Synthesis, Anticancer Activities, and Cellular Uptake Studies of Lipophilic Derivatives of Doxorubicin Succinate

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 (IC₅₀ = 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