Two new secophragmalin-type limonoids, secotrichagmalins B (<b>1</b>) and C (<b>2</b>) along with two known compounds, were isolated from the fruits of <i>Trichilia connaroides</i>. The structures of the new compounds were elucidated by analysis of spectroscopic (IR, MS, and 2D NMR) data and single crystal X-ray diffraction studies. In addition, semisynthetic derivatives (<b>2a</b>-<b>2l</b>) were efficiently synthesized and evaluated for their in vitro cytotoxicity along with the isolated limonoids against a panel of human cancer cell lines. The results indicated that new analogues <b>2a</b>, <b>2d</b>, and <b>2e</b> showed cytotoxicity on the DU145 cell line with IC<sub>50</sub> values of 3.6, 4.2, and 5.2 μM, respectively. Flow cytometric analysis revealed that these analogues arrested the cell cycle in the G0/G1 phase and markedly induced apoptosis.