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EP1104423A1 - Anhydrides analogues de cantharidine modifiee utiles pour traiter le cancer - Google Patents

Anhydrides analogues de cantharidine modifiee utiles pour traiter le cancer

Info

Publication number
EP1104423A1
EP1104423A1 EP99930941A EP99930941A EP1104423A1 EP 1104423 A1 EP1104423 A1 EP 1104423A1 EP 99930941 A EP99930941 A EP 99930941A EP 99930941 A EP99930941 A EP 99930941A EP 1104423 A1 EP1104423 A1 EP 1104423A1
Authority
EP
European Patent Office
Prior art keywords
cancer
cells
cantharidin
treatment
cell
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99930941A
Other languages
German (de)
English (en)
Other versions
EP1104423A4 (fr
Inventor
Adam Mccluskey
Jennette A. Sakoff
Stephen Ackland
Alistair T. R. Sim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
The University of Newcastle
Newcastle Innovation Ltd
Original Assignee
The University of Newcastle
Newcastle Innovation Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The University of Newcastle, Newcastle Innovation Ltd filed Critical The University of Newcastle
Publication of EP1104423A1 publication Critical patent/EP1104423A1/fr
Publication of EP1104423A4 publication Critical patent/EP1104423A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to compounds useful in the treatment of certain forms of cancer; processes for producing these compounds; methods of treatment using these compounds
  • the compounds are specific inhibitors of protein phosphatases 1 and
  • protein phosphatases The regulation of protein phosphatases is integral to the control of many cell processes, including cell growth, transformation, tumour suppression, gene transcription,
  • the first gap (G,) is followed by a phase of DNA synthesis (S-phase); this is followed by a second gap (G 2 ) which in turn is followed by mitosis (M) which produces two daughter cells in G,.
  • S-phase phase of DNA synthesis
  • G 2 second gap
  • M mitosis
  • cdkl a universal protein kinase
  • the kinase activity of cdkl is dependant' on phosphorylation and the association with a regulatory subunit, cyclin B.
  • the periodic association of different cyclins with different cyclin dependent kinases (cdk) has been shown to drive different phases of the cell cycle; thus cdk4-cyclin Dl drives cells
  • the phase at which the cell cycle is halted will depend upon the type of DNA damaging agent used and the point during the cell cycle that the damage was incurred (O'Connor, 1997).
  • the cell cycle is controlled and regulated by an intricate phosphorylation network (Stein et al, 1998). More particularly, activation of cdk/cyclin complexes requires the phosphorylation of a
  • phosphatase cdc25 is only active in its phosphorylated form. Therefore, protein phosphatase 2A (PP2A) can inhibit the activation of cdk/cyclin complexes by inhibiting CAK activity and by dephosphorylating cdc25.
  • the G,/S checkpoint is predominantly regulated by the cdk/cyclin D E complex
  • pRb tumour suppressor protein retinoblastoma
  • E2F controls the transcription of proteins needed for DNA synthesis and entry into S-phase including thymidylate synthase. - -
  • PPl protein phosphatase 1
  • PP2A protein phosphatase 1
  • Serine/threonine phosphatases which are responsible for protein dephosphorylation, comprise a unique class of enzymes consisting of four primary
  • protein phosphatases 1 and 2 A share sequence identity between both enzyme subunits (50% for residues 23-292; 43% overall), are present in all eukaryotic cells and are together responsible for 90% of all cellular dephosphorylation.
  • Knowledge of structure and subsequent correlation of binding function for both PPl and PP2A would therefore provide a vital link toward understanding the biochemical role of these enzymes.
  • the natural toxins, okadaic acid, calyculin A, microcystin-LR and tautomycin are representative of a structurally diverse group of compounds that are all potent protein
  • phosphatase 1 (PPl) and 2 A (PP2A) inhibitors phosphatase 1 (PPl) and 2 A (PP2A) inhibitors.
  • Okadaic acid is more specific for PP2A (IC 50 InM) than PPl (IC 50 60nM), while calyculin is slightly more specific for PPl (IC 50
  • phosphatase inhibitors are known to abrogate cell cycle checkpoints, particularly the G 2 checkpoint of the cell cycle and induce cellular mitoses (Yamashita et al., 1990). Abrogation of the G 2 checkpoint means that the cell does not have the capacity to detect DNA damage or malformation of the genome prior to entry into mitosis. Therefore, cells which have a deficient G 2 checkpoint
  • okadaic acid is known as a tumour promoter, in some cell types, it has been shown to revert the phenotype of oncogene-transformed cells to that of normal cells, and to inhibit neoplastic transformation of fibroblasts (Schonthal, 1991).
  • okadaic acid has been shown to selectively enhance the cytotoxicity of vinblastine and the formation of apoptotic cells, in HL60 cells which are p53 nul (Kawamura, 1996).
  • calyculin enhances irradiation killing in fibroblast cells at doses that are non toxic when given as a single treatment. (Nakamura and Antoku, 1994).
