Elongated and multiple spacers in activatible prodrugs

• US 7,223,837 B2
• Filed: 03/25/2002
• Issued: 05/29/2007
• Est. Priority Date: 03/23/2001
• Status: Expired due to Term

• Current Assignee: Byondis B.V.
• Original Assignee: Syntarga BV (Synthon International Holding BV)
• Inventors: De Groot, Franciscus Marinus Hendrikus, Beusker, Patrick Henry, Scheeren, Johannes Wilhelm, De Vos, Dick, Koekkoek, Ralph, Busscher, Guuske Frederike, Seelen, Antoinette Eugenie, Albrecht, Carsten, Van Berkom, Leonardus Wilhelmus Adriaan
• Primary Examiner(s): Lukton; David
• Application Number:
  US10/472,921
• Publication Number:
  US 20040121940A1
• Time in Patent Office: 1,891 Days
• Field of Search: 530/330, 530/331, 514/2, 514/18, 514/19
• US Class Current: 530/331
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61K 47/67 Enzyme prodrug therapy, e.g. gene directed enzyme drug therapy [GDEPT] or VDEPT
• CPC Class Codes: A61K 47/6889 Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
• CPC Class Codes: A61K 47/6899 Antibody-Directed Enzyme Prodrug Therapy [ADEPT]
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

This invention is directed to prodrugs that can be activated at the preferred site of action in order to selectively deliver the corresponding therapeutic parent drugs to target cells or to the target site. This invention will therefore primarily but not exclusively relate to tumor cells as target cells. More specifically the prodrugs are compounds of the formula V—(W)_k—(X)_l—A—Z, wherein: V is a specifier; (W)_k—(X)_l—A is an elongated self-elimination spacer system; W and X are each a 1,(4+2n) electronic cascade spacer, being the same or different; A is either a spacer group of formula (Y)_m wherein: Y is a 1,(4+2n) electronic cascade spacer, or a group of formula U being a cyclization elimination spacer; Z is a therapeutic drug; k, l and m are integers from 0 (included) to 5 (included); n is an integer of 0 (included) to 10 (included), with the provisos that: —when A is (Y)_m: k+l+m≧1, and if k+l+m=1; —when A is U: k+l≧1.

Claims

1. A compound of the formula:

V—

(W)_k—

(X)_l—

A—

Z

wherein;

V is an enzymatically removable specifier, optionally being removable after prior binding to a receptor;

(W)_k—

(X)_l—

A is an elongated self-eliminating spacer system;

W and X are each a 1,(4+2n) electronic cascade self-eliminating spacer, being the same or different;

A is either a spacer group of formula (Y)_m, wherein Y is a 1,(4+2n) electronic cascade self-eliminating spacer, or a group of formula U being a cyclisation self-elimination spacer;

Z is a therapeutic or diagnostic moiety;

k and l are independently an integer from 0 (included) to 5 (included);

m is an integer from 1 (included) to 5 (included);

n is an integer from 0 (included) to 10 (included), and k+1>

0.

2. The compound of claim 1, wherein group U is an ω

-amino aminocarbonyl cyclisation spacer, Z is a moiety bearing a hydroxyl group, and Z is bonded to U via the hydroxyl group of Z.

3. The compound of claim 1, wherein the electronic cascade spacers W, X and Y are independently selected from compounds having the formula:

4. The compound of claim 2, wherein A is an ω

-amino aminocarbonyl cyclisation elimination spacer U and U is a moiety having the formula;

5. The compound of claim 1 wherein A is an electronic cascade spacer having the structural formula:

6. The compound of claim 5 wherein Z is a moiety bearing a phenolic hydroxyl group, and Z is bonded to A via the phenolic hydroxyl group of Z.

7. The compound of claim 1 wherein the specifier V contains a substrate that can be cleaved by plasmin.

8. The compound of claim 1 wherein the specifier V contains a substrate that can be cleaved by a cathepsin.

9. The compound of claim 1 wherein the specifier V contains a substrate that can be cleaved by cathepsin B.

10. The compound of claim 1 wherein the specifier V contains a substrate that can be cleaved by β

-glucuronidase, prostate-specific antigen (PSA), urokinase-type plasminogen activator (u-PA), or a member of the family of matrix metalloproteinases.

