It should be noted that the clinical trials of a very close
aplidine analogue, didemnin B (129; Scheme 21), were
discontinued because of the toxicities observed, including
significant immunosuppression. In contrast, evidence for a
lack of myelosuppression by aplidine was reported using a
murine competitive repopulating model as the test system,
and no hematological toxicity has been observed clinically.
It is very interesting both chemically and pharmacologically
that the removal of two hydrogen atoms, i.e., conversion of
the lactyl side chain to a pyruvyl side chain, appears to
significantly alter the toxicity profile, as this is the only
formal change in the molecule when compared to didemnin
B. However, the comments on dosage regimens should be
taken into account when such comparisons are made in the
future
It should be noted that the clinical trials of a very close
aplidine analogue, didemnin B (129; Scheme 21), were
discontinued because of the toxicities observed, including
significant immunosuppression. In contrast, evidence for a
lack of myelosuppression by aplidine was reported using a
murine competitive repopulating model as the test system,
and no hematological toxicity has been observed clinically.
It is very interesting both chemically and pharmacologically
that the removal of two hydrogen atoms, i.e., conversion of
the lactyl side chain to a pyruvyl side chain, appears to
significantly alter the toxicity profile, as this is the only
formal change in the molecule when compared to didemnin
B. However, the comments on dosage regimens should be
taken into account when such comparisons are made in the
future
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