  • Data also shows that okadaic acid can abrogate the G
  • okadaic acid has been shown to significantly increase the fraction of quiescent cells entering the S-phase via modifications in the phosphorylation state of pRb (Lazzereschi et al.. 1997). Other studies have shown that the hyperphosphoryation
  • okadaic acids class of compounds with the exceptions of okadaic acid, cantharidin (Honaken) and thyrisferyl 23 -acetate (Matszawa et. al) (being PP2A selective) exhibit poor selectivity. Furthermore, the concentration of PPl and PP2A
  • Cantharidin (exo.exo-2,3-dimethyl-7-oxobicyclo[2.2.1]heptane-2,3-dicarboxylic acid anhydride), is a major component of the Chinese blister beetles:
  • tumour suppressor gene p53 which is abnormally expressed in more than 50% of tumours.
  • chemotherapeutic agents which selectively target cancer cells with mutant p53 is certainly desirable, for two main reasons. Firstly, cells that have an
  • abnormal p53 status are inherently resistant to conventional chemotherapy and produce the more common, and more aggressive tumours such as colon carcinoma and non small cell lung cancer.
  • a chemotherapy regime that targeted only those cells with a mutant p53 phenotype would potentially produce fewer side effects since only the cancer cells would be killed and not the p53 proficient normal healthy cells.
  • cell which are the subject of this invention, may possess one or more of the properties of being potent, selective, oxidatively stable, and cell permeable inhibitors of protein phosphatases 1 and 2A. Therefore, according to the first aspect of this invention there are provided cell .
  • permeable inhibitors of protein phosphatases 1 and 2A said inhibitors being anhydride modified cantharidin analogues.
  • R 2 can cyclise to form a ring as follows:
  • R 3 and R 4 are H. aryl or alkyl.
  • the aryl group may suitably be phenyl or naphthyl for example, and may be attached via a carbon spacer of between 6 and 10 carbon atoms.
  • the alkyl group may suitably be phenyl or naphthyl for example, and may be attached via a carbon spacer of between 6 and 10 carbon atoms.
  • the alkyl group may suitably be phenyl or naphthyl for example, and may be attached via a carbon spacer of between 6 and 10 carbon atoms.
  • the alkyl group may be phenyl or naphthyl for example, and may be attached via a carbon spacer of between 6 and 10 carbon atoms.
  • C C 10 suitably be C C 10 .
  • the process may include the
  • a process for producing anhydride modified cantharidin analogues involving the step of reacting a
  • the process may further involve hydrogenation of the adduct of the diene and ene and/or optionally, ring opening of the adduct.
  • reaction conditions for the production of the anhydride modified cantharidin analogues are dependent on the aromaticity of the starting diene. Suitable reaction conditions are exemplified below.
  • a method of treating a cancer which method comprises administering to a patient in need of such treatment, an effective amount of an anhydride modified cantharidin analogue of the first aspect of this invention, together with a pharmaceutically acceptable carrier, diluent
  • the method may be carried out in conjunction with one or more further treatments for treating the cancer.
  • a method of sensitising cancer cells to at least one method of treating cancer which method of
  • sensitising comprises administering to a patient in need of such treatment, an effective amount of an anhydride modified cantharidin analogue of the first aspect of this invention, together with a pharmaceutically acceptable carrier, diluent and/or excipient.
  • a method of treating cancer which method comprises: administering to a patient in need of such treatment, an effective amount of an •
  • anhydride modified cantharidin analogue to sensitise cancer cells of the patient to one or
  • the method may also comprise
  • the one or more cancer treatments mentioned above may be selected from
  • Figure 1 is a schematic representation of the structure activity data generated for
  • FIG. 1 New cantharidin analogues.
  • Figure 3 Cytotoxicity of cantharidin and the new cantharidin analogues.
  • FIG. 4 Cell cycle analysis 12h following exposure to cantharidin, MK-2 or MK-4.
  • Figure 5 Cell cycle analysis 18h after 6Gy of radiation and 12h after exposure to cantharidin, MK-2 or MK-4.
  • Figure 8 Combination index versus fraction affected: HCT116 colon cells in simultaneous combination with taxotere and MK-4
  • Figure 9 Combination index versus fraction affected: HT29 colon cells in simultaneous combination with taxotere and MK-4.
  • cantharidin analogues encompassed by the present invention generally depend on the aromaticity of the starting diene. This is illustrated by a description of examples of the methods wherein the starting materials are furan (Method 1 below); thiophene (Method 2 below); and pyrrole (Method 3 below).
  • Method 1 Furan as the starting diene
  • a solution of furan (5 equivalents) is dissolved in a suitable solvent (about 5 times the volume of furan, the solvent can be for example, ether (for room temperature
