WO2001060387A1 - Multiple drug resistance reversal agent - Google Patents
Multiple drug resistance reversal agent Download PDFInfo
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- WO2001060387A1 WO2001060387A1 PCT/US2001/004920 US0104920W WO0160387A1 WO 2001060387 A1 WO2001060387 A1 WO 2001060387A1 US 0104920 W US0104920 W US 0104920W WO 0160387 A1 WO0160387 A1 WO 0160387A1
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- compound
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- VJKZBDAZASXXOA-IWGRKNQJSA-N CCC(CCOCCNC(/C(/C)=C/CCC#C)=O)NC(/C(/C)=C/CCC#C)=O Chemical compound CCC(CCOCCNC(/C(/C)=C/CCC#C)=O)NC(/C(/C)=C/CCC#C)=O VJKZBDAZASXXOA-IWGRKNQJSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/765—Polymers containing oxygen
- A61K31/77—Polymers containing oxygen of oxiranes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
Definitions
- the present invention relates to agents for the treatment of cancer. More specifically, the invention relates to agents which reverse multiple drug resistance in many types of cancer.
- TECHNICAL BACKGROUND Cancer involves the out-of-control growth and spread of abnormal cells.
- cancer cells grow and divide in a rapid, abnormal fashion. These rapid growing cells can start in one part of the body and spread to another location. These cells accumulate and form lumps know as tumors. The tumors can compress, invade, and destroy normal tissue. When cells break away from tumors, the cells can travel through the bloodstream or the lymphatioc system to other areas ofthe body. There, the cancerous cells may settle and form "colony" tumors. In the new location, the cancer cells continue to grow. It is estimated that in the United States one-half of all men and one-third of all women will develop some form of cancer during their lifetimes. Today, when many types of cancers are detected early enough, the cancer may be cured or controlled. Millions of people are living with cancer or have been cured of the disease.
- Cancer is currently treated with a combination of methods.
- the means of treating the cancer depends on the stage ofthe tumor and the type of cancer.
- Treatment options may include surgery, radiation, chemotherapy, hormone therapy, and immunotherapy.
- Radiation therapy uses high-energy particles or waves, such as x-rays or gamma rays, to destroy or damage cancer cells.
- Hormone therapy is treatment with hormones, drugs that interfere with hormone production or hormone action, or surgical removal of hormone-producing glands to kill cancer cells or slow their growth.
- Immunotherapy is the use of treatments that promote or support the body's immune system response to a disease such as cancer.
- Chemotherapy uses anti-cancer drugs.
- Systemic chemotherapy uses anti-cancer drugs given orally or interveinously. The chemotherapy drugs enter the bloodstream and reach all areas of the body, making it possible to treat a spreading cancer.
- MDR multiple drug resistance
- Multi-drug resistance is due primarily to the expression of Pgp (P-glycoprotein), an ATP-driven membrane-bound multi-drug transporter. Pgp has multiple sites which can bind and transport anti-cancer drugs. These multiple sites make Pgp a powerful causal agent in MDR. Nearly all forms of cancer have been shown to develop resistance mainly through the overexpression of Pgp (P-glycoprotein), an ATP-driven membrane-bound multi-drug transporter. Pgp has multiple sites which can bind and transport anti-cancer drugs. These multiple sites make Pgp a powerful causal agent in MDR. Nearly all forms of cancer have been shown to develop resistance mainly through the overexpression of
- Pgp While normally present only at very low levels, Pgp is greatly over expressed in drug resistant cancer cells, cells that become cross resistant to multiple chemotherapeutic agents following extended exposure to an anti-cancer agent. Resistant forms are most common with cancers that have reoccurred following previous episodes. Pgp has now been detected in most classes of cancer cells including adrenocortical, bladder, brain, breast, colon, head and neck, liver, Hodgkin's lymphoma, lung, esophagus, ovarian, renal, retinoblastoma, soft tissue sarcoma, stomach, testes, and thyroid. In most instances, Pgp expression is believed to be responsible for the failure of chemotherapy, the clinical manifestation of MDR.
- MDR reversal agents Various transport inhibitors have been investigated as MDR reversal agents. Most have been known compounds approved for other applications, for example, verapamil, the calcium ion channel blocker used to treat hypertension, the immunosuppresant cyclosporin and its analogs, and known kinase inhibitors, such as staurosporin. Many of the agents used to treat MDR must be used at high levels to show effective reversal ofthe drug resistance. These agents can be expensive which increases the already great expense of cancer treatment. Moreover, the agents can be quite toxic to normal cells.