11. The compound of claim 1 to 5 wherein the specifier V contains a nitro-(hetero)aromatic moiety that can be removed by reduction under hypoxic conditions or by reduction by a nitroreductase.

12. The compound of claim 1 wherein the spacer system (W)_k—

(X)_l—

A is p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl, p-aminobenzyloxycarbonyl-p-amino-benzyloxycarbonyl-p-aminobenzyloxycarbonyl, p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl, p-aminobenzyloxycarbonyl-p-aminocinnamyloxycarbonyl, p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl, p-aminophenylpentadienyloxycarbonyl-p-aminocinnamyloxycarbonyl p-aminophenylpentadienyloxycarbonyl-p-aminobenzyloxycarbonyl, p-aminophenylpentadienyloxycarbonyl-p-aminophenylpentadienyloxycarbonyl, p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl, p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl, p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl, p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl, p-aminobenzyloxycarbonyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl, p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycaxbonyl(methylamino)ethyl(methylamino)carbonyl, p-aminobenzyloxycarbonyl-p-aminobenzyl, p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyl, p-aminocinnamyloxycarbonyl-p-aminobenzyl, p-aminobenzyloxycarbonyl p-aminocinnamyl, p-aminocinnamyloxycarbonyl-p-aminocinnamyl, p-aminophenylpentadienyloxycarbonyl-p-aminocinnamyl, p-aminophenylpentadienyloxycarbonyl-p-aminobenzyl, or p-aminophenylpentadienyloxycarbonyl-p-aminophenylpentadienyl.

13. The compound of claim 1 wherein the moiety Z is an anticancer agent.

14. The compound of claim 13 wherein the said moiety Z is the amino containing cytotoxic moiety daunorubicin, doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, an anthracycline, mitomycin C, mitomycin A, 9-amino camptothecin, aminopterin, actinomycin, bleomycin, N⁸-acetyl spermidine, 1-(2-chloroethyl)-1,2-dimethanesulfonyl hydrazine, tallysomycin, or derivatives thereof,

the hydroxyl containing cytotoxic moiety etoposide, camptothecin, irinotecan, topotecan, 9-amino camptothecin, paclitaxel, docetaxel, esperamycin, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4-ene-2,6-diyne-13-one, anguidine, doxorubicin, morpholine-doxorubicin, N-(5,5-diacetoxypentyl) doxorubicin, vincristine, vinblastine, or derivatives thereof,

the sulfhydryl containing cytotoxic moiety esperamicin, 6-mercaptopurine, or derivatives thereof,

the carboxyl containing cytotoxic moiety methotrexate, camptothecin (ring-opened form of the lactone), butyric acid, retinoic acid, or derivatives thereof.

15. The compound of claim 1 wherein the moiety Z represents the anticancer drug paclitaxel or a paclitaxel derivative that is coupled to the promoiety V—

(W)_k—

(X)_l—

U—

via its 2′

-hydroxyl group.

16. The compound of claim 1 wherein the specifier V is a tripeptide.

17. The compound of claim 16 wherein the covalent linkage of said tripeptide specifier moiety to its immediately adjacent moiety is at the C-terminus of said tripeptide specifier moiety.

18. The compound of claim 17 wherein the C-terminal amino acid residue is arginine or lysine, the middle amino acid residue is selected from the group consisting of alanine, valine, leucine, isoleucine, methionine, phenylalanine, cyclohexylglycine, tryptophan and proline, and the N-terminal amino acid residue is a D-amino acid residue, a protected L-amino acid residue, or protected glycine.

19. The compound of claim 1 wherein the specifier V is D-alanylphenylalanyllysine, D-valylleucyllysine, D-alanylleucyllysine, D-valylphenylalanyllysine, D-valyltryptophanyllysine, or D-alanyltryptophanyllysine.

20. The compound of claim 1 wherein the specifier V is an amino-terminal capped peptide covalently linked at its C-terminus to its immediately adjacent moiety.

