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Fuskova A, Fuska J, Rosazza JP, Nicholas AW.
Neoplasma. 1984;31(1):31-6.
Novel cytotoxic and
antitumor agents. IV. Withaferin A: relation of its structure to the in vitro
cytotoxic effects on P388 cells.
In vitro effects of withaferin A and its 9 new derivatives on P388 cells have
been studied. The cytotoxicity was calculated from the utilization of precursors
in protein and nucleic acid (NA) synthesis and from capacity to suppress cell
proliferation. The most potent agents proved to be 4-dehydrowithaferin A and
withaferin A diacetate exhibited an equal inhibitory effect on thymidine,
uridine, and L-valine incorporation. They stopped cell proliferation and, at the
same time, killed the cells. Cytotoxicity was found to be due to a double bond
at position C2-3, by dissociating this bond the cytotoxicity markedly decreased
in all derivatives. A dissociation of the double bond at C24-25 or a removal of
OH group from C27 did not cause any significant changes in the biological
effects of the derivatives. An addition of a carbonyl group at C4 increased the
effects of the agent. An addition of OH groups to the molecule of withaferin A
resulted chiefly in a qualitative change in the action of derivatives manifested
by a significant decrease in L-valine inhibition. As withaferin A promptly
reacted with L-cysteine, it was presumed that one of the possible target sites
in the cell might be the SH groups of enzymes which react with the lactone and
epoxide groups of the agent.
PMID: 6700792
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