Ursolic　acid　(UA)　is　a　natural　product　which　has　been　shown　to　possess　a　wide　range　of　pharmacological　activities,　in　particular　those　with　anticancer　activity.　In　this　study,　13　novel　ursolic　acid　derivatives　were　designed　and　synthesized　in　an　attempt　to　further　improve　compound　potency.　The　structures　of　the　newly　synthesized　compounds　were　confirmed　using　mass　spectrometry,　infrared　spectroscopy,　and　1　H　NMR.　The　ability　of　the　UA　derivatives　to　inhibit　cell　growth　was　assayed　against　both　various　tumor　cell　lines　and　a　non-pathogenic　cell　line,　HELF.　Analysis　of　theoretical　toxicity　risks　for　all　derivatives　was　performed　using　OSIRIS　and　indicated　that　the　majority　of　compounds　would　present　moderate　to　low　risks.　Pharmacological　results　indicated　that　the　majority　of　the　derivatives　were　more　potent　growth　inhibitors　than　UA.　In　particular,　5b　demonstrated　IC　50　values　ranging　from　4.09　±　0.27　to　7.78　±　0.43　μm　against　12　different　tumor　cell　lines.　Flow　cytometry　analysis　indicated　that　5b　induced　G0/G1　arrest　in　three　of　these　cell　lines.　These　results　were　validated　by　structural　docking　studies,　which　confirmed　that　UA　could　bind　to　cyclins　D1　(Cyc　D1)　and　cyclin-dependent　kinases　(CDK6),　the　key　regulators　of　G0/G1　transition　in　cell　cycle,　while　the　piperazine　moiety　of　5b　could　bind　with　glucokinase　(GK),　glucose　transporter　1　(GLUT1),　and　ATPase,　which　are　the　main　proteins　involved　in　cancer　cell　metabolism.　Acridine　orange/ethidium　bromide　staining　confirmed　that　5b　was　capable　of　inducing　apoptosis　and　decreasing　cell　viability　in　a　dose-dependent　manner.　A　series　of　UA　piperazine　derivatives　were　designed　and　synthesized　to　improve　the　anticancer　activity　and　to　explore　the　structure-activity　relationships.　The　effects　of　the　most　potent　compound　5b　on　cell　proliferation,　apoptosis　induction　and　cell　cycle　were　evaluated.　Furthermore,　we　also　analyzed　the　protein-ligand　interaction　with　5b　by　using　molecular　modelling　studies.　©　2015　John　Wiley　&　Sons　A/S.