21. The compound of claim 20 wherein the said amino-terminal capped peptide specifier is benzyloxycarbonylphenylalanyllysine, benzyloxycarbonylvalyllysine, D-phenylalanylphenylalanyllysine, benzyloxycarbonylvalyllysine, tertbutyloxycarbonylphenylalanyllysine, benzyloxycarbonylalanylarginine, benzyloxycarbonylphenylalanyl-N-tosylarginine, 2-aminoethylthiosuccinimidopropionylvalinylcitrulline, 2-aminoethylthiosuccinimidopropionyllysylphenylalanyllysine, acetylphenylalanyllysine, or benzyloxycarbonylphenylalanyl-O-benzoylthreonine.

22. The compound of claim 1 which is N-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)doxorubicin, N-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)-doxorubicin, N-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxy-carbonyl)daunorubicin, N-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-amino-benzyloxycarbonyl-p-aminobenzyloxycarbonyl)daunorubicin, N-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)mitomycin C, N-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)-mitomycin C, N-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)-9-aminocamptothecin, N-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)-9-aminocamptothecin, 2′

-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)paclitaxel, 2′

-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)paclitaxel, 7-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)paclitaxel, 7-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)paclitaxel, 2′

-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)docetaxel, 2′

-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)docetaxel, 7-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)docetaxel, 7-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)docetaxel, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)camptothecin, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)camptothecin, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)-9-aminocamptothecin, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)-9-aminocamptothecin, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)etoposide, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)etoposide, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)irinotecan, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)irinotecan, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)topotecan, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)topotecan, N-(D-alanylphenylalanyllysyl-p-aminocinnamyloxy-carbonyl-p-aminobenzyloxycarbonyl)doxorubicin, N-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)daunorubicin, N-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)mitomycin C, N-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)-9-aminocamptothecin, 2′

-O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)paclitaxel, 7-O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)paclitaxel, 2′

-O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)docetaxel, 7-O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)docetaxel, O-(D-alanylphenylalanyllysyl-p-aminocinnamyl-oxycarbonyl-p-aminobenzyloxycarbonyl)camptothecin, O-(D-alanylphenylalanyllysyl-p-amino-cinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)-9-aminocamptothecin, O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)etoposide, O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)irinotecan, O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)topotecan, N-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)doxorubicin, N-(D-alanylphenylalanyllysyl-p-amino-cinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)daunorubicin, N-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)mitomycin C, N-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)-9-aminocamptothecin, 2′

-O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)paclitaxel, 7-O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)paclitaxel, 2′

-O-(D-alanylphenylalanyllysyl-p-amino-cinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)docetaxel, 7-O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)docetaxel, O-(D-alanylphenyl-alanyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)camptothecin, O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)-9-aminocamptothecin, O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)etoposide, O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)irinotecan, O-(D-alanylphenylalanyllysyl-p-aminocinnamyl-oxycarbonyl-p-aminocinnamyloxycarbonyl)topotecan, 2′

-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)paclitaxel, 7-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)paclitaxel, 2′

-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)docetaxel, 7-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)-docetaxel, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)camptothecin, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)-9-aminocamptothecin, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)etoposide, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)irinotecan, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)topotecan, 2′

-O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)paclitaxel, 7-O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)paclitaxel, 2′

-O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)docetaxel, 7-O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)docetaxel, O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)camptothecin, O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)-9-aminocamptothecin, O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)etoposide, O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)irinotecan, O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)topotecan, 2′

-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)paclitaxel, 7-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)paclitaxel, 2′

-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)docetaxel, 7-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)docetaxel, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)camptothecin, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)-9-aminocamptothecin, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)etoposide, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)irinotecan, O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)topotecan, N-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxy-carbonyl)doxorubicin, N-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxy-carbonyl-p-aminobenzyloxycarbonyl)doxorubicin, N-(D-valylleucyllysyl-p-aminobenzyloxy-carbonyl-p-aminobenzyloxycarbonyl)daunorubicin, N-(D-valylleucyllysyl-p-aminobenzyloxy-carbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)daunorubicin, N-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)mitomycin C, N-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)mitomycin C, N-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyl-oxycarbonyl)-9-aminocamptothecin, N-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)-9-aminocamptothecin, 2′

-O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)paclitaxel, 2′

-O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxy-carbonyl)paclitaxel, 7-O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxy-carbonyl)paclitaxel, 7-O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxy-carbonyl-p-aminobenzyloxycarbonyl)paclitaxel, 2′

