Abstract: Synthesis natural tubulisine derivatives of formula (A) having a high cytotoxicity wherein: B is selected from CH2, CH2—CH2 or CH2—CH2—CH2, D is an aromatic linker, X1 is alkyl or alkenyl, X2 is selected from the X2a, substituted or non substituted, selected from: aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, or heteroarylalkyl, X2b: alkylene-O-alkyl, wherein alkylene is C2-C10, X2c: CH2—O-alkyl, X3 is selected from H, or together with X4 forms the group ?O, X4 is selected from H, halogen, OH, SH, alkyl, alkenyl, (OR5)n—OR6, OC(O)R7, NR6R7, or together with X4 forms the group ?O, R5 is an alkylene, n is zero or an integer from 1 to 10, R6 and R7, equal to or different from each other, have the following meanings: z1: H, alkyl, z2 substituted or non substituted: aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, X5 is z2, or has the meaning of z3=alkyl, alkenyl, X6 is selected from NR8R9, OR8, NH—NR8R9, SR8, R10, wh