Three series of gamma-carboline derivatives were designed and synthesized. All the compounds were tested for their cytotoxic activities in vitro against five human tumor cell lines (A549, SGC, HCT116, MCF-7, K562) and one multi-drug resistant subline (K562R). Most compounds showed moderate to potent cytotoxic activities against the tested cell lines. Sulfonate 11f exhibited more potent cytotoxic activities against almost all of the tested cells in comparison with the positive control, taxol, with IC(50) values ranging from 0.15 to 4.5 microM. The structure-activity relationships were discussed and a statistically reliable QSAR model (r(2)=0.936, q(2)=0.581) was established by the CoMFA analysis performed using the cytotoxic data against K562 cell line as a template.