Actinomycins

Actinomycin D (dactinomycin) is a member of the actinomycin family of compounds, which was isolated from several Streptomyces strains. It contains a phe-noxazine chromophore attached to two cyclic depsipeptides containing five amino acid residues. It can be considered as a hybrid compound that behaves both as a DNA intercalator and a minor groove binding agent. Although it differs from most intercalating drugs in that it lacks a positive charge, it has been suggested that this is compensated by its high dipole moment, arising from a non-symmetrical distribution of polar substituents.15 Dactinomycin is used to treat sarcomas, pediatric solid tumors (e.g. Wilms' tumor, a type of renal tumor), germ cell cancers (testicular cancer), and choriocarcinoma.

H3C-N a-ring HN NH b-ring N-CH

CH3 CH3

Actinomycin D (dactinomycin)

Actinomycin D is the paradigm of intercalating compounds with sequence selectivity. X-Ray diffraction16,17 and molecular modelling studies18 have been extensively employed to characterize its complex with DNA. The actinomycin chromophore favours guanine-cytosine pairs and is therefore inserted between the G-C step. Hydrogen bonds are established between the guanine 2-amino group and the carbonyl oxygen of threonine, and also between the guanine N-3 atom and the NH group of the same threonine residue, helping to stabilize the actinomycin-DNA complex. The proline, sarcosine, and methylvaline residues of the pentapeptide side chain are involved in further hydrophobic interactions with the DNA minor groove (Fig. 7.5). Several proposals have been put forward regarding the nature of the preferred flanking base sequences adjacent to the GC intercalation site.19 The formation of this very stable actinomycin-DNA complex prevents the unwinding of the double helix which leads to inhibition of the DNA-dependent RNA polymerase activity and hence transcription.20 Like in the case of other intercalating agents, topoisomerase II inhibition may also be one of the causes of cytotoxicity.

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