Interaktive Computergraphik und Molekülmodellierung/ Interactive Computer Graphics and Molecular Modelling

Brickmann, Jürgen; Waldherr-Teschner, Michael

doi:10.1524/itit.1991.33.2.83

Cited by 3 publications

(3 citation statements)

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“…The H,H-COSY spectrum of 13 showed three separate spin systems which were assigned to the substructures >NCH2(4)CH2(5)N<, >NCH2(7)CH2(8)CH2(9)0-, and >NCH2(10)CH2(11)C1. The assignment of the CH2 groups ( 8), (9), and (11) was already clear from their characteristic chemical shifts in the ID *H NMR spectrum. Consequently, using the COSY spectrum, the assignment of CH2 groups ( 7) and (10) 3-(trimethylsilyl)propanesulfonic acid sodium salt (TMPS) or tetramethylsilane (TMS) for compound 7.…”

Section: Identification Of Cyclophosphamide Hydrolysismentioning

confidence: 92%

“…Since Zon et al7 found a £1/2 of 20 min for the hydrolysis of this compound into 9 under highly acidic conditions (pD ~0) at 20 °C using :H NMR, we decided to monitor the hydrolysis of a 26.8 mM solution of 7 under similar conditions (1 N HC1, 24 °C) using 31P NMR. In the first spectrum (obtained 11 min after dissolving 7 in this medium), the resonance of 7 was already undetectable and only the signals of compounds 13 and 9 were observed. The £1/2 for the hydrolysis of 13 thus formed (which was only degraded into 3 under these conditions) was estimated to be 6 min.…”

Section: T H I S C O N T E N T Imentioning

confidence: 99%

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Chemical and Biological Evaluation of Hydrolysis Products of Cyclophosphamide

Gilard¹,

Martino²,

Malet‐Martino³

et al. 1994

J. Med. Chem.

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31P NMR spectroscopy was used to study the products of the decomposition of cyclophosphamide (1) in buffered solutions at pH's ranging between 1.2 and 8.6 at 20 degrees C and at pH 7.4 at 37 degrees C. At pH 1.2, 1 undergoes a rapid breakdown (t1/2 = 1.4 days) of the two P-N bonds, giving compounds 2 [HN(CH2CH2Cl)2] and 3 [H2N(CH2)3OP(O)(OH)2] as hydrochlorides. No intermediates were detected. At pH's between 5.4 and 8.6, hydrolysis of 1 during 17 days leads to the sole and previously unknown nine-membered ring compound 13. 13 results from the intramolecular alkylation of 1 giving the bicyclic compound 7 followed by the exothermal hydrolytic breakdown of the P-N bond of its six-membered ring. At pH 2.2 and 3.4, the two hydrolytic pathways coexist since, beside compounds 2 and 3, the hydrochloride of compound 9 [Cl(CH2)2NH(CH2)2NH(CH2)3OP(O)(OH)2] is formed, resulting from the acid-catalyzed breakdown of the P-N bond in the nine-membered ring compound 13. At pH 2.2, the presence of chloride ion affected neither the stability of 1 nor the contribution of the two competing hydrolytic pathways. At pH's ranging from 3.4 to 8.6, there is little degradation of 1 since more than 95% of initial 1 was still present after 7 days at 20 degrees C. Under physiological conditions (pH 7.4, 37 degrees C) after 6 days, 45% of 1 is hydrolyzed (t1/2 = 6.6 days), leading essentially (30% of initial 1) to the nine-membered ring compound 13. The rate of hydrolysis of 13 and the nature of its hydrolysis products were found to depend on pH over the range 0-8.6. After a single ip injection to mice, compounds 3, 9, and 13 were less toxic than 1. They did not exhibit any direct cytotoxic efficacy on the colony-forming capacity of L1210 cells in vitro, and they had no antitumor activity in vivo against P388 leukemia.