- stipiamide has been shown to an effective MDR reversal agent. Stipiamide was discovered using a specific MDR screen targeting Pgp activity. Stipiamide, unlike other MDR reversal agents is not an analog of known channel blockers and not approved for other purposes. Stipiamide has been chemically, synthesized making it possible to make large amounts of it to treat MDR. Andrus, M. B. & Lepore, S. D. J. Am. Chem. Soc. 1997, 1 19: 2327 However, stipiamid is highly toxic and can harm normal cells. Additionally, stipiamide can only bind one of the potential drug binding sites on Pgp requiring more stipiamide to completely shut down Pgp.
- Polyvalency has become a popular strategy for increasing the binding affinity of ligands to multimeric receptors such as Pgp. Mammen, M. et al., Angew. Chem. Int. Ed. 1998, 37: 2754.
- a weak binding molecule can be converted into a polyvalent tight binding molecule provided the receptor possesses various binding sites or can be dimerized.
- the origin of the overall enhanced binding can be attributed to the more favorable second and subsequent binding events where much less entropy is lost due to induced proximity.
- the successful examples are the FK506 and cyclosporin dimers of Schreiber, the vancomycin dimers of Whitesides and Griffin, and the polysaccharides of Kiessling, Whitesides, and Fan. See, e.g., Crabtree, G. R. & Schreiber, S. L., Trends Biochem. Sci. 1996, 21 : 418; Jianghong, R. et al. Chem. & Biol.
- Pgp is a particularly challenging polyvalency target.
- Pgp is an ATP-dependent drug efflux pump whose overexpression confers multidrug resistance to cancer cells.
- the development of resistance in cancer cells to chemotherapeutic agents has been a major impediment to effective clinical treatments.
- no polyvalent anti-Pgp agents have been effectively synthesized.
- the present invention relates to a MDR reversal agent.
- the agent is polyvalent, possessing two or more binding domains spaced to effectively bind the substrate binding domains of Pgp to which anti-cancer drugs can bind and be transported out of a cancer cell.
- the MDR reversal agent is based upon the naturally occurring compound (-)- stipiamide. Stipiamide is represented by the following chemical structure:
- stipiamide is an effective MDR reversal agent, it is also highly toxic. Recently, 6,7-dehydrostipiamide (DHS) was synthesized. Other MDR agents were also synthesized based on DHS, for example napthyl-DHS is represented by the following chemical structure:
- stipiamide derivatives are less toxic than the naturally occurring stipiamide and are effective at reversing MDR in many types of cancer cells.
- the multiple drug resistence reversal agent of the present invention is a polyvalent MDR reversal agent based on stipiamide.
- the MDR reversal agent has two or more stipiamide-based domains linked into a potent polyvalent MDR reversal agent.
- the stipiamide-based domains are linked by hydrocarbon linkers. Generally, the domains are spaced by a number of hydrocarbon spacers. The spacers have a length selected to position the nitrogen atoms of the stipiamide-based domains about 3 A to about 50 A apart from each other.
- a polyvalent compound ofthe present invention may be the homodimer of the following formula:
- R represents an aromatic group such a benzyl, napthyl, or other substituted phenyl group
- R 2 represents a hydrocarbon spacer such as ethylene glycol and the like.
- the hydrocarbon spacer can be repeated X times to provide a distance from about 3 A to about 50 A between the nitrogen atoms of each of the dimers. A molecule with a distance of about 50A between nitrogen atoms has been shown to effectively reverse Pgp activity.
- Another embodiment of the MDR reversal agent ofthe present invention has the following formula.
- X represents a number of joined ethylene glycol spacers.
- the number X of joined ethylene glycol spacers can vary between about 0 to about 20 spacers.
- a group of spacers in the range from about 2 to about 14 spacers can allow for both of the binding domains to tightly bind to Pgp.
- a length of about 12 spacers has been shown to tightly bind the
- the invention also relates to method of reversing multiple drug resistance in a human cell.
- an effective dose of the MDR reversal agent ofthe invention is administered to the cell.
- the MDR reversal agent is contacted with a Pgp molecule, the ATPase activity of Pgp is significanly decreased suggesting that contacted Pgp will not function as a MDR causing agent.
- the affinity of Pgp for a substrate that is known to bind to Pgp is also reduced in the presence of the MDR agent of the present invention.
