrophotometry, ¹H NMR and ESI-mass spectrometry techniques are reported.     

Radiation-induced radicals in alpha-D-glucose: Comparing DFT cluster calculations with magnetic resonance experiments

Using density functional theory (DFT) calculations, an enhanced theoretical examination was made of the radiation-induced radicals in alpha-d-glucose. For the carbon-centred radicals in this sugar, the effect of the model space on the radical geometry as well as on the calculated radical hyperfine coupling tensors was examined. The findings were compared with previously published tensors, as determined by electron paramagnetic resonance (EPR) experiments and single molecule DFT calculations. A cluster approach was adopted, in which intermolecular interactions (predominantly hydrogen bonds) between the radical species and its environment were explicitly incorporated. This substantially improved the correspondence with experimental findings in comparison with single molecule calculations of an earlier examination. In a direct comparison between both computational methods for the glucose radicals, it was shown that the extent of the model space plays an important part in the determination of the radical geometry. Furthermore, the model space also has an impact on the calculated hyperfine coupling tensors. Full cluster EPR calculations, in which the paramagnetic properties are calculated for the entire model space of the cluster, give an excellent agreement with the experimental EPR measurements.     

Melt grafting of polymethyl methacrylate onto poly(ethylene‐co‐1‐octene) by reactive extrusion: Model compound approach

The grafting of poly(methylmethacrylate) onto poly(ethylene‐co‐1‐octene) by in situ radical polymerization of methyl methacrylate is a process where the side reactions are difficult to characterize. To increase the understanding of both the nature and the extent of such reactions, products resulting from the same chemical system, where polymer is replaced by squalane and/or pentadecane, are analyzed. The influence of the temperature, the nature of peroxides (used as radicals generators) and the monomer concentration are investigated toward the chain length of the grafts. The resulting grafted PMMA and PMMA homopolymer are qualitatively analyzed by MALDI‐TOF spectroscopy and size exclusion chromatography. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 5215–5226, 2007