WO2014048480A1 - Organogold complexes for use in treating cancer - Google Patents

Organogold complexes for use in treating cancer Download PDF

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WO2014048480A1
WO2014048480A1 PCT/EP2012/069141 EP2012069141W WO2014048480A1 WO 2014048480 A1 WO2014048480 A1 WO 2014048480A1 EP 2012069141 W EP2012069141 W EP 2012069141W WO 2014048480 A1 WO2014048480 A1 WO 2014048480A1
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alkyl
crc
hydrogen
compound
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PCT/EP2012/069141
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French (fr)
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Eva Ran HOFFMANN
Eddy Michel Elie VISEUX
Sonya Clare NEWCOMBE
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The University Of Sussex
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/5045—Complexes or chelates of phosphines with metallic compounds or metals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/09—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton the carbon skeleton being further substituted by at least two halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/5022—Aromatic phosphines (P-C aromatic linkage)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings

Definitions

  • the present invention relates to organogold complexes for use in treating cancer.
  • organogold complexes including both gold(l) and gold(lll) have been investigated as potential anticancer drug candidates. Indeed, two compounds- auranofin and aurothiomalate- are currently undergoing phase II and phase I clinical trials for treatment of lymphomas and non-small cell lung cancer, respectively.
  • the structure of gold(l) complexes are usually derivatives of phosphine gold chlorides salts, cationic phosphine complexes, cationic carbene complexes or gold thiolates including analogues of the anti-rheumatoid auranofin.
  • the present invention relates to a compound of formula (I) for use in therapy,
  • L denotes a phosphine or N-heterocyclic carbene ligand
  • R denotes hydrogen, alkyl, or haloalkyl; or optionally substituted
  • G denotes hydrogen, alkyl, cycloalkyl, (hetero)aryl, A-R, or a group deriving from an a- or ⁇ -amino acid, wherein optionally L may derive from a G substituent in an identical compound of formula (I), such that a macrocycle containing two Au atoms is formed, with the L substituent on each Au metal atom deriving from the G substituent on the corresponding compound of formula (I).
  • a group deriving from an a- or ⁇ -amino acid is meant a moiety which contains a chiral a- or ⁇ -amino acid which is bonded to the rest of the molecule via its C- or N-terminus.
  • the amino acid can be bonded directly to the N(Au)AR moiety via its C-terminus.
  • the N atom itself in N(Au)AR can correspond to the N-terminus of the chiral a- or ⁇ -amino acid.
  • the invention also allows for a linker group to be included between the N(Au)AR moiety and the C- or N-terminus of the chiral a- or ⁇ -amino acid, such as a group deriving from a C 3 -C 6 -dicarboxylic acid.
  • a linker group to be included between the N(Au)AR moiety and the C- or N-terminus of the chiral a- or ⁇ -amino acid, such as a group deriving from a C 3 -C 6 -dicarboxylic acid.
  • Further aspects of the invention relate to compounds which contain amino acid derivatives in which the carboxylic acid group of the C-terminus has been replaced with a phosphine group such as PPh 2 .
  • the group deriving from an a- or ⁇ -amino acid may contain a single amino acid, or it may contain a peptide.
  • the peptide chain may act as a co-therapeutic agent which acts in combination with the gold.
  • the peptide may aid in the delivery of the gold complex to the desired location within the subject being treated, for example by helping transport across cell membranes or by selectively accumulating in a desired location.
  • the present invention relates to a compound of formula (la) for use in therapy L Au N
  • L denotes P(R 1 ) 3 or
  • each R 1 independently denotes Ci-C 4 -alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 R a
  • R 2 denotes H, (CH 2 ) k C(0)NR 3 R 3 ;
  • k denotes an integer from 0 to 4.
  • each R 3 independently denotes hydrogen, d-C 4 -alkyl, S0 2 R;
  • each R 4 independently denotes CrC 4 -alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 R a ;
  • R denotes hydrogen, CrC 6 -alkyl or CrC 6 -fluoroalkyl; phenyl optionally substituted with 1 to 5 R a ; or a pyridinyl which is optionally quaternized with hydrogen or methyl;
  • G denotes hydrogen, CrC 6 -alkyl, C 3 -C 6 -cycloalkyl; phenyl optionally substituted with 1 to 5 R a ; naphthyl optionally substituted with 1 to 5 R a ; C 5 -Ci 0 - heteroaryl optionally substituted with 1 to 5 R a ; A-R, or G 1 -CHR x R y ;
  • t denotes an integer from 1 to 4.
  • u denotes 0 or 1 ;
  • v denotes 0 or 1 ;
  • R x denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
  • R y denotes (CH 2 ) u C(0)R p or (CH 2 ) u C0 2 R c when G 1 denotes a bond;
  • R z denotes C(0)R p , C0 2 R c or CH 2 P(R 14 ) 2 ;
  • each R a independently denotes halogen, OH, N0 2 , CrC 4 -alkyl, CrC 4 -alkoxy or N(R b ) 2 ;
  • each R b independently denotes hydrogen, CrC 4 -alkyl, -CH 2 C 6 H 5 ,
  • each R c independently denotes hydrogen, d-C 4 -alkyl, or PG ac ;
  • R 9 denotes hydrogen or CrC 4 -alkyl
  • R 5 denotes hydrogen, C C 4 -alkyl, OS0 2 C C 6 -alkyl, OS0 2 -C C 6 -fluoroalkyl; OS0 2 -phenyl optionally substituted with 1 to 5 R a ; or PG al ;
  • R 6 denotes hydrogen or CrC 4 -alkyl
  • R 7 and R 8 independently denote R b ;
  • R 9 and R 10 independently denote hydrogen or CrC 4 -alkyl
  • R 11 denotes hydrogen, Ci-C 4 -alkyl or CrC 4 -alkylene-P(R 14 ) 2 ;
  • R 12 denotes hydrogen, Ci-C 4 -alkyl or CrC 4 -alkylene-P(R 14 ) 2 ;
  • R 13 denotes hydrogen, OH, C C 4 -alkoxy, OS0 2 Ci-C 6 -alkyl,
  • OS0 2 -CrC 6 -fluoroalkyl OS0 2 -phenyl optionally substituted with 1 to 5 R a ;
  • R 14 denotes CrC 4 -alkyl, cyclohexyl, adamantyl, or phenyl optionally substituted with 1 to 5 R a ;
  • R p denotes a peptide which optionally links the compound of formula (I) to a co-active
  • PG ac denotes a protecting group for a carboxylic acid
  • PG am denotes a protecting group for an amine
  • PG al denotes a protecting group for an alcohol
  • L may derive from a G substituent in an identical compound of formula (la), such that a macrocycle containing two Au atoms is formed, with the L substituent on each Au metal atom deriving from the G substituent on the corresponding compound of formula (la).
  • the present invention relates to a compound of formula (lb) for use in therapy
  • L denotes P(R 1 ) 3 or N /
  • each R 1 independently denotes Ci-C 4 -alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 R a
  • R 2 denotes H, -(CH 2 ) k C(0)NR 3 R 3 ;
  • k denotes an integer from 0 to 4.
  • each R 3 independently denotes H, d-C 4 -alkyl, S0 2 R;
  • R denotes hydrogen, CrC 6 -alkyl or CrC 6 -fluoroalkyl; phenyl optionally substituted with 1 to 5 R a ; or a pyridinyl which is optionally quaternized with hydrogen or methyl;
  • t denotes an integer from 1 to 4.
  • u denotes 0 or 1 ;
  • v denotes 0 or 1 ;
  • R x denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
  • R y denotes (CH 2 ) u C(0)R p or (CH 2 ) u C0 2 R c when G 1 denotes a bond;
  • R z denotes C(0)R , C0 2 R c or CH 2 P(R 14 ) 2 ;
  • each R a independently denotes halogen, OH, N0 2 , CrC 4 -alkyl, CrC 4 -alkoxy or N(R b ) 2 ;
  • each R b independently denotes hydrogen, CrC 4 -alkyl, -CH 2 C 6 H 5 ,
  • each R c independently denotes hydrogen, d-C 4 -alkyl, or PG ac ;
  • R 9 denotes hydrogen or CrC 4 -alkyl
  • R 5 denotes hydrogen, C C 4 -alkyl, OS0 2 C C 6 -alkyl, OS0 2 -C C 6 -fluoroalkyl; OS0 2 -phenyl optionally substituted with 1 to 5 R a ; or PG al ;
  • R 6 denotes hydrogen or CrC 4 -alkyl
  • R 7 and R 8 independently denote R b ;
  • R 9 and R 10 independently denote hydrogen or CrC 4 -alkyl
  • R denotes hydrogen, CrC 4 -alkyl or CrC 4 -alkylene-P(R ) 2 ;
  • R 12 denotes hydrogen, CrC 4 -alkyl or CrC 4 -alkylene-P(R 14 ) 2 ;
  • R 13 denotes hydrogen, OH, C C 4 -alkoxy, OS0 2 C C 6 -alkyl,
  • OS0 2 -C C 6 -fluoroalkyl OS0 2 -phenyl optionally substituted with 1 to 5 R a ;
  • R 14 denotes CrC 4 -alkyl, cyclohexyl, adamantyl, or phenyl optionally substituted with 1 to 5 R a ;
  • R denotes a peptide which optionally links the compound of formula (I) to a co-active
  • PG ac denotes a protecting group for a carboxylic acid
  • PG am denotes a protecting group for an amine; and denotes a protecting group for an alcohol.
  • the compounds of the present invention can be formed by functionalising the C-terminus of an a- or ⁇ -amino acid.
  • the present invention preferably relates to a compound of formula (lc') or (lc") for use in therapy
  • L denotes P(R 1 ) 3 or
  • each R 1 independently denotes CrC 4 -alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 R a ;
  • each R 4 independently denotes CrC 4 -alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 R a ;
  • R x denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
  • R N denotes NHR P or NR b R d ;
  • R d denotes R b ;
  • R d and R x may together form -(CH 2 ) 3 -;
  • u denotes 0 or 1 ;
  • R, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R a , R b , R c and R p are as defined for the compound of formula (lb).
  • the compounds of the present invention can also be formed by including a linker group between the N-terminus of an a- or ⁇ -amino acid and the coordinating nitrogen atom.
  • the present invention preferably relates to a compound of formula (Id') or (Id") for use in therapy
  • L denotes P(R 1 ) 3 or
  • each R 1 independently denotes Ci-C 4 -alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 R a ;
  • each R 4 independently denotes CrC 4 -alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 R a ;
  • R 9 denotes R b ;
  • R x denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
  • R 9 and R x may together form -(CH 2 ) 3 -;
  • u denotes 0 or 1 ;
  • v denotes 0 or 1 ;
  • R, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R a , R b , R c , R z , and t are as defined for the compound of formula (lb).