- Figure 1 depicts chemical structure representations of (-)-stiamide, truncated- DHS, and dual domain stipiamide homodimers.
- Figure 2 depicts a structural representation of a portion ofthe synthesis of the dual domain homodimers ofthe present invention.
- Figure 3 is a structural representation of a portion ofthe synthesis of the dual domain homodimers ofthe present invention.
- Figure 4 is a structural representation ofthe synthesis of a monomeric control substrate.
- the present invention relates to the synthesis and use of polyvalent MDR reversal with two or more domains based on stipiamide.
- the domains are configured to prevent substrate binding to Pgp, which has been shown to be the active MDR mechanism in many cancer cell lines.
- the stipamimde based domains ofthe polyvalent MDR reversal agents are bound by a series of hydrocarbon spacers such as ethylene glycol.
- the spacers separate the stipiamide-based domains to allow for optimal binding to Pgp.
- such spacers have a length selected to position the nitrogen atoms ofthe stipiamide-based domains from about 3 A to about 50A apart.
- the MDR reversal agent is a homodimer of the following formula:
- R represents a substituted phenyl group such as napthyl, benzyl, and the like.
- a number X of hydrocarbon spacers R 2 join the two domains of the MDR reversal agent.
- the MDR reversal agent has three or four stipiamide-based domains joined by a tri- or tetra-valent structure.
- the stipiamide-based domains are joined by a hydrocarbon ring and have five or more stipiamide-based domains.
- a dual-domain MDR reversal agents 3 consists of two stipiamide-based domains bound by polyethylene glycol (PEG) spacers.
- PEG polyethylene glycol
- the MDR agent is designed to span the multiple binding sites on Pgp, occlude the channel, and lead to more effective MDR reversal.
- PEG spacers of various lengths have been made and attached via a carbamate linkage to two Pgp binding polyenes.
- the bivalent homodimeric polyene 3 is based on stipiamide 1 and is joined with ethylene glycol spacers.
- the bivalent homodimer 3 is a strong MDR reversal agent.
- the homodimer 3 incorporates two of the truncated-DHS monomers 2.
- the monomers 2 are joined by number of ethylene glycol spacers. This number is shown as X in Figure 1 and can range from 0 to about 20 ethylene glycol spacers.
- Pgp has two binding sites that are associated with its ability to confer multiple drug resistance on a cell. Photoaffinity labeling has been used to identify these two non- identical sites most likely formed by the TM5-6 and 1 1-12 regions of Pgp. Germann, U.
- TM5-6 and 11-12 regions are located in close proximity ofthe cytosolic ATP- binding sites of Pgp. This proximity supports the notion that ATP hydrolysis induces conformational changes that are conveyed to the TM regions leading to drug displacement and efflux. Conformational changes in the substrate-binding domain following ATP hydrolysis have recently been determined. Ramachandra, M. et al., supra;
- PEG linkers that now provide for a distance range from 3 to 50A. Double Sonogashira couplings are also used to generate the homodimers 3.
- the dual-domain compounds 3 are designed by linking two Pgp binding agents with polyene ethylene glycol (PEG) tethers of different lengths.
- PEG polyene ethylene glycol
- the PEG tethers provide a measure of the distances between proposed intra- and inter-transmembrane binding sites of Pgp.
- the induced proximity ofthe two domains increases the effective concentration ofthe second binding event to Pgp, provided the proper distance is bridged between the two sites.
- the strategv is inspired by the many examples of induced proximity displayed in cellular processes, ir. particular cell signaling, where receptor dimerization leads to autophosphorylation, and the two-sided peptide antigen interaction between the extracellular T-cell receptor and the major histocompatibility complex ofthe immune system.
- the napthyl aryl group (Np) is more potent at MDR reversal and is used in the dual-domain compounds.
- the dual-domain homo-dimeric compounds are made using a N,N'-disuccinimidyl carbonate (DSC) based strategy for the formation of carbamate linked material.
- DSC N,N'-disuccinimidyl carbonate
- DSC is used to couple hindered alcohols with highly functionalized amines at 1 :1 stoichiometry in a single-flask operation giving carbamates in high yield.
- Mono-protected (TBS-) tri-, hepta-, and dodeca-ethylene glycols are reacted with N,N'-disuccinimidyl carbonate (DSC) and triethylamine in acetonitrile to give the bis-succinimidyl carbonate intermediates.
