Considering　the　increasing　risk　of　nuclear　attacks　worldwide,　the　development　of　develop　potent　and　safe　radioprotective　agents　for　nuclear　emergencies　is　urgently　needed.　γ-tocotrienol　(GT3)　and　δ-tocotrienol　(DT3)　have　demonstrated　a　potent　radioprotective　effect　by　inducing　the　production　of　granulocyte-colony　stimulating　factor　(G-CSF)　in　vivo.　However,　their　application　is　limited　because　of　their　low　bioavailability.　The　utilization　of　ester　prodrugs　can　be　an　effective　strategy　for　modifying　the　pharmacokinetic　properties　of　drug　molecules.　In　this　study,　we　initially　confirmed　that　DT3　exhibited　the　most　significant　potential　for　inducing　G-CSF　effects　among　eight　natural　vitamin　E　homologs.　Consequently,　we　designed　and　synthesized　a　series　of　DT3　ester　and　ether　derivatives,　leading　to　improved　radioprotective　effects.　The　metabolic　study　conducted　in　vitro　and　in　vivo　has　identified　DT3　succinate　5b　as　a　prodrug　of　DT3　with　an　approximately　seven-fold　higher　bioavailability　compared　to　DT3　alone.　And　DT3　ether　derivative　8a　were　relatively　stable　and　approximately　4　times　more　bioavailable　than　DT3　prototype.　Furthermore,　5b　exhibited　superior　ability　to　mitigate　radiation-induced　pancytopenia,　enhance　the　recovery　of　bone　marrow　hematopoietic　stem　and　progenitor　cells,　and　promote　splenic　extramedullary　hematopoiesis　in　sublethal　irradiated　mice.　Similarly,　8a　shown　potential　radiation　protection,　but　its　radiation　protection　is　less　than　DT3.　Based　on　these　findings,　we　identified　5b　as　a　DT3　prodrug,　and　providing　an　attractive　candidate　for　further　drug　development.　©　2024　Elsevier　Masson　SAS