<div notation="docdba" type="abstract" xml:lang="en"><p>The invention provides aplidine derivatives and synthetic methods. They are represented by the formula: where the different symbols have the meaning indicated in the description.</p></div>
1. A compound of the formula: <img class="EMIRef" id="460666114-ib0242" /> wherein: X is independently -C(R)<2> , -O-, -S-, or -NR-, in which R is independently H or an organic group selected from an alkyl group, an alkenyl group, an aryl group, an aralkyl group, and their substituted derivatives substituted with one or more of a heterocyclic group, an alkoxy group, an hydroxy group, a mercapto group, an optionally protected amino group, a guanidino group, or a halogen group; Y is CO or -COCHCH<3> CO- R<4> is H or an organic group selected from an amido group RCONH- or an acyl group RCO-where R is as defined, an alkyl group, an alkenyl group, an aryl group, an aralkyl group, and substituted derivatives substituted with one or more of a heterocyclic group, an alkoxy group, an hydroxy group, a mercapto group, an optionally protected amino group, a guanidino group, or a halogen group, X<1> is O or S; and when Y is CO, then a) X<2> is CR, O (and R<2> is absent), S (and R<2> is absent), or N, in which R is independently H or an organic group selected from an alkyl group, an alkenyl group, an aryl group, an aralkyl group, and their substituted derivatives substituted with one or more of a heterocyclic group, an alkoxy group, an hydroxy group, a mercapto group, an optionally protected amino group, a guanidino group, or a halogen group; and R<1> and R<2> are each independently H or an organic group selected from an alkyl group, an alkenyl group, an aryl group, an aralkyl group, an amido group RCONH- or an acyl group RCO- where R is an alkyl group, an alkenyl group, an aryl group, an aralkyl group, and substituted derivatives substituted with one or more of an alkoxy group, an hydroxy group, a mercapto group, an optionally protected amino group, a guanidino group, or a halogen group, [and R<1> or R<2> when X<2> is N, and R<4> , can further be -SO<2> R, where R is as defined]; or b) Aa8 being of formula: <img class="EMIRef" id="460666114-ib0243" /> where R<3> is independently H or an organic group selected from an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a group RSO<2> - or an acyl group RCO-, where R is an alkyl group, an alkenyl group, an aryl group, an aralkyl group, and substituted derivatives substituted with one or more of a mercapto group, an optionally protected amino group, a guanidino group, or a halogen group; c) R<1> and R<2> with X<2> form an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heterocyclic group, where the optional substituents are selected from alkyl group, alkenyl group, aryl group, aralkyl group, and substituted derivatives substituted with one or more of a carbonyl group, an hydroxy group, a mercapto group, an optionally protected amino group, a guanidino group, or a halogen group; or d) aa8 is replaced by an organic group selected from an aryl group, an aralkyl group, a group RSO<2> - or an acyl group RCO- where R is an alkyl group, an aryl group, an aralkyl group, and substituted derivatives substituted with one or more of a carbonyl group, an alkoxy group, an hydroxy group, a mercapto group, an amino group, a guanidino group, or a halogen group; when Y is is -COCHCH<3> CO-, then a) X<2> is N, and R<1> and R<2> are each independently H or an organic group selected from an alkyl group, an alkenyl group, an aryl group, an aralkyl group, an amido group RCONH-, a group -SO<2> R or an acyl group RCO-where R is an alkyl group, an alkenyl group, an aryl group, an aralkyl group, and substituted derivatives substituted with one or more of a heterocyclic group, an alkoxy group, an hydroxy group, a mercapto group, an optionally protected amino group, a guanidino group or a halogen group, or; or b) Aa8 being of formula: <img class="EMIRef" id="460666114-ib0244" /> where R<3> is RSO<2> - where R is alkyl, or R<3> is an alkenyl group, an aralkyl group, and substituted derivatives substituted with one or more of a carbonyl group, an hydroxy group, a mercapto group, an optionally protected amino group, a guanidino group, or a halogen group; c) R<1> and R<2> with X<2> form an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heterocyclic group, where the optional substituents are selected from alkyl group, alkenyl group, aryl group, aralkyl group, and substituted derivatives substituted with one or more of a carbonyl group, an hydroxy group, a mercapto group, an optionally protected amino group, a guanidino group, or a halogen group; or d) aa8 is replaced by an organic group selected from an aryl group, an aralkyl group or a group RSO<2> - where R is an alkyl group, an aryl group, an aralkyl group, and substituted derivatives substituted with one or more of an alkoxy group, an hydroxy group, a mercapto group, an amino group, a guanidino group, or a halogen group; and pharmaceutically acceptable salts thereof; with the proviso that the compound is not one of <img class="EMIRef" id="460666114-ib0245" /> or <img class="EMIRef" id="460666114-ib0246" /> 2. A compound according to claim 1, wherein X is -NR-, in which R is as defined. 