  • Thiophene (l .Ol ⁇ g, 0.012 mol) and maleic anhydride (0.558.0.006 mol) are mixed at room temperature in 2.5 mL of distilled dichloromethane. This mixture is then placed inside a high pressure reactor. They are compressed to a pressure of 17kbar at
  • the complexes are precipitated by the addition of a saturated sodium tetraphenylborate solution.
  • the types of cancer which are amenable to treatment by these compounds include those types of cancer which are inherently resistant to conventional chemotherapy. Typically, these types of cancer are represented by the more common ⁇ and more aggressive tumour types such as, but not limited to, colon cancer and non small-cell lung cancer.
  • the compounds of this invention are suitably administered intravenously, although other modes of administration are possible.
  • Pharmaceutically acceptable diluents, adjuvants, carriers and/or excipients may be used in conjunction with the compounds of this invention.
  • Suitable such pharmaceutically acceptable substances are those within the
  • Actual dosage levels of the compounds of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired response for a particular patient, composition and mode of administration.
  • the dosage level can be readily determined by the physician in accordance with
  • the compounds of this invention may also sensitise cancer cells to other tissues.
  • these methods include irradiation and
  • platinum anti-cancer agents for example cisplatin.
  • sensitisation may also be brought about by, for example the use of the plant alkaloids vinblastine and vincristine, both of which interfere with tubulin and the formation of the mitotic spindle, as well as taxanes and antimetabolites. including 5-
  • fluorouracil methotrexate and antifolates.
  • the compounds of this invention sensitise those cells with deficient p53 activity.
  • various cancer cell lines may be chosen. These are typically both haematopoietic and
  • solid tumour cell lines with varying p53 status include: L1210 (murine leukaemia, p53 wildtype), HL60 (human leukaemia, p53 nul), A2780 (human ovarian carcinoma, p53 wildtype), ADDP (cisplatin resistant A2780 cells, p53 mutant), SW480 (human
  • the cells are fixed in 70% ethanol and stored at - 20°C until analysis is performed (1-2 weeks). After fixing, the cells are pelleted and incubated in PBS
  • FACScan fluorescence is collected in fluorescence detector 2 (FL2), filter 575/30 nm band pass. Cell cycle distribution is assessed using Cell Quest software (Becton
  • yl]2,5-diphenyl-tetrazolium bromide assay is used to determine whether a synergistic
  • cells are plated at a density of 1000 cells/well in lOO ⁇ l medium, while all other cell lines are plated at a density of 2000-25000 cells/well.
  • the cells are left for 24h prior to treatment to ensure exponential growth has been achieved, 24h after plating (day 0), lOO ⁇ l of phosphatase inhibitor is added to each well, control wells received lOO ⁇ l of
  • inhibitory effects are evaluated using the MTT assay and absorbance read at 540 nm.
  • the IC 50 is the drug concentration at which cell growth is 50% inhibited based on the difference of optical density on day 0 and day 3 of drug exposure. Cytotoxicity is evaluated using a spectrophotometric assay which determines the percentage of cell growth following exposure of the cells to various concentrations of the phosphatase inhibitors for a period of 72 hours. The subsequent dose response curve is used to calculate IC 50 values (the drug concentration at which cell growth is 50% inhibited).
  • the G 2 checkpoint by either, caffeine or UCN-01 also enhances the cytotoxicity of ⁇ irradiation in cells with mutant p53 (CA46 and HT-29 cells) (Powell et al, 1995; Russell et al., 1995; Wang et al., 1996). DNA damage induced by irradiation causes both a G, and G 2 cell cycle arrest. In p53 mutant cells, the G, checkpoint is absent.
  • P53 mutant cells are generally more resistant to conventional
  • checkpoint will be picked up by the G 2 checkpoint. If the cells are deficient in both of these checkpoints then it is believed that the cells will be unable to initiate repair mechanisms and will be more unstable and
  • Cisplatin is another commonly used anticancer treatment which binds to DNA and produces DNA crosslinks and strand breaks. Cisplatin is particularly useful in the treatment of testicular carcinoma, small cell carcinoma of the lung, bladder cancer, and ovarian cancer. Repair of cisplatin induced DNA damage is mediated via nucleotide - excision repair which is coordinated by p53 activation of Gadd45 (Smith et al., 1994). In this context, it has been suggested that cells that are p53 mutant are more sensitive to cisplatin treatment (Hawkins et al., 1996). A number of researchers have investigated this proposal in p53 mutant cell lines and in p53 mutant tumours, with mixed results. While it is apparent that cisplatin is more cytotoxic in cells lines that are deficient in p53 (induced via papillomavirus) compared to the p53 proficient cells (Hawkins et al.,
  • mutant cells is desirable since 50% of tumours have either a mutated or deleted p53 gene. Many of these p53 deficient cells and tumours are inherently resistant to conventional chemotherapy and represent the common more aggressive tumour types