  • the compounds of the present invention can utilise the N-terminus of an a- or ⁇ -amino acid as the coordinating atom.
  • the present invention preferably relates to a compound of formula (le') or (le") for use in therapy
  • L denotes P(R 1 ) 3 or
  • each R 1 independently denotes Ci-C 4 -alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 R a ;
  • each R 4 independently denotes CrC 4 -alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 R a ;
  • R x denotes methyl, ethyl isopropyl, sec-butyl, 2-methyl-propyl, CH(OR 5 )CH 3 , (CH 2 ) 4 OR 5 , CH 2 SR 6 , CH 2 CH 2 SCH 3 , (CH 2 ) 4 NR 7 R 8 , (CH 2 ) 3 NHC(NH)(NH 2 ),
  • the compound of formula (lb) does not contain a group deriving from an a- or ⁇ -amino acid.
  • the present invention preferably relates to compounds of formula (If) use in therapy
  • L denotes P(R 1 ) 3 or
  • each R 1 independently denotes CrC 4 -alkyl, cyclohexyl, adamantyl; or phenyl optionally substituted with 1 to 5 R a ;
  • each R 4 independently denotes CrC 4 -alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 R a ;
  • R denotes hydrogen, d-C 6 -alkyl or CrC 6 -fluoroalkyl; phenyl optionally substituted with 1 to 5 R a ; or a pyridinyl which is optionally quaternized with hydrogen or methyl;
  • G denotes hydrogen, CrC 6 -alkyl, C 3 -C 6 -cycloalkyl, phenyl optionally substituted with 1 to 5 R a ; naphthyl optionally substituted with 1 to 5 R a ; C 5 -Ci 0 - heteroaryl optionally substituted with 1 to 5 R a ; or A-R;
  • each R a independently denotes halogen, OH, N0 2 , CrC 4 -alkyl, CrC 4 -alkoxy or N(R b ) 2 ;
  • each R b independently denotes hydrogen, CrC 4 -alkyl, (CH 2 )i- 4 C0 2 R c or p G am.
  • each R c independently denotes hydrogen, CrC 4 -alkyl, or PG ac ;
  • PG ac denotes a protecting group for a carboxylic acid
  • PG am denotes a protecting group for an amine.
  • the C-terminal carboxylic acid may be replaced with a phosphine group denoted as CH 2 P(R 14 )2-
  • the N(AR)G moiety contains two coordinating groups, that is a coordinating group on the G substituent in addition to the N(AR)G nitrogen coordinating group. It is therefore possible to form macrocyclic compounds containing two Au metal atoms and two N(AR)G moieties, wherein each compound of formula (I) bonds to both metal atoms and the ligands are arranged "top-to-tail" as shown below:
  • the present invention preferably relates to a compound of formula (I la * ) or (lla") for use in therapy
  • w denotes an integer from 1 to 4.
  • u denotes 0 or 1 ;
  • R N denotes NHR P or NR b R b and
  • R, R 2 , R 3 , R 14 , R b and R p are as defined for the compound of formula (lb).
  • the present invention relates to a compound of formula (lib') or ) for use in therapy
  • t denotes an integer from 1 to 4.
  • v denotes 0 or 1 ;
  • R z denotes C(0)R p or C0 2 R c ;
  • Y is as defined for the compound of formula (I la);
  • R, R b , R c , R p , and u are as defined for the compound of formula (lb).
  • the present invention relates to a compound of formula (lie') ) for use in therapy
  • u denotes 0 or 1 ;
  • v denotes 0 or 1 ;
  • R 9 denotes R b ;
  • R x denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
  • R 9 and R x may together form -(CH 2 ) 3 -;
  • R, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R b and R c are as defined for the compound of formula (lb).
  • R denotes CrC 6 -alkyl, CrC 6 -fluoroalkyl; or phenyl optionally substituted with 1 to 5 R a .
  • A-R denotes S0 2 CH 3 , S0 2 Ci-C 6 -perfluoroalkyl, S0 2 C 6 H 5 Me, S0 2 C 6 H 5 N0 2 or COC 6 H 5 Br.
  • A-R denotes S0 2 CH 3 , S0 2 CF 3 , S0 2 C 6 H 5 Me, S0 2 C 6 H 5 N0 2 or COC 6 H 5 Br.
  • L denotes P(R 1 ) 3 .
  • L denotes P(R 1 ) 3 ;
  • R 1 denotes CH 3 , C 2 H 5 ; or phenyl optionally substituted with 1 to 5 R a .
  • L denotes P(CH 3 ) 3 , P(C 2 H 5 ) 3 or PPh 3 .
  • L denotes P(R 1 ) 3 ;
  • R 1 denotes phenyl optionally substituted with 1 to 5 R a .
  • L denotes PPh 3 .
  • R 14 denotes CH 3 , C 2 H 5 ; or phenyl optionally substituted with 1 to 5 R a .
  • R 14 denotes CH 3 or phenyl.
  • R 14 denotes phenyl
  • R 5 denotes hydrogen, C C 4 -alkyl, OS0 2 Ci-C 6 -alkyl, OS0 2 -C C 6 -fluoroalkyl; OS0 2 -phenyl optionally substituted with 1 to 5 R a .
  • R 5 denotes hydrogen, C C 4 -alkyl, S0 2 C C 6 -alkyl, S0 2 -C C 6 -fluoroalkyl, S0 2 C 6 H 5 Me, or S0 2 C 6 H 5 N0 2 .
  • R 5 denotes hydrogen, C C 4 -alkyl, S0 2 CH 3 , S0 2 CF 3 , S0 2 C 6 H 5 Me, or
  • R 5 denotes hydrogen or C C 4 -alkyl.
  • R 5 denotes hydrogen
  • v denotes 1 ;
  • t denotes an integer from 2 to 4.
  • v denotes 1 ;
  • v denotes 0.
  • R b denotes hydrogen, C C 4 -alkyl, -CH 2 C 6 H 5 , (CH 2 ) 1-4 C0 2 CH 3 , or phenyl.
  • R b denotes hydrogen, C C 4 -alkyl, or (CH 2 ) 1-4 C0 2 CH 3 .
  • R b denotes hydrogen, C C 4 -alkyl, -CH 2 C 6 H 5 , or phenyl.
  • R b denotes hydrogen or C C 4 -alkyl.
  • R b denotes hydrogen or C C 4 -alkyl.
  • R c denotes hydrogen or C C 4 -alkyl.
  • R c denotes hydrogen or methyl.
  • R c denotes methyl
  • R c denotes hydrogen
  • w 1 or 2.
  • R 11 denotes hydrogen or Ci-C 4 -alkyl
  • R 12 denotes hydrogen or C C 4 -alkyl.
  • G 1 denotes a bond
  • G 1 denotes a bond
  • R y denotes (CH 2 ) u C0 2 R c .
  • G denotes a bond
  • R y denotes (CH 2 ) u C(0)R p .
  • R y denotes NHR .
  • R y denotes N(R b ) 2 .
  • R y denotes (CH 2 ) u C(0)R p or (CH 2 ) u C0 2 R c .
  • R y denotes (CH 2 ) u C(0)R p ,.
  • R y denotes (CH 2 ) u C0 2 R c .
  • R y denotes CH 2 P(R 14 ) 2 .
  • R x denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
  • R x denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
  • x denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
  • R x denotes methyl, isopropyl, sec-butyl or 2-methyl-propyl.
  • R z denotes C(0)R p or C0 2 R c .
  • R z denotes C(0)R p in the compounds of formula (la), (lb), (Id), (le), and (lib).
  • R z denotes C0 2 R c .
  • R z denotes CH 2 P(R 14 ) 2 .
  • R z denotes CH 2 P(R 14 ) 2 ;
  • R 14 both denote CrC 4 -alkyl or phenyl.
  • R N denotes NHR P .
  • R N denotes NR b R d .
  • R N denotes NR b R b .
  • R p denotes a peptide having from 1 to 50 amino acids.
  • R p denotes a peptide having from 1 to 30 amino acids.
  • R denotes a peptide having from 1 to 20 amino acids.
  • R denotes a peptide having from 1 to 20 amino acids.
  • R p denotes a peptide having from 2 to 10 amino acids.
  • R 13 denotes OH, C C 4 -alkoxy, OS0 2 Ci-C 6 -alkyl, OS0 2 -CrC 6 -fluoroalkyl; OS0 2 -phenyl optionally substituted with 1 to 5 R a ;
  • R 13 denotes OH, C C 4 -alkoxy, OS0 2 Ci-C 6 -alkyl, OS0 2 -C C 6 -fluoroalkyl, OS0 2 C 6 H 5 Me, or OS0 2 C 6 H 5 N0 2 .
  • R 13 denotes OH, OS0 2 CH 3 , OS0 2 CF 3 , OS0 2 C 6 H 5 Me, or OS0 2 C 6 H 5 N0 2 .
  • R 13 denotes OH
  • the Au atom is Au(l).
  • L denotes P(R 1 ) 3 ;
  • R 1 denotes d-C 4 -alkyl or phenyl
  • R denotes hydrogen, C C 6 -alkyl or CrC 6 -fluoroalkyl; or phenyl optionally substituted with 1 to 5 R a ;
  • G denotes hydrogen, C C 6 -alkyl, C 3 -C 6 -cycloalkyl, or A-R;
  • each R a independently denotes halogen, OH, N0 2 , C C 4 -alkyl, C C 4 -alkoxy or N(R b ) 2 ;
  • each R b independently denotes hydrogen, C C 4 -alkyl, CH 2 C 6 H 5 , phenyl or (CH 2 ) 1-4 C0 2 R c ;
  • each R c independently denotes hydrogen or CrC -alkyl.
  • each R c independently denotes hydrogen or CrC -alkyl.
  • L denotes P(R 1 ) 3 ;
  • R 1 denotes CrC 4 -alkyl or phenyl
  • G denotes A-R
  • A-R denotes S0 2 CH 3 , S0 2 Ci-C 6 -perfluoroalkyl, SC ⁇ CeHsMe, SO2C 6 H 5 NO2 or COC 6 H 5 Br.
  • L denotes P(R 1 ) 3 ;
  • R 1 denotes Ci-C 4 -alkyl or phenyl
  • G denotes A-R
  • A-R denotes A-R denotes S0 2 CH 3 , S0 2 CF 3 , S0 2 C6H 5 Me, SO2C6H5NO2 or COC 6 H 5 Br.
  • Therapeutically active compounds containing gold-nitrogen bonds are not commonplace. Amagi et al. have reported therapeutically active compounds containing gold-nitrogen bonds. However, these derive from 5-fluorouracil compounds that themselves are therapeutically active (see Bull. Chem. Soc. Jpn. 62, 1078-1080).