- MDR reversal assays with the MCF7adrR a d CHO taxol resistant cells have been performed with the dual-domain compounds of the present invention.
- the compounds ofthe invention are used for the treatment of resistant forms of cancer. They can be added in conjunction with existing anti-cancer drugs, such as adriamycin, taxol, etc. to treat cancers that are not responding to standard levels of drug. For example, the compounds restore the cytotoxicity of the anti-cancer agent adriamycin to resistant human breast cancer cells (MCF7adrR) at low concentration (260 nM, with 2 nM adriamycin).
- the invention compounds are less toxic and have lower therapeutic indices (0.25, vs 5 for verapamil).
- Dimesylate 6 was produced from triethylene glycol, esyl chloride (2.1 equivalents), and triethylamide (2.4 equivalents) in methylene chloride (0.2 M). Sodium bicarbonate work- up and silica gel chromatography were used to isolate the product (97%).
- Pgp ATPase stimulation activity was determined along with displacement ofthe prazosin analog, iodoarylazidoprazosin ( 125 IAAP).
- the effect on ATPase activity of Pgp and binding ofthe IAAP substrate to Pgp are shown in Table 1.
- the effect >f the homodimers ofthe present invention on ATPase activity and IAAP binding to Pgp are very potent. ATPase stimulation reaches a maximum at low concentration (1 ⁇ M) and steadily drops off as the concentration is increased (not shown).
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Abstract
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01910773A EP1272202A1 (en) | 2000-02-16 | 2001-02-16 | Multiple drug resistance reversal agent |
AU2001238344A AU2001238344A1 (en) | 2000-02-16 | 2001-02-16 | Multiple drug resistance reversal agent |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18290000P | 2000-02-16 | 2000-02-16 | |
US60/182,900 | 2000-02-16 |
Publications (1)
Publication Number | Publication Date |
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WO2001060387A1 true WO2001060387A1 (en) | 2001-08-23 |
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ID=22670535
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2001/004920 WO2001060387A1 (en) | 2000-02-16 | 2001-02-16 | Multiple drug resistance reversal agent |
Country Status (3)
Country | Link |
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EP (1) | EP1272202A1 (en) |
AU (1) | AU2001238344A1 (en) |
WO (1) | WO2001060387A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1238654A2 (en) * | 2001-03-06 | 2002-09-11 | Kao Corporation | Composition for external application containing a diamide derivative |
-
2001
- 2001-02-16 EP EP01910773A patent/EP1272202A1/en not_active Withdrawn
- 2001-02-16 AU AU2001238344A patent/AU2001238344A1/en not_active Abandoned
- 2001-02-16 WO PCT/US2001/004920 patent/WO2001060387A1/en not_active Application Discontinuation
Non-Patent Citations (3)
Title |
---|
KANAI M. ET AL.: "Varying the Size of Multivalent Ligands: The Dependence of Concanavalin A Binding on Neoglycopolymer Length", J. AM. CHEM. SOC., vol. 119, 1997, pages 9931 - 9932, XP002942857 * |
KIM ET AL.: "Isolation and Structural Elucidation of Stipiamide, A new Antibiotic Effective to Multidrug-Resistant cancer cells", J. OF ANTIBIOTICS, vol. 44, no. 5, 1991, pages 553 - 556, XP002942856 * |
SUNDRAM U. N. ET AL.: "Novel Vancomycin Dimers with Activity against Vancomycin-Resistant Enterococci", J. AM. CHEM. SOC., vol. 118, 1996, pages 13107 - 13108, XP002942858 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1238654A2 (en) * | 2001-03-06 | 2002-09-11 | Kao Corporation | Composition for external application containing a diamide derivative |
EP1238654A3 (en) * | 2001-03-06 | 2004-01-14 | Kao Corporation | Composition for external application containing a diamide derivative |
US7087646B2 (en) | 2001-03-06 | 2006-08-08 | Kao Corporation | Composition for external application |
EP1803439A3 (en) * | 2001-03-06 | 2008-06-11 | Kao Corporation | Composition for external application containing a diamide derivative |
US7528171B2 (en) | 2001-03-06 | 2009-05-05 | Kao Corporation | Composition for external application |
US7550135B2 (en) | 2001-03-06 | 2009-06-23 | Kao Corporation | Composition for external application |
Also Published As
Publication number | Publication date |
---|---|
EP1272202A1 (en) | 2003-01-08 |
AU2001238344A1 (en) | 2001-08-27 |
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