Wyniki wyszukiwania

1

The intercalation of imidazoacridinones into DNA induces conformational changes in their side chain

100%

Mazerski J., Muchewicz K.

Acta Biochimica Polonica

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2000

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tom 47

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nr 1

Imidazoacridinones (IAs) are a new group of highly active antitumor compounds. The intercalation of the IA molecule into DNA is the preliminary step in the mode of action of these compounds. There are no experimental data about the structure of an intercalation complex formed by imidazoacridinones. Therefore the design of new potentially better compounds of this group should employ the molecular modelling techniques. The results of molecular dynamics simulations performed for four IA analogues are presented. Each of the compounds was studied in two systems: i)in water, and ii)in the intercalation complex with dodecamer duplex d(GCGCGCGCGCGC)2. Significant differences in the conformation of the side chain in the two environments were observed for all studied IAs. These changes were induced by electrostatic as well as van der Waals interactions between the intercalator and DNA. Moreover, the results showed that the geometry of the intercalation complex depends on: i)the chemical constitution of the side chain, and ii)the substituent in position8 of the ring system.

2

The ability to overcome multidrug resistance of tumour cell lines by novel acridine cytostatics with condensed heterocyclic rings

72%

Bontemps-Gracz M. M., Kupiec A., Antonini I., Borowski E.

Acta Biochimica Polonica

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2002

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tom 49

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nr 1

Two recently synthesized groups of acridine cytostatics containing fused heterocyclic ring(s): pyrazoloacridines (PAC) and pyrazolopyrimidoacridines (PPAC) were tested in regard to their in vitro cytotoxic activity towards a panel of sensitive and resistant human tumor cell lines. The obtained results corroborate our earlier hypothesis on the essential role of heterocyclic ring fused to the acridine moiety in the ability of acridine cytostatics to overcome multidrug resistance of tumor cells. The presence, location and kind of substituents considerably influenced both the cytotoxic activity of the derivatives and their ability to overcome multidrug resistance. The same factors also affected the cytostatics ability to differentiate between tumor cell lines with various types of drug exporting pumps.

3

The role of side chains in the interaction of new antitumor pyrimidoacridinetriones with DNA: molecular dynamics simulations

72%

Mazerski J., Antonini I., Martelli S.

Acta Biochimica Polonica

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2000

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tom 47

|

nr 1

Pyrimidoacridinetriones (PATs) are a new group of highly active antitumor compounds. It seems reasonable to assume that, like for some other acridine derivatives, intercalation into DNA is a necessary, however not a sufficient condition for antitumor activity of these compounds. Rational design of new compounds of this chemotype requires knowledge about the structure of the intercalation complex, as well as about interactions responsible for its stability. Computer simulation techniques such as molecular dynamics (MD) may provide valuable information about these problems. The results of MD simulations performed for three rationally selected PATs are presented in this paper. The compounds differ in the number and position of side chains. Each of the compounds was simulated in two systems: i)in water, and ii) in the intercalation complex with the dodecamer duplex d(GCGCGCGCGCGC)2. The orientation of the side chain in relation to the ring system is determined by the position of its attachment. Orientation of the ring system inside the intercalation cavity depends on the number and position of side chain(s). The conformations of the side chain(s) of all PATs studied in the intercalation complex were found to be very similar to those observed in water.

Ograniczanie wyników

3 Acta Biochimica Polonica

2 Antonini I.

2 Mazerski J.

1 Bontemps-Gracz M. M.

1 Borowski E.

1 Kupiec A.

1 Martelli S.

1 Muchewicz K.

1 2002

2 2000

The intercalation of imidazoacridinones into DNA induces conformational changes in their side chain

The ability to overcome multidrug resistance of tumour cell lines by novel acridine cytostatics with condensed heterocyclic rings

The role of side chains in the interaction of new antitumor pyrimidoacridinetriones with DNA: molecular dynamics simulations