-O-(D-valylleucyllysyl-p-aminobenzyloxy-carbonyl-p-aminobenzyloxycarbonyl)docetaxel, 2′

-O-(D-valylleucyllysyl-p-aminobenzyloxy-carbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)docetaxel, 7-O-(D-valyl-leucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)docetaxel, 7-O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)docetaxel, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)camptothecin, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)camptothecin, O-(D-valylleucyllysyl-p-aminobenzyl-oxycarbonyl-p-aminobenzyloxycarbonyl)-9-aminocamptothecin, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)-9-amino-camptothecin, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)-etoposide, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)etoposide, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)irinotecan, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)irinotecan, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)topotecan, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)topotecan, N-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)doxorubicin, N-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)daunorubicin, N-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)mitomycin C, N-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)-9-aminocamptothecin, 2′

-O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)paclitaxel, 7-O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)paclitaxel, 2′

-O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)docetaxel, 7-O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)docetaxel, O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)camptothecin, O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)-9-aminocamptothecin, O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)etoposide, O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)irinotecan, O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminobenzyloxycarbonyl)topotecan, N-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)doxorubicin, N-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)daunorubicin, N-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)mitomycin C, N-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)-9-amino-camptothecin, 2′

-O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)paclitaxel, 7-O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)paclitaxel, 2′

-O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)docetaxel, 7-O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)docetaxel, O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)camptothecin, O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)-9-aminocamptothecin, O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)etoposide, O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)irinotecan, O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-p-aminocinnamyloxycarbonyl)topotecan, 2 ′

-O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)paclitaxel, 7-O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)paclitaxel, 2′

-O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)docetaxel, 7-O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)docetaxel, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)camptothecin, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)-9-aminocamptothecin, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)etoposide, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)irinotecan, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)topotecan, 2′

-O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)paclitaxel, 7-O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)-paclitaxel, 2′

-O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)docetaxel, 7-O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl-(methylamino)ethyl(methylamino)carbonyl)docetaxel, O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)camptothecin, O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)-9-aminocamptothecin,O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)etoposide, O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)irinotecan, O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)topotecan, 2′

-O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)paclitaxel, 7-O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)paclitaxel, 2′

-O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)docetaxel, 7-O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)docetaxel, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)camptothecin, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)-9-aminocamptothecin, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)etoposide, O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)irinotecan, O-(D-valyl-leucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)topotecan, or a salt thereof.

23. The compound of claim 22 which is N-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)doxorubicin.

24. The compound of claim 22 which is N-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl-p-aminobenzyloxycarbonyl)doxorubicin.

25. The compound of claim 22 which is 2′

-O-(D-alanylphenylalanyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)paclitaxel.

26. The compound of claim 22 which is 2′

-O-(D-valylleucyllysyl-p-aminobenzyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)paclitaxel.

27. The compound of claim 22 which is 2′

-O-(D-alanylphenylalanyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)paclitaxel.

28. The compound of claim 22 which is 2′

-O-(D-valylleucyllysyl-p-aminocinnamyloxycarbonyl(methylamino)ethyl(methylamino)carbonyl)paclitaxel.

29. The compound of claim 1 wherein the moiety Z is an antibiotic, an anti-inflammatory agent, or an anti-viral agent.

30. The compound of claim 1 wherein the specifier V contains a polymer.

31. The compound of claim 1, wherein the specifier V is removed by an enzyme that is transported to the vicinity of target cells or target tissue via antibody-directed enzyme prodrug therapy (“

ADEPT”

), polymer-directed enzyme prodrug therapy (“

PDEPT”

), virus-directed enzyme prodrug therapy (“

VDEPT”

) or gene-directed enzyme prodrug therapy (“

GDEPT”

).

32. A process for preparing a pharmaceutical composition in a solid or a liquid formulation for administration orally, topically or by injection, said process comprising mixing a compound according to claim 1 with a pharmaceutically acceptable carrier.

33. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

34. The compound of claim 1 wherein the specifier V contains a moiety capable of targeting the compound to the target site by selectively complexing with a receptor or other receptive moiety associated with a target cell population.

35. The compound of claim 1 wherein the specifier V contains an antigen-recognizing immunoglobulin or an antigen-recognizing fragment of an immunoglobulin.