3. A compound according to claim 2, wherein X is -NH- or -NMe-. 4. A compound according to claim 3, wherein X is -NH-. 5. A compound according to claim 1, wherein X is -O-. 6. A compound according to any of claims 1 to 5, wherein Y is -CO-. 7. A compound according to claim 1, wherein X is -NH- or -O- and Y is -COCHCH<3> CO- or -CO-. 8. A compound according to any preceding claim, wherein R<4> is methyl. 9. A compound according to any preceding claim, wherein X<1> is O. 10. A compound according to any preceding claim, wherein X<2> R<1> is an optionally substituted aralkyloxy group. 11. A compound according to claim 10, wherein X<2> R<1> is a benzyloxy group. 12. A compound according to any of claims 1 to 9, wherein X<2> R<1> is an optionally substituted amino group. 13. A compound according to claim 12, wherein X<2> R<1> is a group -NHR<1> , where R<1> is an optionally substituted alkyl group, alkenyl group, aryl group, or aralkyl group. 14. A compound according to claim13, wherein R<1> is an alkyl group or an aryl group. 15. A compound according to claim 14, wherein R<1> is a phenyl group or a butyl group. 16. A compound according to any of claims 1 to 9, wherein X<2> R<1> is an optionally substituted alkyl group. 17. A compound according to claim 16, where X<2> R<1> is a propyl group, isopropyl group, pentyl group or biotin group. 18. A compound according to any of claims 1 to9, wherein -C(=O) X<2> R<1> R<2> form an optionally substituted amino acid acyl group. 19. A compound according to claim 18, wherein the optionally substituted amino acid acyl group is optionally substituted proline. 20. A compound according to claim 19, wherein the optionally substituted proline is optionally substituted norvaline-proline, optionally substituted alanine-proline, Boc-proline, optionally substituted alkyl-proline 21. A compound according to claim 19, wherein the optionally substituted proline is norvaline-proline, Z-norvaline-proline, alanine-proline, Z-alanine-proline, Boc-alanine-proline, isobutyrylproline or optionally protected D-lactylproline. 22. A compound according to any of claims 1 to 8, wherein X<1> is S and X<2> R<1> is a group -NHR<1> , where R<1> is an optionally substituted alkyl group, alkenyl group, aryl group, or aralkyl group. 23. A compound according to claim 22, wherein R<1> is an alkyl group or an aryl group. 24. A compound according to claim 23, wherein R<1> is a phenyl group or a butyl group. 25. A compound according to any of claims 1 to 9, wherein R<1> and R<2> with X<2> form an optionally substituted heterocyclic group.. 26. A compound according to claim 25, wherein the heterocyclic group is coumarin. 27. A compound according to any of claims 1 to 8, wherein aa8 is replaced by an organic group RSO<2> , where R is as defined. 28. A compound according to claim 27, wherein R is methyl. 29. A compound according to claim 1, which is selected from: 8-[Phenylurea]-didemnin A, 8-[Butylurea]-didemnin A, 3-[Val]-8-[isobutyryl]-didemnin A, 3-[Hiv]-9-[Isobutyryl]-aplidine, 3-[Val]-9-[lsobutyryl]-aplidine, 3-[hiv]-8-[isobutyryl]-didemnin A, 3-[Hiv]-9-[Ala]-aplidine, 3-[Hiv]-9-[Nva-Pro]-aplidine, 8-[Phenylthiourea]-didemnin A, 8-[Coumarin]-didemnin A, 8-[Butylthiourea]-didemnin A, 8-[Methylsulphonyl]-didemnin A, 3-[Val]-Z-didemnin A, 3-[Hiv]-8-[Val]-didemnin A, 3-[Hiv]-8-[butyryl]-didemnin A, 3-[Hiv]-9-[Z-ala]-aplidine, 3-[Hiv]-Z-didemnin A, 3-[Hiv]-9-[Z-Nva-Pro]-aplidine 3-[Hiv]-9-[Boc-Ala]-aplidine, 3-[Hiv]-8-[Boc-Val]-didemnin A, 9-[Methylsulphonyl] aplidine, 3-[Hiv]-9-[Isobutiryl] aplidine, 3-[Hiv]-8-[Val]-9-[Isobutyryl]-didemnin A; or 3-[Hiv]-8-[hexanoyl]-didemnin A. 30. A compound which is selected from: 9[norvaline]aplidine 3-[val]-didemnin A, 3-[hiv]-didemnin A, 9-[Z-Nva]-aplidine, 8-[Gly]-9-[Coumarin]-didemnin A, 8-[Biotin]-didemnin A, 3-[Hiv]-7,8-[Spiro]-9-[Boc]-aplidine 7,8-[Spiro]-9-[pyr]-aplidine, 3-[Hiv]-9-[lac(OTBDMS)]-aplidine, 7,8-[Spiro]-9-[Boc]-aplidine, 3-[val]-9-[lac(OTBDMS)]-aplidine 3-[Hiv]-9-[D-lac(OTBDMS)]-aplidine, 7,8-[Spiro]-9-[Isobutyryl]-aplidine, 3-[Hiv]-7,8-[Spiro]-9-[pyr]-aplidine, 3-[Hiv]-7,8-[Spiro]-9-[Isobutyryl]-aplidine, 3-[Hiv]-7,8-[Spiro]-9-[Acryloyl]-aplidine, or 3-[Aip]-aplidine. 31. A compound according to claim 29, which is 8-[Phenylurea]-didemnin A. 32. A compound according to any preceding claim, in the form a pharmaceutically acceptable salt.