  • gold-nitrogen compounds can themselves be therapeutically active, providing the chemical environment of the nitrogen atom is stable enough to remain in solution in vivo, yet capable of allowing the gold atom to react to provide a therapeutic effect.
  • each of Xi, X 2 , X 4 and X 5 denotes N, CR 15 or CR 16 ,
  • X 3 denotes N, CR 15 , CR 16 or O, providing that
  • L denotes P(R 1 ) 3 or
  • each R 1 independently denotes CrC 4 -alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 R a ;
  • each R 4 independently denotes CrC 4 -alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 R a ;
  • R 15 denotes O " C0 2 " , NR b “ , N-AR “ , A-N-A-R “ , ANR b “ or R 17 , providing that when R 15 denotes R 17 , the compound of formula (III) is accompanied by a counterion Z ⁇ ;
  • R denotes hydrogen, d-C 6 -alkyl or CrC 6 -fluoroalkyl; or phenyl optionally substituted with 1 to 5 R a ;
  • each R 16 independently denotes hydrogen, halogen, OH, N0 2 , CrC 4 -alkyl, CrC 4 -alkoxy, C(0)OR c , C(0)N(R b ) 2 , N(R b ) 2 , S0 2 R, S0 2 OR or S0 2 N(R b ) 2 ,
  • R 16 groups may together form -(CH) 4 -, -N(CH) 3 -, -CHN(CH) 2 -, -NN(CH) 2 -,-NCHNCH-, -N(CH) 2 N-, -CHNHCH-, -NH(CH) 2 -, -NHCHN-, -NHNCH-; each R a independently denotes halogen, OH, N0 2 , CrC 4 -alkyl, CrC 4 -alkoxy or N(R b ) 2 ;
  • each R b independently denotes hydrogen, d-C 4 -alkyl, -CH 2 C 6 H 5 , or (CH 2 )i- 4 C0 2 R c , or phenyl;
  • each R c independently denotes hydrogen or CrC 4 -alkyl
  • R 17 denotes hydrogen, halogen, CrC 4 -alkyl, CrC 4 -alkoxy, C(0)OR c , C(0)N(R b ) 2 , N(R b ) 2 , S0 2 R, S0 2 OR or S0 2 N(R b ) 2 ;
  • Z ⁇ denotes a pharmaceutically acceptable anion
  • one of X-i, X 2 , X 3 , X 4 or X 5 denotes CR 15 , with the remaining moieties denoting CR 16 .
  • Xi denotes CR 15
  • X 2 , X 3 , X 4 and X 5 denote CR 16 .
  • Xi denotes CR 15
  • X 2 denotes N
  • X 3 , X 4 and X 5 denote CR 16 .
  • Xi denotes CR 15
  • X 4 denotes N
  • X 2 , X 3 and X 5 denote CR 16 .
  • Xi denotes CR 15
  • X 3 denotes N
  • X 2 , X 4 and X 5 denote CR 16 .
  • Xi denotes CR 15
  • X 3 denotes O
  • X 2 , X 4 and X 5 denote CR 16 .
  • Xi denotes CR 15
  • X 5 denotes N
  • X 2 , X 3 and X 4 denote CR 16 .
  • A-R denotes S0 2 CH 3 , S0 2 Ci-C 6 -perfluoroalkyl, S0 2 C 6 H 5 Me, S0 2 C 6 H 5 N0 2 6 H 5 Br.
  • A-R denotes S0 2 CH 3 , S0 2 CF 3 , S0 2 C 6 H 5 Me, S0 2 C 6 H 5 N0 2 or COC 6 H 5 Br.
  • L denotes P(R 1 ) 3 .
  • L denotes P(R 1 ) 3 ;
  • R 1 denotes CH 3 , C 2 H 5 ; or phenyl optionally substituted with 1 to 5 R a .
  • L denotes P(CH 3 ) 3 , P(C 2 H 5 ) 3 or PPh 3 .
  • L denotes PPh 3 .
  • R 15 denotes O “ , C0 2 " , NR b ⁇ , N-AR “ , A-N-A-R “ or ANR b ⁇ .
  • R 15 denotes O “ , C0 2 " , NR b “ , N-AR “ or ANR b “ .
  • R 15 denotes O " , C0 2 " , NR b ⁇ , N-AR " , ANR b ⁇ or R 17 .
  • R 15 denotes O " , C0 2 " , NR b ⁇ , N-AR " , ANR b ⁇ or R 17 .
  • R 15 denotes O " C0 2 " , CONR b “ , NR b “ or N-AR " .
  • R 15 denotes CONR b " , NR b “ , N-AR " or R 17 .
  • R 15 denotes CONR b " , NR b “ , or N-AR " .
  • R 15 denotes NR b " or N-AR " .
  • R 15 denotes N-AR " or R 17 .
  • R 15 denotes N-AR " .
  • R 15 denotes R 17 .
  • each R 16 independently denotes hydrogen, halogen, OH, N0 2 , CrC 4 -alkyl, CrC 4 -alkoxy, C(0)OR c , C(0)N(R b ) 2 or N(R b ) 2 ,
  • R 16 groups may together form -(CH) 4 - or -N(CH) 3 -.
  • each R 16 independently denotes hydrogen, halogen, N0 2 , CrC 4 -alkyl, or CrC 4 -alkoxy,
  • R 16 groups may together form -(CH) 4 - or -N(CH) 3 -.
  • each R 16 independently denotes hydrogen, halogen, OH, N0 2 , CrC 4 -alkyl, CrC 4 -alkoxy, C(0)OR c , C(0)N(R b ) 2 or N(R b ) 2 , wherein two adjacent R 16 groups may together form -(CH) 4 -.
  • R 16 independently denotes hydrogen, halogen, OH, N0 2 , CrC 4 -alkyl, CrC 4 -alkoxy, C(0)OR c , C(0)N(R b ) 2 or N(R b ) 2 , wherein two adjacent R 16 groups may together form -(CH) 4 -.
  • each R 16 independently denotes hydrogen, halogen, N0 2 , CrC 4 -alkyl, or CrC 4 -alkoxy,
  • each R 16 independently denotes hydrogen or CrC 4 -alkyl
  • each R 16 independently denotes hydrogen
  • each R 16 independently denotes hydrogen, halogen, OH, N0 2 , C C 4 -alkyl, Ci-C 4 -alkoxy, C(0)OR c , C(0)N(R b ) 2 or N(R b ) 2 .
  • each R 16 independently denotes hydrogen, halogen, N0 2 , CrC 4 -alkyl, or Ci-C 4 -alkoxy.
  • each R 16 independently denotes hydrogen or Ci-C -alkyl.
  • each R 16 independently denotes hydrogen.
  • R 17 denotes hydrogen, halogen, C C 4 -alkyl, C C 4 -alkoxy, C(0)OR c , C(0)N(R b ) 2 , or N(R b ) 2 .
  • R 17 denotes hydrogen, halogen, C C 4 -alkyl, C C 4 -alkoxy, C(0)N(R b ) 2 , N(R b ) 2 , S0 2 R, or S0 2 N(R b ) 2 .
  • R 17 denotes hydrogen, halogen, Ci-C 4 -alkyl, or Ci-C 4 -alkoxy
  • R 17 denotes hydrogen
  • each R c denotes CrC 4 -alkyl.
  • Z " denotes CI “ , Br “ , HS0 4 “ , S0 3 NH 2 " , H 2 P0 4 “ , N0 3 " , acetate, propionate, succinate, glycolate, stearate, lactate, malate, tartarate, citrate, ascorbate, palmate, maleate, hydroxymaleate, phenylacetate, glutamate, benzoate, salicyclate, sulfanilate, 2-acetoxybenzoate, fumarate, toluenesulfonate, methanesulfonate, ethane disulphonate, trifluoromethanesulphonate, oxalate, or isethionate.
  • Z " denotes CI “ , Br “ , HS0 4 “ , S0 3 NH 2 " , H 2 P0 4 “ , N0 3 " , acetate, propionate, succinate, glycolate, stearate, lactate, malate, tartarate, citrate, ascorbate, palmate, maleate, hydroxymaleate, phenylacetate, glutamate, benzoate, salicyclate, sulfanilate, 2-acetoxybenzoate, fumarate, toluenesulfonate, methanesulfonate, ethane disulphonate, trifluoromethanesulphonate, oxalate, or isethionate.
  • Z " denotes CI “ , Br “ , HS0 4 “ , S0 3 NH 2 “ , H 2 P0 4 “ , N0 3 “ , acetate, propionate, succinate, glycolate, stearate, lactate, malate, tartarate, citrate, ascorbate, maleate, hydroxymaleate, glutamate, benzoate, salicyclate, fumarate, toluenesulfonate, or oxalate.
  • Z ⁇ denotes CP, ⁇ , HS0 4 ⁇ , acetate, propionate, succinate, glycolate, stearate, lactate, malate, tartarate, citrate, ascorbate, maleate, hydroxymaleate, glutamate, benzoate, fumarate, or oxalate.
  • the Au atom is Au(l).
  • the peptide group R may serve one of several roles. It could be an agonist or antagonist, or may serve as a biologically tolerable linking group to a co-active.
  • co-active is meant a compound that is induces a biological response in a subject treated by the compound.
  • a co-active can be therapeutically active (i.e. a drug).
  • the peptide group is not linked to a co-active.
  • R is an agonist or antagonist.
  • alkyl or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • “CrC 6 alkyl” is intended to include Ci , C2, C3, C4, C 5 and C 6 alkyl groups.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.
  • haloalkyl is meant both branched and straight chain saturated ali aliphatic hydrocarbon groups having the specified number of carbon atoms, wherein at least one of the hydrogen atoms has been replaced by F, CI, Br or I.
  • haloalkyl refers to perfluoralkyl.
  • cycloalkyl refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems.
  • Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl and the like.
  • Branched cycloalkyl groups such as 1 -methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl”.
  • aryl is intended to mean an aromatic moiety containing, if specified, the specified number of carbon atoms; for example phenyl or naphthyl.
  • heteroaryl is intended to mean an aromatic moiety containing, if specified, the specified number of atoms with at least one of the ring atoms being selected from N, O or S.
  • heteroaryl rings include pyrrole, furan, thiophene, imidazole, pyrazole, 1 ,2,3-triazole, 1 ,2,4-triazole, tetrazole, thiazole, oxazole, isooxazole, benzofuran, isobenzofuran, indole, isoindole, benzothiophene, benzo[c]thiophene, benzimidazole, indazole, purine, benzoxazole, benzothiazole, pyridine, pyrimidine, pyrazine, pyrazidine, quinoline, isoquinoline, quinoxaline, quinazoline and cinnoline.