  • Thymidylate synthase TS
  • TS catalyses a critical
  • TS is a key regulatory enzyme during the S-phase of the cell cycle. Lack of dTTP results in DNA damage and ultimately cell death, but the process(es) by . which cell death occurs is not clear.
  • TS inhibitors such as fluorouracil, raltitrexed, and
  • Thymitaq (Zarix, Ltd) be used in combination with cantharidin analogues. Thymitaq is a direct and specific TS inhibitor which does not require active transport into the cell nor does it require intracellular activation for its action.
  • Example 1 is not to be construed as limiting on the scope of the invention as indicated above.
  • Example 1 is not to be construed as limiting on the scope of the invention as indicated above.
  • Anhydride modified cantharidin analogues were synthesised by a variety of
  • cantharidin analogues have been synthesised.
  • the present inventors have
  • endothal fhioanhydride is three fold more potent than cantharidin, with the S atom being an important factor. It is thus
  • the 7-S group presents itself to the active sites metals and the N-H of the maleimide occupies the hydrogen bond cavity normally reserved for the 7-0 substituent cantharidin.
  • Protein phosphatase 1 and 2A were partially purified from chicken skeletal muscle essentially as described by Cohen Protein phosphatase activity was measured at
  • the cells lines chosen for study included both haematopoietic and solid tumour cell lines with varying p53 status and include: L1210 (murine leukaemia, p53 wildtype), HL60 (human leukaemia, p53 nul), A2780 (human ovarian carcinoma, p53 wildtype), ADDP (cisplatin resistant A2780 cells, p53 mutant), SW480 (human colon carcinoma, p53 mutant),
  • WiDr human colon carcinoma, p53 mutant
  • HT29 human colon carcinoma, p53 mutant
  • HCT116 human colon carcinoma, p53 wildtype
  • Anti-cancer screening of the protein phosphatase inhibitors is assessed using the
  • MTT assay determines cell viability by the ability of mitochondrial dehydrogenase to produce formazan crystals from 3-(4,5-dimethylthiazol-2-yl) -2, 5- diphenyltetrazolium bromide.
  • the viable cell number/well is directly proportional to the
  • MK-1 analogue did not show any significant cytotoxicity in any of the cell lines tested (IC 50 >1000 ⁇ M). Only marginal cytotoxicity across all cell lines tested was observed for MK-3 (IC 50 247 to >1000 ⁇ M), MK-7 (IC 50 180-367 ⁇ M) and MK-8 (IC 50 173-385 ⁇ M). Greater cytotoxicity was observed with TABLE 1
  • Tumour Cell p53 ICso (mean + SE ⁇ after 72h continuous exposure ( ⁇ M) type line status Cantharidin MK-1 MK-2 MK-3 MK-4 MK-5 MK-7 MK-8 MK-9
  • MK-2 (IC 50 157-248 ⁇ M) and MK-9 (IC 50 107-233 ⁇ M) which was also consistent across the nine cell lines.
  • the greatest cytotoxicity was observed with the MK-4 and MK-5 analogues, however, the magnitude of this response was cell line dependent.
  • MK-4 and MK-5 were selectively more cytotoxic in the human colon cancer
  • ovarian IC 50 275-333 ⁇ M; 260-567 ⁇ M
  • osteosarcoma IC 50 450 ⁇ M; >1000 ⁇ M
  • the ability of the protein phosphatase inhibitors to abrogate the G j or G 2 checkpoint of the cell cycle may be determined by cell cycle analysis using flow
  • cytometry Briefly, asynchronous cell cultures are harvested 18h after 6Gy irradiation and/or 12h incubation with the protein phosphatase inhibitor. Depending upon the p53 status of the cell line, radiation treatment alone will induce arrest in either G ! and/or G 2 phase of the cell cycle.
  • HL60, HT29 and HCT1 16 cells to cantharidin and the new cantharidin analogues MK-2 and MK-4 after 12h exposure.
  • cantharidin and MK-2 produced a similar response and induced G 2 arrest in all four cell lines tested.
  • MK-4 also induced G 2 arrest
  • HL60, HT29 and HCT116 cells The cells were treated with 6Gy of radiation and then
  • MK-4 induced Gj arrest in all cell lines. MK-4 also abrogated Gj arrest in L1210, HL60 and HCT116 cells. In HT29 cells, MK-4 induced abrogation of the G 2 checkpoint. It is important to note that the exposure of HT29 cells to MK-4 induced the greatest
  • cytotoxicity IC 50 14 ⁇ M as determined by the MTT assay.
  • the ability to abrogate the G 2 checkpoint was more lethal than the ability to abrogate the Gj checkpoint.
  • phosphatase inhibitor in various drug ratio combinations for 72h and then assayed for cytotoxicity. Similarly, the cells are exposed to 8 Gy of radiation and incubated with the
  • HCTl 16 and HT29 cells was additive and not synergistic using drug molar ratios of 1 : 1 ,
  • MK-4 in HT29 cells was also additive using drug molar ratios of 1 : 10, 1 : 100, 1 : 1000
  • a synthetic inhibitor such as 3 represents a significant advance on the currently widespread inhibitors of PPl and PP2A.
  • dicarboxylic acid moiety gives rise to a PPl selective compound.
  • the retinoblastoma protein associates with the protein phosphatase type 1 catalytic subunit. Genes Dev. 7, 555-569.
  • retinoblastoma protein a master regulator of cell cycle, differentiation and apoptosis. Eur.J.Biochem. 246:581-601.