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Section: Identification Of Cyclophosphamide Hydrolysismentioning

confidence: 92%

Section: T H I S C O N T E N T Imentioning

confidence: 99%

Chemical and Biological Evaluation of Hydrolysis Products of Cyclophosphamide

Gilard¹,

Martino²,

Malet‐Martino³

et al. 1994

J. Med. Chem.

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“…In this study, we have obtained log P estimations with software based on both types of approaches: three substructure approaches (CLOGP version 4.34, , KOWWIN, MOLCAD , ) and one whole-molecule approach (HINT). The fragmental system CLOGP 4,5 from Hansch and Leo is based on (in contrast to other fragmental methods) the principles of “constructionism”.…”

Section: Methodsmentioning

confidence: 99%

Suitability of Molecular Descriptors for Database Mining. A Comparative Analysis

2002

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Database mining methods rely on the molecular descriptors used to characterize a structural database. In the present investigation, five different types of descriptors (log P, UNITY fingerprints, ISIS keys, VolSurf, and GRIND) are applied to characterize various databases (n ) 1007, 100, and 229) comprising drugs almost exclusively. The validity of the descriptors is comparatively analyzed via principal component analysis and its hierarchical variant, consensus principal component analysis. Both pharmacodynamic and pharmacokinetic aspects of database mining are treated. For pharmacodynamic aspects, clustering behavior achieved with the different descriptors is tested on the chemically homogeneous -blockers, benzodiazepines, and penicillins and on the chemically more diverse class I antiarrhythmics. The following ranking is observed: UNITY fingerprints > ISIS keys and GRIND > VolSurf > log P. Regarding information content, the CPCA superweight plot indicates similarity between fingerprints and ISIS keys as well as between VolSurf and log P, while GRIND differs from all the remaining descriptors. Solubility data and blood/brain barrier penetrating behavior serve as test cases for pharmacokinetic aspects. Comparison of the descriptors applied to these data reveals that VolSurf has the most realistic and consistent behavior, GRIND shows intermediate behavior, while UNITY fingerprints and ISIS keys are not well suited for pharmacokinetic profiling. From this comparative analysis, we conclude that VolSurf descriptors exhibit particular advantages in treating pharmacokinetic aspects; UNITY fingerprints, ISIS keys, and GRIND descriptors are of special value for tackling pharmacodynamic aspects of database mining. The parameter log P is of limited applicability in database mining because of rather poor reliability and lack of completeness of data.

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Some Disaccharide‐derived Building Blocks of Potential Industrial Utility

et al. 1992

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The utilization of inexpensive, bulk‐scale accessible, renewable disaccharides as organic raw materials necessitates their practice‐oriented conversion into products with different functional groups and, hence, broader application profiles. The backlog for the development of practical reaction channels to versatile building blocks from disaccharides being particularly obvious. Correspondingly, this account describes a series of examples by which the reaction potential inherent in disaccharides such as sucrose, lactose, maltose and isomaltulose is utilized towards the acquisition of versatile building blocks without cleaving the intersaccharidic linkage. ‐ The glucose portion of sucrose, e.g. can be converted into dihydropyranones with the carbonyl function at C‐2 or C‐4, the reducing glucose parts of maltose and lactose may be transformed into enediolone, enelactone, or enollactone structures, whilst the fructose moiety of isomaltulose elaborates a furan ring by threefold, acid‐induced elimination of water to yield the terminally O‐glucosylated HMF, i.e. glucosyloxymethyl‐furan‐2‐carboxaldehyde. ‐ All reaction sequences comply with criteria of practicallity and therefore being transformable to large scale without major changes. Another novel entry reaction into O‐functionalized disaccharide derivatives, the cathodic deprotonation and subsequent trapping of the mono‐anion with suitable reagents according to Hamann, was evaluated in terms of understanding the regioselectivity attainable through computer simulations of relevant conformers of sucrose in solution, and the corresponding molecular electrostatic potential (MEP) profiles.

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Interaktive Computergraphik und Molekülmodellierung/ Interactive Computer Graphics and Molecular Modelling

Cited by 3 publications

References 0 publications

Chemical and Biological Evaluation of Hydrolysis Products of Cyclophosphamide

Chemical and Biological Evaluation of Hydrolysis Products of Cyclophosphamide

Suitability of Molecular Descriptors for Database Mining. A Comparative Analysis

Some Disaccharide‐derived Building Blocks of Potential Industrial Utility

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