  • protecting groups may be present in the compounds of the present invention.
  • the use of protecting groups is well known in the art (see for example, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Edn., John Wiley & Sons).
  • the skilled person will be aware of particular groups available for protecting amine, amide, carboxylic acid and alcohol groups, and the conditions under which protection and deprotection can occur.
  • Any suitable protecting groups may be present in the compounds of the invention, either to aid in the synthesis of the compounds of formula I, or to prevent unwanted side reactions occurring with reactive side groups in the compounds of formulae II and III.
  • Suitable protecting groups for an amine include carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC),
  • Suitable protecting groups for a carboxylic acid include benzyl and alkyl esters, silyl esters, orthoesters and oxazoline.
  • Suitable protecting groups for an alcohol include acetyl (Ac) benzoyl, benzyl (Bn), ⁇ -methoxyethoxymethyl ether (MEM), dimethoxytrityl
  • the compounds of the invention which contain an amino acid derivative may be synthesised from suitable amino acids using a variety of synthetic strategies. For example, a typical synthetic routes are shown in the following schemes:
  • Protection of the carboxylic acid can also allow functionalisation of the amino acid nitrogen to allow coordination to a metal centre, either directly (Scheme 3) or via a linker group (Scheme 4):
  • the carboxylic acid moiety in the amino acid may also be removed (for example with lithium aluminium hydride (LAH)) to allow functionalisation with a phosphine moiety, as shown in Scheme 5:
  • LAH lithium aluminium hydride
  • R am corresponds to an amino acid side chain, which may be protected as necessary. While the above schemes are shown with respect to ⁇ -L-amino acids, the methodologies described would be equally applicable to ⁇ and/or D-amino acids. Likewise, the amino acids may be coupled to a suitable peptide R using standard methodology.
  • the compounds of the invention namely compounds of formula (I), (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), (lie) and (III) as well as the preferred embodiments of these compounds described herein, are therapeutically active.
  • the present invention relates to a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), (lie) or (III) for use in therapy.
  • the present invention relates to a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), (lie) or (III) for use in treating cancer.
  • the present invention relates to a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), (lie) or (III) for use in treating cancer, wherein the cancer cells are hyperpolarised.
  • the present invention relates to a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), (lie) or (III) for use in treating cancer, wherein the cancer cells comprise hyperpolarised mitochondria.
  • the present invention relates to compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), (lie) or (III) for use in treating cancer, wherein the cancer cells are characterised by overexpressing thioredoxin reductase.
  • the cancer is selected from adenocarcinoma, malignant mesothelioma, thyroid cancer, prostate cancer or colorectal cancer.
  • the cancer is a slow growing cancer.
  • slow growing cancer is meant a tumour with a doubling time (i.e. the time taken to double in size) of at least 250 days.
  • a “slow growing cancer” is a cancer with an S-phase fraction of less than 6% (i.e. less than 6% of the cells in the cancer are in the process of dividing).
  • a “slow growing cancer” has less than 3.5% of the cells Ki-67 positive. Ki-67 is a marker to determine the growth of human cells. Methods for staining and detecting Ki-67 are described below.
  • the present invention relates to compound of formula (I), (la), (lb), (lc), (Id), (le), (If), (Ma), (Mb), (lie) or (III) for use in modifying the activity of a selenosulphide protein, preferably thioredoxin reductase.
  • a selenosulphide protein preferably thioredoxin reductase.
  • the present invention relates to compound of formula (I), (la), (lb), (lc), (Id), (le), (If), (I la), (lib), (lie) or (III) for use in inhibiting a selenosulphide protein, preferably thioredoxin reductase.
  • a selenosulphide protein preferably thioredoxin reductase.
  • treating refers to the reduction, alleviation or elimination, preferably to normal levels, of one or more of the symptoms of said disease, disorder or condition which is being treated, e.g. normal blood pressure, cardiac function, etc., relative to the symptoms prior to treatment. Where not explicitly stated, treatment encompasses prevention. "Preventing” refers to absolute prevention, i.e. maintenance of normal levels with reference to the extent or appearance of a particular symptom (e.g. hypertension) or reduction or alleviation of the extent or timing (e.g. delaying) of the onset of that symptom.
  • the present invention also relates to pharmaceutical compositions comprising a compound according to formula (I), (la), (lb), (lc), (Id), (le), (If), (I la), (lib), (lie) or (III) and one or more pharmaceutically acceptable excipients and/or diluents.
  • pharmaceutically acceptable is meant that the ingredient must be compatible with other ingredients in the composition as well as physiologically acceptable to the recipient.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • “Pharmaceutically acceptable anion” refers to negative ions in pharmaceutically acceptable salts.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's
  • “Therapeutically effective amount” is intended to include an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to treat cancer in a host.
  • the amount of each compound of the combination may be selected so that when the combination is administered, the effect of the combination is effective to treat cancer in a host.
  • composition useful in the treatment of cancer comprising the administration of a therapeutically effective amount of the combinations of this invention, with or without pharmaceutically acceptable carriers or diluents.
  • the pharmaceutical composition of this invention may additionally comprise an optional anti-proliferative cytotoxic agent or agents, an optional quiescence agent, and a pharmaceutically acceptable carrier.
  • compositions of the present invention may further comprise one or more pharmaceutically acceptable additional ingredient(s) such as alum, stabilizers, antimicrobial agents, buffers, coloring agents, flavoring agents, adjuvants, and the like.
  • additional ingredient(s) such as alum, stabilizers, antimicrobial agents, buffers, coloring agents, flavoring agents, adjuvants, and the like.
  • the compounds of the combination of the present invention and compositions of the present invention may be administered orally or parenterally including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • the compounds of the combination and compositions of this invention may be administered, for example, in the form of tablets or capsules, powders, dispersible granules, or cachets, or as aqueous solutions or suspensions.
  • carriers which are commonly used include lactose, corn starch, magnesium carbonate, talc, and sugar, and lubricating agents such as magnesium stearate are commonly added.
  • useful carriers include lactose, corn starch, magnesium carbonate, talc, and sugar.
  • emulsifying and/or suspending agents are commonly added.
  • sweetening and/or flavoring agents may be added to the oral compositions.
  • the compounds of the combination or pharmaceutically acceptable salts thereof are formulated with a sulfobutylether-7- ⁇ - cyclodextrin or a 2-hydroxypropyl-p-cyclodextrin for intravenous administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously in the wax, for example by stirring. The molten homogeneous mixture is then poured into conveniently sized molds and allowed to cool and thereby solidify.
  • Liquid preparations include solutions, suspensions and emulsions. Such preparations are exemplified by water or water/propylene glycol solutions for parenteral injection. Liquid preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
  • a pharmaceutically acceptable carrier such as an inert compressed gas.
  • solid preparations which are intended for conversion, shortly before use, to liquid preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • the compounds of the combination described herein may also be delivered transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the combinations may also be used in conjunction with other well known therapies that are selected for their particular usefulness against the condition that is being treated.
  • the active ingredients of the combination compositions of this invention are employed within the dosage ranges known to one skilled in the art.
  • the compounds of the combination may be administered separately in the appropriate dosage ranges.
  • the invention also extends to pharmaceutical compositions as described above for use as a medicament.
  • the precise dosage of the active compound to be administered and the length of the course of treatment will of course, depend on a number of factors including for example, the age and weight of the patient, the specific condition requiring treatment and its severity, and the route of administration.
  • the present invention preferably provides a method of treating cancer, preferably as described hereinbefore, in a human or non-human animal wherein a compound of formula (I), (la), (lb), (lc), (Id), (le), (If), (I la), (lib), (lie) or (III) is administered to said animal.
  • the present invention preferably provides the use of a compound of formula (I), (la), (lb), (lc), (Id), (le), (If), (Ma), (Mb), (lie) or (III) for the preparation of a medicament for the treatment of cancer, preferably as described hereinbefore.
  • the present invention preferably provides the use of a compound of formula (I), (la), (lb), (lc), (Id), (le), (If), (Ma), (Mb), (lie) or (III) in treating cancer.
  • these methods and uses relate to the treatment of the preferred cancers described hereinbefore, e.g. slow growing cancers, adenocarcimas, and cancers associated with hyperpolarised cells (typically hyperpolarised
  • the method of treatment according to the invention may advantageously be combined with administration of one or more active ingredients which are effective in treating the disorder or disease to be treated.
  • active ingredients which are effective in treating the disorder or disease to be treated.
  • compositions of the invention may additionally contain one or more of such active ingredients.
  • Figure 1 Cell viability in response to gold(l) complexes.
  • Cell viability was determined by measuring the fluorescence of untreated ('Medium'), DMSO-treated (' ⁇ ⁇ '), and gold(l) treated cells.
  • the 'No cells' control was used as background subtraction.
  • the normalized fluorescence was calculated as the background- subtracted fluorescence reading, divided by the background-subtracted
  • Figure 2 Cell viability in response to gold(l) complex 7.
  • Cell viability was determined by measuring the fluorescence of untreated ('Medium'), DMSO-treated (' ⁇ ⁇ '), and gold(l) treated cells. The normalized fluorescence was calculated as the background-subtracted fluorescence reading, divided by the background- subtracted fluorescence reading of the DMSO-treated control. The error bars correspond to the standard deviation of the mean of four to eight replicates.
  • Figure 3 IC 50 estimation for compounds 1 and 2. Representative response curves for CV-1 control cells and the two cancer cells lines are shown. The IC 50 values were estimated from curve-fitting using GraphPad. S.E. represents the standard error of the mean, calculated from n independent experiments.
  • Figure 4 Cell viability assays for the ligands of compounds 1 and 2 using the resazurin reductase activity assay on breast cancer cell line MDA-MB-231 and control epithelial cell line (CV-1 ). Cell viability was determined by measuring the fluorescence of DMSO-treated ( ⁇ ⁇ '), and ligand treated cells. The 'No cells' control was used for background subtraction. The normalized fluorescence was calculated as the background-substracted fluorescence reading, divided by the background-subtracted fluorescence reading of the DMSO-treated control. The error bars correspond to the standard deviation of the mean of three replicates.
  • Figure 5 Nigericin sensitizes CV-1 cells to gold(l) compounds.
  • CV-1 and MDA- MB-231 cell lines were treated with increasing concentrations of nigericin in addition to 4.28 or 5 ⁇ gold(l) compound (black bars) or 0 ⁇ gold(l), (la), DMSO- treatment (grey bars).
  • Ethanol-only treatment of the cell lines was used as 'Ethanol' control.
  • 'No cells' control was used for background subtraction. The error bars represent standard deviation of the mean of three replicates.
  • FIG. 6 TrxR activity in vitro is inhibited by gold(l) complexes.
