US20070129353A1 - Alpha-helix mimetics and method relating to the treatment of cancer stem cells - Google Patents

Alpha-helix mimetics and method relating to the treatment of cancer stem cells Download PDF

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US20070129353A1
US20070129353A1 US11/594,576 US59457606A US2007129353A1 US 20070129353 A1 US20070129353 A1 US 20070129353A1 US 59457606 A US59457606 A US 59457606A US 2007129353 A1 US2007129353 A1 US 2007129353A1
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cancer
alkyl
compound
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Michael Kahn
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Choongwae Pharmaceutical Co Ltd
Institute for Chemical Genomics
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Institute for Chemical Genomics
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Publication of US20070129353A1 publication Critical patent/US20070129353A1/en
Assigned to CHOONGWAE PHARMA CORPORATION reassignment CHOONGWAE PHARMA CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: INSTITUTE FOR CHEMICAL GENOMICS
Assigned to INSTITUTE FOR CHEMICAL GENOMICS reassignment INSTITUTE FOR CHEMICAL GENOMICS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KAHN, MICHAEL
Priority to US12/616,712 priority patent/US8293743B2/en
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N

Definitions

  • A is —(C ⁇ O)
  • B is —CHR 6 )—
  • D is —(C ⁇ O)—
  • E is -(ZR 8 )—
  • G is —(NH)— or —(CH 2 )—
  • W is a substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, the ⁇ -helix mimetic compounds of this invention have the following formula (V): wherein K is nitrogen, oxygen, or sulfur, L is nitrogen, oxygen, —(CH)—, or —(CH 2 )—, J is nitrogen, oxygen, or sulfur, Z is nitrogen or CH, and R 1 , R 2 ,
  • FIG. 25 shows that increasing concentrations of compounds PRI-001, PRI-002, PRI-003, PRI-004, PRI-005, and PRI-006 were effective, as compared with ICG-001, on SW480 cells.
  • FIG. 26 shows pluc-6270 expression (luciferase) in SW480 cells treated with varying concentrations of ICG-001, PRI-003, and PRI-004.
  • a ⁇ -helix mimetic structure having the following formula (I): wherein A is —(C ⁇ O)—CHR 3 —, or —(C ⁇ O), B is N—R 5 — or —CHR 6 —, D is —(C ⁇ O)—(CHR 7 )— or —(C ⁇ O)—, E is -(ZR 8 )— or (C ⁇ O), G is —(XR 9 ) n —, —(CHR 10 )—(NR 6 )—,—(C ⁇ O)—(XR 12 )—, —(C ⁇ N—W—R 1 )—, —(C ⁇ O)—, X—(C ⁇ O)—R 13 , X—(C ⁇ O)—NR 13 R 14 , X—(SO 2 )—R 13 , or X—(C ⁇ O)—OR 13 , W is —Y(C ⁇ O)—, —
  • a feature of many ⁇ -helix mimetic compounds is that they provide a scaffolding that places three hydrophobic functional groups, which may also be referred to as pharmacophore rings, in a specific, spatially-defined orientation referred to as an “optimized chemical space”.
  • the optimized chemical space may be triangular, with the centers of three functional groups forming the three points of the triangle.
  • An example of an optimized chemical space is one in which the lengths of the three sides of the triangle are around 9.6 ⁇ 0.5 Angstroms (symbolized hereafter by “A”), 9.2 ⁇ 0.5 ⁇ , and 10.3 ⁇ 0.5 ⁇ .
  • FIG. 13C depicts two superimposed structures having three such pharmacophore rings forming a triangle in space. A number of different compounds exhibit such an optimized chemical space, and may be considered to be within the scope of the invention.
  • the compounds of general formula (I) of the present invention have one or more asymmetric carbons depending on it's substituents.
  • the compounds of general formula (I) contains one or more asymmetric carbons
  • two kinds of optical isomers exist when the number of asymmetric carbon is 1, and when the number of asymmetric carbon is 2, four kinds of optical isomers and two kinds of diastereomers exist.