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  • General Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract

L'invention porte sur des anhydrides analogues de cantharidine modifiée utiles pour traiter certaines formes de cancer, et sur des procédés de criblage desdits analogues pour ce qui est de leurs activités anticancéreuses et/ou leur capacité de sensibilisation des cellules cancéreuses à des traitements anticancéreux. Les analogues de la cantharidine modifiée présentent la structure (I) ou (II) dans laquelle R1, R2, R3 et R4 sont H aryle ou alkyle; X est O, N ou S; Y est OS, NH, NR, R est aryle ou alkyle; A et B sont H ou CH3; W et Z sont CHOH ou C=O. Ces composés inhibent la phosphatase protéique.
EP99930941A 1998-07-14 1999-07-14 Anhydrides analogues de cantharidine modifiee utiles pour traiter le cancer Withdrawn EP1104423A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
AUPP4665A AUPP466598A0 (en) 1998-07-14 1998-07-14 Product and process
AUPP466598 1998-07-14
PCT/AU1999/000567 WO2000004023A1 (fr) 1998-07-14 1999-07-14 Anhydrides analogues de cantharidine modifiee utiles pour traiter le cancer

Publications (2)

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EP1104423A1 true EP1104423A1 (fr) 2001-06-06
EP1104423A4 EP1104423A4 (fr) 2001-10-24

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EP99930941A Withdrawn EP1104423A4 (fr) 1998-07-14 1999-07-14 Anhydrides analogues de cantharidine modifiee utiles pour traiter le cancer

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EP (1) EP1104423A4 (fr)
JP (1) JP2002520415A (fr)
KR (1) KR20010074721A (fr)
AU (1) AUPP466598A0 (fr)
CA (1) CA2337771A1 (fr)
WO (1) WO2000004023A1 (fr)

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WO1995007022A1 (fr) * 1993-09-07 1995-03-16 Zeneca Limited Fongicides
DE69431071T2 (de) * 1993-12-29 2003-03-20 Matrix Pharma Zusammensetzung für lokale freigabe von zytostatika

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JP2002520415A (ja) 2002-07-09
CA2337771A1 (fr) 2000-01-27
AUPP466598A0 (en) 1998-08-06
WO2000004023A1 (fr) 2000-01-27
WO2000004023A9 (fr) 2000-04-20
KR20010074721A (ko) 2001-08-09

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