  • Increasing concentrations of compounds 1 and 2 or 'ligand only' were added to TrxR and GR enzymes and their activity monitored by fluorescence. Normalized fluorescence values were calculated by taking the fluorescence value of the treated well and dividing it by the fluorescence value of 0 nM compound (DMSO-only treatment).
  • Triflic amide was prepared using the procedure reported by Burdon et al., J. Chem. Soc, 1957, 2574. Dry diethyl ether and tetrahydrofuran were distilled from sodium/benzophenone under an atmosphere of nitrogen. Dichloromethane, toluene, triethylamine, and diisopropylamine were distilled from calcium hydride under atmosphere of nitrogen. Under anhydrous conditions, all apparatus was flame-dried before either cooling under reduced pressure (0.3 mmHg) or under a continuous flow of nitrogen or argon.
  • Evaporation under reduced pressure was performed on a Buchi rotary evaporator, using a diaphragm pump. Reduced pressure was achieved by using a Leybold static oil pump (0.05 mmHg) unless otherwise stated.
  • the IR spectra were recorded on spectrometer Perkin Elmer FT-IR Spectrum One equipped with a diamond top plate. Mass spectra were obtained using VG Autospec Magnetic Sector MS and Bruker Daltonic FT-ICR-MS Ape III instruments, using electron impact (El) or fast atom bombardment (FAB). The 1 H nuclear magnetic resonance spectra were recorded on a Varian 400 (400 MHz) or Varian 500 (500 MHz).
  • Triphenylphosphine gold chloride (75.6 mg, 0.153 mmol) was added and stirred for 1 .5 h. The reaction mixture was filtered through Celite and the filtrate concentrated under reduced pressure to give the corresponding compound as white solid (1 .548 g, 90%).
  • Methyl-3-bromopropionate (1.0 mL, 9.28 mmol) in dichloromethane (8.0 mL) was added dropwise to a solution of triethylamine (2.61 mL, 18.57 mmol) and (2S)- 2-[(diphenylphosphino)methyl]pyrrolidine (2.50 g, 9.28 mmol) in dichloromethane (27 mL). The resultant solution was stirred at 30 °C for 18 h. The reaction mixture was poured into water/dichloromethane (1 :1 , 200 mL).
  • Triethylamine (0.26 mL, 1 .88 mmol) was added and the suspension stirred for 10 min.
  • 4-dimethylaminopyridine (15 mg, 0.12 mmol) and succinic anhydride (125 mg, 1 .25 mmol) were added and the reaction stirred for 16 h.
  • the reaction mixture was shaken with 3 x 20 mL portions of hydrochloric acid (2 M) and the aqueous washings extracted with diethyl ether (3x20 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield the title compound as a white solid (0.199 g, 60%).
  • the aqueous layer was extracted with chloroform (4x50 mL) and the combined organic layers washed with water (50 mL), 10% NaOH (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate.
  • the pH of the aqueous layer was brought down to 8 by adding dilute hydrochloric acid dropwise and further extracted with diethyl ether (3x50 mL).
  • the organic layer was dried over anhydrous magnesium sulphate and filtered.
  • the chloroform and ether solutions were combined and concentrated under reduced pressure to leave a pale brown solid. The solid was recrystallised from methanol to yield the title compound as an off white solid (0.19 g, 16%).
  • the breast cancer cell lines MDA-MB-231 and MDA-MB-468 as well as green monkey kidney epithelial cells (CV1 ) were obtained from Cancer Research UK.
  • Cells were grown in 25 ml Dulbecco's modified medium (DMEM, 21969; Gibco) supplemented with 12% fetal calf serum (16010-159; lot 1014583; PAA), 1 % penicillin/streptomycin and 1 % L-glutamate in 75 cm 3 cell culture flasks (Corning).
  • the media and supplements were obtained from Gibco/invitrogen. Cell cultures were maintained at 37°C and 5% C0 2 .
  • Cells were split every 3-4 days, cells never reached a confluency greater than 95% to avoid cells growing on top of each other. Prior to trypsinization of cells in preparation for splitting, cells were inspected on a standard light microscope and only propagated further or used in assays if they appeared 'normal' (not floating) and were not contaminated (e.g. by bacteria or yeast). A maximum of 25 passages were carried out.
  • Cells were washed twice in 13 mis of phosphate buffered saline (pH 7.25). Cells were trypsinized with 2.5 mg trypsin (27250-018; GIBCO)/ml phosphate buffered saline (pH 7.25) for 5 min. at 37°C and 5% C0 2. The trypsin was removed from the cells adding 10 ml of DMEM, supplemented as above ("Cell Culture”) to the culture flask and then adding the cell suspension to a 30 ml tube (201 150, Greiner Bio One). The cells were centrifuged at1500 rpm in a Rotina 38R (Hettich) for 5 min. (room temperature, -21 °C) and the supernatant was aspirated before cells were resuspended in 10mls of DMEM, supplemented as above.
  • Haemocytometer counts were carried out at this stage to determine 'cell concentration'.
  • Cell viability was determined using the CellTiter-Blue® Cell Viability Assay (G8080, Promega) following the instructions by the supplier. It was found that confluency of the cells prior to incubation with the gold(l) complexes influenced cell viability. Therefore, cells were initially grown to a 'cell concentration' between 2 ⁇ 10 5 to 5 x 10 5 cells/ml, as determined by haemocytometer counts after trypsinization of the cells (see above). At this 'cell concentration', cells were healthy and no substantial level of 'floating', detached cells were noticed. Moreover, cell viability was substantially higher after treatment with the gold(l) complexes within this range, compared to higher, commonly-used concentrations (or confluencies leading to higher concentrations using the cell concentration measure defined above).
  • ⁇ 5000 cells were then seeded into wells of 96-well black-walled, clear bottomed plates (655090; Greiner). The plates were incubated for 24 hours, as described above, to allow cells to adhere to the well.
  • the gold(l) compounds were prepared from powder immediately prior to use by dissolving the compound in undiluted (-100%) DMSO to give a stock concentration of 100 mM.
  • the plates were incubated for a further 44 hours, at 37°C and 5% C0 2 (in the dark). After 44 hours, 20 ⁇ of CellTiter-Blue® was added to each well of the plate and the plate incubated for a further 4 hours at 37 C and 5% C0 2 (in the dark). Fluorescence readings from each well were then measured at 560nm/590nm using a Promega Glomax multi detection system. Cell viability was determined as follows. Fluorescence of each well was recorded as total fluorescence ' .
  • thioredoxin reductase and glutathione reductase activity were measured using abeam thioredoxin reductase and glutathione reductase assay kits (ab83463 and ab83461 , respectively) following the instructions by the supplier. Briefly, thioredoxin reductase (T9698, Sigma) or glutathione reductase (G9297, sigma) both at concentrations of 0.0005 units/ ⁇ were treated with increasing concentrations of compound 1 , compound 2, or the indicated ligands. The absorbance was measured on a BIO-TEK synergy HT plate reader at 405 nm, every 30 seconds for up to 20 minutes. TrxR and GR activities were calculated as nmol TNB ⁇ min "1 ⁇ ml "1 sample volume.
  • the complexes 1-7 were tested for antiproliferative effects on two commonly-used breast cancer cell lines (MDA-MB-231 and MDA-MB-468) as well as CV-1 cells from normal, African green monkey kidney epithelial cells (control), using a range of concentrations that spanned two orders of magnitude.
  • This initial screen revealed that all of the compounds exhibited marked cytotoxic effects, with preferential inhibition of the two cancer cell lines ( Figures 1 and 2).
  • the MDA-MB- 468 cell line was consistently more sensitive to the gold(l) complexes compared to the MDA-MB-231 .
  • Compounds 1 , 2, 3 and 6 were comparable to auranofin in the inhibition of the MDA-MB-231 cell line.
  • Relative to the inhibition of the CV-1 cell line compounds 4 and 5 inhibited MDA-MB-231 as well as auranofin.
  • Further analysis of compounds 1 and 2 revealed IC 50 values in the low and even sub- micromolar ranges ( Figure 3).
  • Mitochondrial hyperpolarization of adenocarcinomas from which the two cell lines used in this study are derived is hypothesized to be the cause of the selective inhibition of cell proliferation due to enhanced accumulation of gold(l) in the mitochondria. This predicts that hyperpolarizing the mitochondrial membranes of CV-1 cells with the K7H + ionophore, nigericin, should sensitize them further to the gold complexes. To test this, CV-1 cells were treated with increasing
  • Tumour doubling time can be estimated using computed tomography, as described by Henschke et al. in Thracic and Cardiovascular Surgery, 2005, 17(2) pp99-106. This methodology is particularly useful for measuring tumour sizes of lung cancer.
  • the numbe of cells in S-phase can be determined using fluorescence- activated cell sorting, such as the technique described by Pinto et al. in j. Clin Pathol, 2001 , 54, pp543-549 (see section headed DNA Flow Cytometry).
  • fluorescence- activated cell sorting such as the technique described by Pinto et al. in j. Clin Pathol, 2001 , 54, pp543-549 (see section headed DNA Flow Cytometry).
  • the S-phase fraction is:

Abstract

The present invention relates to gold complexes that find use in therapy, particularly in treating cancer. The compounds of the invention have formula (I) wherein L denotes a phosphine or N-heterocyclic carbene ligand; A denotes SO2 or C(=O); R denotes hydrogen, alkyl, or haloalkyl; or optionally substituted (hetero)aryl; and G denotes hydrogen, alkyl, cycloalkyi, (hetero)aryl, A-R, or a group deriving from an a- or β-amino acid.

Description

Organogold Complexes for use in Treating Cancer
Background of the Invention
The present invention relates to organogold complexes for use in treating cancer.
In the past 20 years organogold complexes including both gold(l) and gold(lll) have been investigated as potential anticancer drug candidates. Indeed, two compounds- auranofin and aurothiomalate- are currently undergoing phase II and phase I clinical trials for treatment of lymphomas and non-small cell lung cancer, respectively. The structure of gold(l) complexes are usually derivatives of phosphine gold chlorides salts, cationic phosphine complexes, cationic carbene complexes or gold thiolates including analogues of the anti-rheumatoid auranofin.
Despite these recent advances, there remains a need for further anticancer drugs.
Summary of the Invention
In one aspect, the present invention relates to a compound of formula (I) for use in therapy,
G
L Au N /
\ A
\ R
(I)
wherein
L denotes a phosphine or N-heterocyclic carbene ligand;
A denotes S02 or C(=0);
R denotes hydrogen, alkyl, or haloalkyl; or optionally substituted
(hetero)aryl; and
G denotes hydrogen, alkyl, cycloalkyl, (hetero)aryl, A-R, or a group deriving from an a- or β-amino acid, wherein optionally L may derive from a G substituent in an identical compound of formula (I), such that a macrocycle containing two Au atoms is formed, with the L substituent on each Au metal atom deriving from the G substituent on the corresponding compound of formula (I).