  • Pure stereoisomers including opticalisomers and diastereoisomers, any mixture, racemates and the like of stereoisomers all fall within the scope of the present invention. Mixtures such as racemates may sometimes be preferred from viewpoint of easiness for manufacture.
  • a “second component piece” of this invention has the following formula S2: Where L 1 is carboxyl-activation group such as halogen atom, R 3 , R 4 is as defined above, and P is an amino protective group suitable for use in peptide synthesis. Preferred protective groups include t-butyl dimethylsilyl (TBDMS), t-Butyloxycarbonyl (BOC), Methylosycarbonyl (MOC), 9H-Fluorenylmethyloxycarbonyl (FMOC), and allyloxycarbonyl (Alloc). When L is —C(O)NHR, —NHR may be an carboxyl protective group. N-Protected amino acids are commercially available.
  • the reverse-turn mimetics of U.S. Pat. No. 6,013,458 to Kahn, et al. are useful as bioactive agents, such as diagnostic, prophylactic, and therapeutic agents.
  • the opiate receptor binding activity of representative reverse-turn mimetics is presented in Example 9 of said U.S. Pat. No. 6,013,458, wherein the reverse-turn mimetics of this invention were found to effectively inhibit the binding of a radiolabeled enkephalin derivative to the ⁇ and ⁇ opiate receptors, of which data demonstrates the utility of these reverse-turn mimetics as receptor agonists and as potential analgesic agents.
  • the ⁇ -helix mimetic structures of the present invention will be useful as bioactive agents, such as diagnostic, prophylactic, and therapeutic agents.
  • a bioactive mimetic may be a library member which is capable of binding to an antibody or receptor, which is capable of inhibiting an enzyme, or which is capable of eliciting or antagonizing a functional response associated, for example, with a cell line.
  • the screening of the libraries of the present invention determines which library members are capable of interacting with one or more biological targets of interest.
  • the bioactive mimetic or mimetics may then be identified from the library members.
  • the resin obtained in Step 3 was treated with formic acid (1.2 mL each well) for 18 hours at room temperature. After the resin was removed by filtration, the filtrate was condensed under a reduced pressure using SpeedVac [SAVANT] to give the product as oil. The product was diluted with 50% water/acetonitrile and then lyophilized after freezing.
  • the resin was treated with formic acid (1.2 mL each well) for 18 hours at room temperature. After the resin was removed by filtration, the filtrate was condensed under a reduced pressure using SpeedVac [SAVANT] to give the product as oil. The product was diluted with 50% water/acetonitrile and then lyophilized after freezing.
  • Dose levels on the order of about 0.001 mg/kg/d to about 100 mg/kg/d of an inventive compound are useful for the inventive methods.
  • the dose level is about 0.1 mg/kg/d to about 100 mg/kg/d.
  • the dose level is about 1 mg/kg/d to about 10 mg/kg/d.
  • the specific dose level for any particular patient will vary depending upon various factors, including the activity and the possible toxicity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; the drug combination; the severity of the disease; and the form of administration.
  • in vitro dosage-effect results provide useful guidance on the proper doses for patient administration. Studies in animal models are also helpful. The considerations for determining the proper dose levels are well known in the art and within the skills of an ordinary physician.
  • the hydroxy-functionalized resin (5.0 g, 0.68 mmol/g, Novabiochem) was placed in 200 mL round-bottom flask. To the mixture of the resin and PPTS (1.7 g, 6.8 mmol) in 1,2-dichloromethane (51 mL) was added bromoacetaldehyde diethylacetal (4.2 mL, 27 mmol) at room temperature. After being stirred under reflux for 4.0 hr, the mixture was filtered and the resin was washed with DMF 50 mL ⁇ 3, DMSO 50 mL ⁇ 3, 1,4-dioxane 50 mL ⁇ 3, CH 2 Cl 2 50 mL ⁇ 3, MeOH 50 mL ⁇ 3, Et 2 O 50 mL ⁇ 3. The resin was dried under reduced pressure for over night to afford the desired bromoacetal resin (5.5 g).
