Synthesis, Anticancer
Activities, and Cellular Uptake Studies of Lipophilic Derivatives
of Doxorubicin Succinate
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Abstract
A number of lipophilic 14-substituted derivatives of
doxorubicin were synthesized through conjugation of doxorubicin-14-hemisuccinate
with different fatty amines or tetradecanol to enhance the lipophilicity,
cellular uptake, and cellular retention for sustained anticancer activity.
The conjugates inhibited the cell proliferation of human leukemia
(CCRF-CEM, 69–76%), colon adenocarcinoma (HT-29, 60–77%),
and breast adenocarcinoma (MDA-MB-361, 66–71%) cells at a concentration
of 1 μM after 96–120 h of incubation. The <i>N</i>-tetradecylamido derivative of doxorubicin 14-succinate (<b>10</b>) exhibited consistently comparable antiproliferative activity to
doxorubicin in a time-dependent manner (IC<sub>50</sub> = 77 nM in
CCRF-CEM cells). Flow cytometry analysis showed a 3-fold more cellular
uptake of <b>10</b> than doxorubicin in SK-OV-3 cells. Confocal
microscopy revealed that the conjugate was distributed in cytoplasmic
and perinuclear areas during the first 1 h of incubation and slowly
relocalized in the nucleus after 24 h. The cellular hydrolysis study
showed that 98% of compound <b>10</b> was hydrolyzed intracellularly
within 48 h and released doxorubicin