Description of the Invention
In the nomenclature of the formula used herein, compounds denoted with ' and " are epimers. In other words, whereas a compound of formula X' may derive from an L-amino acid, a compound of formula X" derives from the corresponding D- amino acid. In general, any reference to a compound of formula X should be interpreted as a reference to a compound of formula X' or X". Thus, a reference to the compound of formula (Ic) should be interpreted as a reference to compounds of formulae (lb') and (lb").
By "a group deriving from an a- or β-amino acid" is meant a moiety which contains a chiral a- or β-amino acid which is bonded to the rest of the molecule via its C- or N-terminus. The amino acid can be bonded directly to the N(Au)AR moiety via its C-terminus. Alternatively, the N atom itself in N(Au)AR can correspond to the N-terminus of the chiral a- or β-amino acid. The invention also allows for a linker group to be included between the N(Au)AR moiety and the C- or N-terminus of the chiral a- or β-amino acid, such as a group deriving from a C3-C6-dicarboxylic acid. Further aspects of the invention relate to compounds which contain amino acid derivatives in which the carboxylic acid group of the C-terminus has been replaced with a phosphine group such as PPh2.
The group deriving from an a- or β-amino acid may contain a single amino acid, or it may contain a peptide. The peptide chain may act as a co-therapeutic agent which acts in combination with the gold. Alternatively, the peptide may aid in the delivery of the gold complex to the desired location within the subject being treated, for example by helping transport across cell membranes or by selectively accumulating in a desired location.
In preferred embodiments, the present invention relates to a compound of formula (la) for use in therapy L Au N
\ R
(la)
wherein
L denotes P(R1)3 or
Figure imgf000005_0001
each R1 independently denotes Ci-C4-alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 Ra
Figure imgf000005_0002
R2 denotes H, (CH2)kC(0)NR3R3;
k denotes an integer from 0 to 4;
each R3 independently denotes hydrogen, d-C4-alkyl, S02R;
each R4 independently denotes CrC4-alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 Ra;
A denotes S02 or C(=0);
R denotes hydrogen, CrC6-alkyl or CrC6-fluoroalkyl; phenyl optionally substituted with 1 to 5 Ra; or a pyridinyl which is optionally quaternized with hydrogen or methyl;
G denotes hydrogen, CrC6-alkyl, C3-C6-cycloalkyl; phenyl optionally substituted with 1 to 5 Ra; naphthyl optionally substituted with 1 to 5 Ra; C5-Ci0- heteroaryl optionally substituted with 1 to 5 Ra; A-R, or G1-CHRxRy;
G1 denotes a bond, -C(=0)(CH2)u- or -C(=0)-(CH2)t-G2; G2 denotes (C(=0))vNR9; or
G2 and CHRxRy together denote
Figure imgf000006_0001
t denotes an integer from 1 to 4;
u denotes 0 or 1 ;
v denotes 0 or 1 ;
Rx denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
CH(OR5)CH3, (CH2)4OR5, CH2SR6, CH2CH2SCH3, (CH2)4NR7R8,
(CH2)3NHC(NH)(NH2), CH2C02Rc, CH2CH2C02Rc, CH2CONR9R10,
CH2CH2CONR9R10,
Figure imgf000006_0002
Ry denotes (CH2)uC(0)Rp or (CH2)uC02Rc when G1 denotes a bond;
Ry denotes (CH2)uC(0)Rp, (CH2)uC02Rc or CH2P(R14)2 when G1 and G2 together denote -C(=0)(CH2)t(C(=0))vNR9;
Ry denotes NHRP or N(Rb)2 when G1 denotes -C(=0)(CH2)u-;
Rz denotes C(0)Rp, C02Rc or CH2P(R14)2;
each Ra independently denotes halogen, OH, N02, CrC4-alkyl, CrC4-alkoxy or N(Rb)2;
each Rb independently denotes hydrogen, CrC4-alkyl, -CH2C6H5,
(CH2)1-4C02Rc, phenyl or PGam;
each Rc independently denotes hydrogen, d-C4-alkyl, or PGac;
R9 denotes hydrogen or CrC4-alkyl;
R5 denotes hydrogen, C C4-alkyl, OS02C C6-alkyl, OS02-C C6-fluoroalkyl; OS02-phenyl optionally substituted with 1 to 5 Ra; or PGal;
R6 denotes hydrogen or CrC4-alkyl; R7 and R8 independently denote Rb;
R9 and R10 independently denote hydrogen or CrC4-alkyl;
R11 denotes hydrogen, Ci-C4-alkyl or CrC4-alkylene-P(R14)2;
R12 denotes hydrogen, Ci-C4-alkyl or CrC4-alkylene-P(R14)2;
R13 denotes hydrogen, OH, C C4-alkoxy, OS02Ci-C6-alkyl,
OS02-CrC6-fluoroalkyl; OS02-phenyl optionally substituted with 1 to 5 Ra;
R14 denotes CrC4-alkyl, cyclohexyl, adamantyl, or phenyl optionally substituted with 1 to 5 Ra;
Rp denotes a peptide which optionally links the compound of formula (I) to a co-active;
PGac denotes a protecting group for a carboxylic acid;
PGam denotes a protecting group for an amine; and
PGal denotes a protecting group for an alcohol,
wherein optionally L may derive from a G substituent in an identical compound of formula (la), such that a macrocycle containing two Au atoms is formed, with the L substituent on each Au metal atom deriving from the G substituent on the corresponding compound of formula (la).
In preferred embodiments, the present invention relates to a compound of formula (lb) for use in therapy
Ry
Figure imgf000007_0001
(lb)
wherein
L denotes P(R1)3 or N /
N
each R1 independently denotes Ci-C4-alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 Ra
Figure imgf000008_0001
R2 denotes H, -(CH2)kC(0)NR3R3;
k denotes an integer from 0 to 4;
each R3 independently denotes H, d-C4-alkyl, S02R;
A denotes S02 or C(=0);
R denotes hydrogen, CrC6-alkyl or CrC6-fluoroalkyl; phenyl optionally substituted with 1 to 5 Ra; or a pyridinyl which is optionally quaternized with hydrogen or methyl;
G1 denotes a bond, -C(=0)(CH2)u- or -C(=0)-(CH2)t-G2;
G2 denotes (C(=0))vNR9; or
G2 and CHRxRy together denote
Figure imgf000008_0002
t denotes an integer from 1 to 4;
u denotes 0 or 1 ;
v denotes 0 or 1 ;
Rx denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
CH(OR5)CH3, (CH2)4OR5, CH2SR6, CH2CH2SCH3, (CH2)4NR7R8, (CH2)3NHC(NH)(NH2), CH2C02Rc, CH2CH2C02Rc, CH2CONR 9D R10
CH2CH2CONR9R10,
Figure imgf000009_0001
Ry denotes (CH2)uC(0)Rp or (CH2)uC02Rc when G1 denotes a bond;
Ry denotes (CH2)uC(0)R , (CH2)uC02Rc or CH2P(R14)2 when G1 and G2 together denote -C(=0)(CH2)t(C(=0))vNR9;
Ry denotes NHRP or N(Rb)2 when G1 denotes -C(=0)(CH2)u-;
Rz denotes C(0)R , C02Rc or CH2P(R14)2;
each Ra independently denotes halogen, OH, N02, CrC4-alkyl, CrC4-alkoxy or N(Rb)2;
each Rb independently denotes hydrogen, CrC4-alkyl, -CH2C6H5,
(CH2)1-4C02Rc, phenyl or PGam;
each Rc independently denotes hydrogen, d-C4-alkyl, or PGac;
R9 denotes hydrogen or CrC4-alkyl;
R5 denotes hydrogen, C C4-alkyl, OS02C C6-alkyl, OS02-C C6-fluoroalkyl; OS02-phenyl optionally substituted with 1 to 5 Ra; or PGal;
R6 denotes hydrogen or CrC4-alkyl;
R7 and R8 independently denote Rb;
R9 and R10 independently denote hydrogen or CrC4-alkyl;
R denotes hydrogen, CrC4-alkyl or CrC4-alkylene-P(R )2;
R12 denotes hydrogen, CrC4-alkyl or CrC4-alkylene-P(R14)2;
R13 denotes hydrogen, OH, C C4-alkoxy, OS02C C6-alkyl,
OS02-C C6-fluoroalkyl; OS02-phenyl optionally substituted with 1 to 5 Ra;
R14 denotes CrC4-alkyl, cyclohexyl, adamantyl, or phenyl optionally substituted with 1 to 5 Ra;
R denotes a peptide which optionally links the compound of formula (I) to a co-active;
PGac denotes a protecting group for a carboxylic acid;
PGam denotes a protecting group for an amine; and denotes a protecting group for an alcohol.
The compounds of the present invention can be formed by functionalising the C-terminus of an a- or β-amino acid. Thus, the present invention preferably relates to a compound of formula (lc') or (lc") for use in therapy
Figure imgf000010_0001
wherein
L denotes P(R1)3 or
Figure imgf000010_0002
each R1 independently denotes CrC4-alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 Ra;
each R4 independently denotes CrC4-alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 Ra;
Rx denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
CH(OR5)CH3, (CH2)4OR5, CH2SR6, CH2CH2SCH3, (CH2)4NR7R8,
(CH2)3NHC(NH)(NH2), CH2C02Rc, CH2CH2C02Rc, CH2CONR9R10,
CH2CH2CONR9R10,
Figure imgf000011_0001
RN denotes NHRP or NRbRd;
Rd denotes Rb; or
Rd and Rx may together form -(CH2)3-;
u denotes 0 or 1 ; and
A, R, R5, R6, R7, R8, R9, R10, R11, R12, R13, Ra, Rb, Rc and Rp are as defined for the compound of formula (lb).
The compounds of the present invention can also be formed by including a linker group between the N-terminus of an a- or β-amino acid and the coordinating nitrogen atom. Thus, the present invention preferably relates to a compound of formula (Id') or (Id") for use in therapy
Figure imgf000011_0002
')
Figure imgf000011_0003
(Id")
wherein L denotes P(R1)3 or
Figure imgf000012_0001
each R1 independently denotes Ci-C4-alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 Ra;
each R4 independently denotes CrC4-alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 Ra;
R9 denotes Rb;
Rx denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
CH(OR5)CH3, (CH2)4OR5, CH2SR6, CH2CH2SCH3, (CH2)4NR7R8,
(CH2)3NHC(NH)(NH2)., CH2C02Rc, CH2CH2C02Rc, CH2CONR9R10,
9R10,
Figure imgf000012_0002
R9 and Rx may together form -(CH2)3-;
u denotes 0 or 1 ;
v denotes 0 or 1 ; and
A, R, R5, R6, R7, R8, R9, R10, R11, R12, R13, Ra, Rb, Rc, Rz, and t are as defined for the compound of formula (lb).