  • the Amino resin (350 mg, 0.65 mmol/g) was placed in 20 mL plastic disposable syringe. The resin was swollen in DMF (3.0 mL) and DMF was sucked out. To the resin was added 0.3 M stocked CH 2 Cl 2 soltuion of 4-Benzyl-3-Boc-2-methylsemicarbazidylacetatic acid (2.7 mL, 0.80 mmol), DIPEA (277 ⁇ L, 1.59 mmol) and HATU (302 mg, 0.80 mmol) at room temperature. After being shaken for 12 hr, the mixture was filtered and the resin was washed with DMF (5.0 mL ⁇ 5 min ⁇ 3) and CH 2 Cl 2 (5.0 mL ⁇ 5 min ⁇ 3). The resin was dried under reduced pressure to afford desired resin.
  • the Amino resin (350 mg, 0.65 mmol/g) was placed in 20 mL plastic disposable syringe. The resin was swollen in DMF (3.0 mL) and DMF was sucked out. To the resin was added 0.3 M stocked CH 2 Cl 2 soltuion of 4-Benzyl-3-Boc-2-allylsemicarbazidylacetatic acid (2.7 mL, 0.80 mmol), DIPEA (277 ⁇ L, 1.59 mmol) and HATU (302 mg, 0.80 mmol) at room temperature. After being shaken for 12 hr, the mixture was filtered and the resin was washed with DMF (5.0 mL ⁇ 5 min ⁇ 3) and CH 2 Cl 2 (5.0 mL ⁇ 5 min ⁇ 3). The resin was dried under reduced pressure to afford desired resin.
  • Table 2 below shows the molecular weight (M.W.) and mass for compounds 1-2217. TABLE 2 Compound No. M.W. Mass 1 533 534 2 551 552 3 563 564 4 602 603 5 457 458 6 561 562 7 579 580 8 591 592 9 630 631 10 485 486 11 559 560 12 577 578 13 589 590 14 628 629 15 483 484 16 557 558 17 575 576 18 587 588 19 626 627 20 481 482 21 561 562 22 579 580 23 591 592 24 630 631 25 485 486 26 558 559 27 576 577 28 588 589 29 627 628 30 482 483 31 547 548 32 565 566 33 577 578 34 616 617 35 471 472 36 575 576 37 593 594 38 605 606 39 644 645 40 499 500 41 573 574 42 591 592 43 603 604 44 642 643
  • Both resistant (R) cell lines showed dramatically increased levels of both cytosolic and nuclear ⁇ -catenin as judged by both immunoblotting ( FIG. 14A ) and immunofluoresence microscopy ( FIG. 14B ) compared to their drug sensitive (S) counterparts.
  • the increased nuclear ⁇ -catenin was reflected in dramatically increased TCF/ ⁇ -catenin transcriptional activity as judged by the TOPFLASH reporter, which could be completely blocked using a dominant negative TCF4 construct ( FIG. 14C ).
  • Coimmunoprecipitation of CBP or p300 showed a strong association of ⁇ -catenin with CBP in the MES-SA/Dx5 cells that was not present in the MES-SA cells while virtually no association of ⁇ -catenin with p300 could be detected in either cell line ( FIG. 18D ).
  • coactivator specific siRNA was utilized (H Ma Oncogene 2005) to knockdown either CBP or p300 in the MES-SA/Dx5 cells.
  • MDR-1 message was specifically decreased by treatment with siRNA to CBP compared to the siRNA control treated cells, whereas p300 siRNA increased MDR-1 message levels compared to control ( FIG. 18E ).
  • the cells were tested at range of concentrations of ICG-001 between 0.625 and 10 ⁇ M and at cisplatin concentrations between 1.25 to 20 ⁇ M. All three ovarian cancer lines tested (A2780, CP70 and IGROV-1) were more sensitive to IC G-001 than to cisplatin. For the cisplatin-resistant line CP70, >90% inhibition was achieved at 5 ⁇ M of ICG-001.

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AU2006311433B2 (en) 2012-06-28
US20100069333A1 (en) 2010-03-18
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AU2006311433A1 (en) 2007-05-18
CA2629136C (en) 2016-03-08
JP2009515890A (ja) 2009-04-16
WO2007056593A3 (en) 2007-07-12
KR101486490B1 (ko) 2015-01-27
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CA2629136A1 (en) 2007-05-18
KR20080070060A (ko) 2008-07-29

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