In further embodiments, the compounds of the present invention can utilise the N-terminus of an a- or β-amino acid as the coordinating atom. Thus, the present invention preferably relates to a compound of formula (le') or (le") for use in therapy
Figure imgf000013_0001
(le') (le")
wherein
L denotes P(R1)3 or
R4
Figure imgf000013_0002
each R1 independently denotes Ci-C4-alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 Ra;
each R4 independently denotes CrC4-alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 Ra;
Rx denotes methyl, ethyl isopropyl, sec-butyl, 2-methyl-propyl, CH(OR5)CH3, (CH2)4OR5, CH2SR6, CH2CH2SCH3, (CH2)4NR7R8, (CH2)3NHC(NH)(NH2),
CH2C0 c, CH2CH2C02Rc, CH2CONR9R10, CH2CH2CONR9R10,
Figure imgf000013_0003
the compound of formula (lb). In some embodiments, the compound of formula (I) does not contain a group deriving from an a- or β-amino acid.
Thus, the present invention preferably relates to compounds of formula (If) use in therapy
Figure imgf000014_0001
(if)
wherein
L denotes P(R1)3 or
R4
Figure imgf000014_0002
each R1 independently denotes CrC4-alkyl, cyclohexyl, adamantyl; or phenyl optionally substituted with 1 to 5 Ra;
each R4 independently denotes CrC4-alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 Ra;
A denotes S02 or C(=0);
R denotes hydrogen, d-C6-alkyl or CrC6-fluoroalkyl; phenyl optionally substituted with 1 to 5 Ra; or a pyridinyl which is optionally quaternized with hydrogen or methyl;
G denotes hydrogen, CrC6-alkyl, C3-C6-cycloalkyl, phenyl optionally substituted with 1 to 5 Ra; naphthyl optionally substituted with 1 to 5 Ra; C5-Ci0- heteroaryl optionally substituted with 1 to 5 Ra; or A-R;
each Ra independently denotes halogen, OH, N02, CrC4-alkyl, CrC4-alkoxy or N(Rb)2;
each Rb independently denotes hydrogen, CrC4-alkyl, (CH2)i-4C02Rc or p Gam. each Rc independently denotes hydrogen, CrC4-alkyl, or PGac;
PGac denotes a protecting group for a carboxylic acid; and
PGam denotes a protecting group for an amine.
As noted above, in the compounds of formula (lb), the C-terminal carboxylic acid may be replaced with a phosphine group denoted as CH2P(R14)2- In such embodiments, the N(AR)G moiety contains two coordinating groups, that is a coordinating group on the G substituent in addition to the N(AR)G nitrogen coordinating group. It is therefore possible to form macrocyclic compounds containing two Au metal atoms and two N(AR)G moieties, wherein each compound of formula (I) bonds to both metal atoms and the ligands are arranged "top-to-tail" as shown below:
Figure imgf000015_0001
For ease of reference, this can be represented as a compound of formula
(II)
Figure imgf000015_0002
(II)
Thus, the present invention preferably relates to a compound of formula (I la*) or (lla") for use in therapy
Figure imgf000016_0001
(Ma*) (Ma")
wherein
Y denotes
Figure imgf000016_0002
w denotes an integer from 1 to 4;
u denotes 0 or 1 ;
RN denotes NHRP or NRbRb and
A, R, R2, R3, R14, Rb and Rp are as defined for the compound of formula (lb).
Preferably, the present invention relates to a compound of formula (lib') or ) for use in therapy
I ifuinno
Figure imgf000016_0003
(lib')
Figure imgf000017_0001
(lib")
wherein
t denotes an integer from 1 to 4;
v denotes 0 or 1 ;
Rz denotes C(0)Rp or C02Rc;
Y is as defined for the compound of formula (I la); and
A, R, Rb, Rc, Rp, and u are as defined for the compound of formula (lb).
Preferably, the present invention relates to a compound of formula (lie') ) for use in therapy
Figure imgf000017_0002
')
Figure imgf000017_0003
(lie")
wherein
u denotes 0 or 1 ;
v denotes 0 or 1 ;
R9 denotes Rb;
Rx denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
CH(OR5)CH3, (CH2)4OR5, CH2SR6, CH2CH2SCH3, (CH2)4NR7R8,
(CH2)3NHC(NH)(NH2), CH2C02Rc, CH2CH2C02Rc, CH2CONR9R10,
CH2CH 9R10,
Figure imgf000018_0001
R9 and Rx may together form -(CH2)3-; and
t, A, R, R1, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, Rb and Rc are as defined for the compound of formula (lb).
Preferably, in the compounds of formula (I), (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), and (lie),
R denotes CrC6-alkyl, CrC6-fluoroalkyl; or phenyl optionally substituted with 1 to 5 Ra.
Preferably, in the compounds of formula (I), (la), (lb), (Ic), (Id), (le), (If), ((lla), (lib), and (lie),
A-R denotes S02CH3, S02Ci-C6-perfluoroalkyl, S02C6H5Me, S02C6H5N02 or COC6H5Br.
Preferably, in the compounds of formula (I), (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), and (lie),
A-R denotes S02CH3, S02CF3, S02C6H5Me, S02C6H5N02 or COC6H5Br. Preferably, in the compounds of formula (I), (la), (lb), (Ic), (Id), (le), and (If), L denotes P(R1)3.
Preferably, in the compounds of formula (I), (la), (lb), (Ic), (Id), (le), and (If), L denotes P(R1)3; and
R1 denotes CH3, C2H5; or phenyl optionally substituted with 1 to 5 Ra.
Preferably, in the compounds of formula (I), (la), (lb), (Ic), (Id), (le), and (If), L denotes P(CH3)3, P(C2H5)3 or PPh3.
Preferably, in the compounds of formula (I), (la), (lb), (Ic), (Id), (le), and (If), L denotes P(R1)3; and
R1 denotes phenyl optionally substituted with 1 to 5 Ra.
Preferably, in the compounds of formula (I), (la), (lb), (Ic), (Id), (le), and (If), L denotes PPh3.
Preferably, in the compounds of formula (I la), (lib), and (lie),
R14 denotes CH3, C2H5; or phenyl optionally substituted with 1 to 5 Ra.
Preferably, in the compounds of formula (I la), (lib), and (lie),
R14 denotes CH3 or phenyl.
Preferably, in the compounds of formula (I la), (lib), and (lie),
R14 denotes phenyl.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le) and (lie) R5 denotes hydrogen, C C4-alkyl, OS02Ci-C6-alkyl, OS02-C C6-fluoroalkyl; OS02-phenyl optionally substituted with 1 to 5 Ra.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le) and (lie) R5 denotes hydrogen, C C4-alkyl, S02C C6-alkyl, S02-C C6-fluoroalkyl, S02C6H5Me, or S02C6H5N02.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le) and (lie) R5 denotes hydrogen, C C4-alkyl, S02CH3, S02CF3, S02C6H5Me, or
Figure imgf000020_0001
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le) and (lie) R5 denotes hydrogen or C C4-alkyl.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le) and (lie) R5 denotes hydrogen.
Preferably, in the compounds of formula (la), (lb), (Id), (lib) and (lie), v denotes 1 ; and
t denotes an integer from 2 to 4.
Preferably, in the compounds of formula (la), (lb), (Id), (lib) and (lie), v denotes 1 ; and
t denotes 2.
Preferably, in the compounds of formula (la), (lb), (Id), (lib) and (lie), v denotes 0.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), and (lie),
Rb denotes hydrogen, C C4-alkyl, -CH2C6H5, (CH2)1-4C02CH3, or phenyl.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), and (lie),
Rb denotes hydrogen, C C4-alkyl, or (CH2)1-4C02CH3.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), and (lie),
Rb denotes hydrogen, C C4-alkyl, -CH2C6H5, or phenyl.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), and (lie),
Rb denotes hydrogen or C C4-alkyl. Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), and (lie),
Rc denotes hydrogen or C C4-alkyl.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), and (lie),
Rc denotes hydrogen or methyl.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), and (lie),
Rc denotes methyl.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), and (lie),
Rc denotes hydrogen.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le), (lla), (lib), and (lie),
u is 0.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le), (lla), (lib), and (lie),
u is 1.
Preferably, in the compounds of formula (lla), and (lib),
w is 1 or 2.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le), and (lie), R11 denotes hydrogen or Ci-C4-alkyl; and
R12 denotes hydrogen or C C4-alkyl.
Preferably, in the compounds of formula (la) and (lb),
G1 denotes a bond Preferably, in the compounds of formula (la) and (lb), G1 denotes a bond; and
Ry denotes (CH2)uC02Rc.
Preferably, in the compounds of formula (la) and (lb), G denotes a bond; and
Ry denotes (CH2)uC(0)Rp.
Preferably, in the compounds of formula (la) and (lb), G1 denotes -C(=0)(CH2)u-.
Preferably, in the compounds of formula (la) and (lb), G1 denotes -C(=0)(CH2)u-; and
Ry denotes NHR .
Preferably, in the compounds of formula (la) and (lb), G1 denotes -C(=0)(CH2)u-; and
Ry denotes N(Rb)2.
Preferably, in the compounds of formula (la) and (lb), G denotes -C(=0)-(CH2)rG2; and
G2 denotes (C(=0))vNRs.
Preferably, in the compounds of formula (la) and (lb),
G1 denotes -C(=0)-(CH2)t-G2;
G2 denotes (C(=0))vNR9; and
Ry denotes (CH2)uC(0)Rp or (CH2)uC02Rc.
Preferably, in the compounds of formula (la) and (lb), G1 denotes -C(=0)-(CH2)t-G2;
G2 denotes (C(=0))vNR9; and
Ry denotes (CH2)uC(0)Rp,.
Preferably, in the compounds of formula (la) and (lb), G1 denotes -C(=0)-(CH2)t-G2; G2 denotes (C(=0))vNR9; and
Ry denotes (CH2)uC02Rc.
Preferably, in the compounds of formula (la) and (lb),
G1 denotes -C(=0)-(CH2)t-G2;
G2 denotes (C(=0))vNR9; and
Ry denotes CH2P(R14)2.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le), and (lie), Rx denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
CH(OR5)CH3, (CH2)4OR5, CH2SR6, CH2CH2SCH3, (CH2)4NR7R8, CH2C02Rc, c, CH2CONR9R10, CH2CH2CONR9R10,
Figure imgf000023_0001
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le), and (lie), Rx denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
CH(OR5)CH3, (CH2)4OR5, CH2SR6, CH2CH2SCH3, (CH2)4NR7R8,
Figure imgf000024_0001
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le), and (lie), x denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
Figure imgf000024_0002
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le), and (lie), Rx denotes methyl, isopropyl, sec-butyl or 2-methyl-propyl.
Preferably, in the compounds of formula (la), (lb), (Id), (le), and (lib), Rz denotes C(0)Rp or C02Rc. Preferably, in the compounds of formula (la), (lb), (Id), (le), and (lib), Rz denotes C(0)Rp.
Preferably, in the compounds of formula (la), (lb), (Id), (le), and (lib), Rz denotes C02Rc.
Preferably, in the compounds of formula (la), (lb), (Id), and (le),
Rz denotes CH2P(R14)2.
Preferably, in the compounds of formula (la), (lb), (Id), and (le),
Rz denotes CH2P(R14)2; and
R14 both denote CrC4-alkyl or phenyl.
Preferably, in the compounds of formula (Ic) and (lla),
RN denotes NHRP.
Preferably, in the compound of formula (Ic)
RN denotes NRbRd.
Preferably, in the compound of formula (lla)
RN denotes NRbRb.
Preferably, in the compounds of formula (I), (la), (lb), (Ic), (Id), (le), (lla), and
(lib),
Rp denotes a peptide having from 1 to 50 amino acids.
Preferably, in the compounds of formula (I), (la), (lb), (Ic), (Id), (le), (lla), and
(lib),
Rp denotes a peptide having from 1 to 30 amino acids.
Preferably, in the compounds of formula (I), (la), (lb), (Ic), (Id), (le), (lla), and
(lib),
R denotes a peptide having from 1 to 20 amino acids. Preferably, in the compounds of formula (I), (la), (lb), (Ic), (Id), (le), (lla), and
(lib),
Rp denotes a peptide having from 2 to 10 amino acids.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le),
R13 denotes OH, C C4-alkoxy, OS02Ci-C6-alkyl, OS02-CrC6-fluoroalkyl; OS02-phenyl optionally substituted with 1 to 5 Ra;
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le),
R13 denotes OH, C C4-alkoxy, OS02Ci-C6-alkyl, OS02-C C6-fluoroalkyl, OS02C6H5Me, or OS02C6H5N02.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le),
R13 denotes OH, OS02CH3, OS02CF3, OS02C6H5Me, or OS02C6H5N02.
Preferably, in the compounds of formula (la), (lb), (Ic), (Id), (le),
R13 denotes OH
Preferably, in the compounds of formula (I), (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), and (lie),
the Au atom is Au(l).
Preferably, in the compounds of formula (If),
L denotes P(R1)3;
R1 denotes d-C4-alkyl or phenyl;
A denotes S02 or C(=0);
R denotes hydrogen, C C6-alkyl or CrC6-fluoroalkyl; or phenyl optionally substituted with 1 to 5 Ra;
G denotes hydrogen, C C6-alkyl, C3-C6-cycloalkyl, or A-R;
each Ra independently denotes halogen, OH, N02, C C4-alkyl, C C4-alkoxy or N(Rb)2;
each Rb independently denotes hydrogen, C C4-alkyl, CH2C6H5, phenyl or (CH2)1-4C02Rc;
each Rc independently denotes hydrogen or CrC -alkyl. Preferably, in the compounds of formula (If),
L denotes P(R1)3;
R1 denotes CrC4-alkyl or phenyl;
G denotes A-R; and
A-R denotes S02CH3, S02Ci-C6-perfluoroalkyl, SC^CeHsMe, SO2C6H5NO2 or COC6H5Br.
Preferably, in the compounds of formula (If),
L denotes P(R1)3;
R1 denotes Ci-C4-alkyl or phenyl;
G denotes A-R; and
A-R denotes A-R denotes S02CH3, S02CF3, S02C6H5Me, SO2C6H5NO2 or COC6H5Br.
Without wishing to be bound by theory, it is believed that the compounds described above are therapeutically active due to the gold-nitrogen bond.
Therapeutically active compounds containing gold-nitrogen bonds are not commonplace. Amagi et al. have reported therapeutically active compounds containing gold-nitrogen bonds. However, these derive from 5-fluorouracil compounds that themselves are therapeutically active (see Bull. Chem. Soc. Jpn. 62, 1078-1080).
It has surprisingly been found that gold-nitrogen compounds can themselves be therapeutically active, providing the chemical environment of the nitrogen atom is stable enough to remain in solution in vivo, yet capable of allowing the gold atom to react to provide a therapeutic effect.
One way of achieving this chemical environment is by utilising a compound of formula (I) as described herein, which contain a gold atom coordinated to an N- AR moiety, which contains a highly electron withdrawing AR group. An alternative chemical environment that has been found to provide gold-nitrogen compounds showing therapeutic activity is gold-N-heteroaromatic compounds.
Thus, a further embodiment of the invention relates to compounds of formula (III) for use in therapy
Figure imgf000028_0001
(III)
wherein
each of Xi, X2, X4 and X5 denotes N, CR15 or CR16,
X3 denotes N, CR15, CR16 or O, providing that
and X2 do not both denote N,
X4 and X5 do not both denote N,
when X3 denotes O, X2 and X4 denote CR16, and
only one of Xi, X2, X3, X4 and X5 denotes CR15;
L denotes P(R1)3 or
Figure imgf000028_0002
each R1 independently denotes CrC4-alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 Ra;
each R4 independently denotes CrC4-alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 Ra;
R15 denotes O" C02 ", NRb ", N-AR", A-N-A-R", ANRb " or R17, providing that when R15 denotes R17, the compound of formula (III) is accompanied by a counterion Z~;
A denotesS02 or C(=0);
R denotes hydrogen, d-C6-alkyl or CrC6-fluoroalkyl; or phenyl optionally substituted with 1 to 5 Ra;
each R16 independently denotes hydrogen, halogen, OH, N02, CrC4-alkyl, CrC4-alkoxy, C(0)ORc, C(0)N(Rb)2, N(Rb)2, S02R, S02OR or S02N(Rb)2,
wherein two adjacent R16 groups may together form -(CH)4-, -N(CH)3-, -CHN(CH)2-, -NN(CH)2-,-NCHNCH-, -N(CH)2N-, -CHNHCH-, -NH(CH)2-, -NHCHN-, -NHNCH-; each Ra independently denotes halogen, OH, N02, CrC4-alkyl, CrC4-alkoxy or N(Rb)2;
each Rb independently denotes hydrogen, d-C4-alkyl, -CH2C6H5, or (CH2)i-4C02Rc, or phenyl;
each Rc independently denotes hydrogen or CrC4-alkyl;
R17 denotes hydrogen, halogen, CrC4-alkyl, CrC4-alkoxy, C(0)ORc, C(0)N(Rb)2, N(Rb)2, S02R, S02OR or S02N(Rb)2; and
Z~ denotes a pharmaceutically acceptable anion.
Preferably, in the compound of formula (III),
one of X-i, X2, X3, X4 or X5 denotes CR15, with the remaining moieties denoting CR16.
Preferably, in the compound of formula (III),
Xi denotes CR15, and
X2, X3, X4 and X5 denote CR16.
Preferably, in the compound of formula (III),
Xi denotes CR15,
X2 denotes N, and
X3, X4 and X5 denote CR16.
Preferably, in the compound of formula (III),
Xi denotes CR15,
X4 denotes N, and
X2, X3 and X5 denote CR16.
Preferably, in the compound of formula (III),
Xi denotes CR15,
X3 denotes N, and
X2, X4 and X5 denote CR16.
Preferably, in the compound of formula (III),
Xi denotes CR15,
X3 denotes O, and X2, X4 and X5 denote CR16.
Preferably, in the compound of formula (III),
Xi denotes CR15,
X5 denotes N, and
X2, X3 and X4 denote CR16.
Preferably, in the compound of formula (III),
A-R denotes S02CH3, S02Ci-C6-perfluoroalkyl, S02C6H5Me, S02C6H5N02 6H5Br.
Preferably, in the compound of formula (III),
A-R denotes S02CH3, S02CF3, S02C6H5Me, S02C6H5N02 or COC6H5Br.
Preferably, in the compound of formula (III),
L denotes P(R1)3.
Preferably, in the compound of formula (III),
L denotes P(R1)3; and
R1 denotes CH3, C2H5; or phenyl optionally substituted with 1 to 5 Ra.
Preferably, in the compound of formula (III),
L denotes P(CH3)3, P(C2H5)3 or PPh3.
Preferably, in the compound of formula (III),
L denotes PPh3.
Preferably, in the compound of formula (III),
R15 denotes O", C02 ", NRb ~, N-AR", A-N-A-R" or ANRb ~.
Preferably, in the compound of formula (III),
R15 denotes O", C02 ", NRb ", N-AR" or ANRb ".
Preferably, in the compound of formula (III),
R15 denotes O", C02 ", NRb ~, N-AR", ANRb ~ or R17. Preferably, in the compound of formula (III),
R15 denotes O" C02 ", CONRb ", NRb " or N-AR".
Preferably, in the compound of formula (III),
R15 denotes CONRb ", NRb ", N-AR" or R17.
Preferably, in the compound of formula (III),
R15 denotes CONRb ", NRb ", or N-AR".
Preferably, in the compound of formula (III),
R15 denotes NRb " or N-AR".
Preferably, in the compound of formula (III),
R15 denotes N-AR" or R17.
Preferably, in the compound of formula (III),
R15 denotes N-AR".
Preferably, in the compound of formula (III),
R15 denotes R17.
Preferably, in the compound of formula (III),
each R16 independently denotes hydrogen, halogen, OH, N02, CrC4-alkyl, CrC4-alkoxy, C(0)ORc, C(0)N(Rb)2 or N(Rb)2,
wherein two adjacent R16 groups may together form -(CH)4- or -N(CH)3-.
Preferably, in the compound of formula (III),
each R16 independently denotes hydrogen, halogen, N02, CrC4-alkyl, or CrC4-alkoxy,
wherein two adjacent R16 groups may together form -(CH)4- or -N(CH)3-.
Preferably, in the compound of formula (III),
each R16 independently denotes hydrogen, halogen, OH, N02, CrC4-alkyl, CrC4-alkoxy, C(0)ORc, C(0)N(Rb)2 or N(Rb)2, wherein two adjacent R16 groups may together form -(CH)4-. Preferably, in the compound of formula (III),
each R16 independently denotes hydrogen, halogen, N02, CrC4-alkyl, or CrC4-alkoxy,
wherein two adjacent R16 groups may together form -(CH)4-.
Preferably, in the compound of formula (III),
each R16 independently denotes hydrogen or CrC4-alkyl,
wherein two adjacent R16 groups may together form -(CH)4-.
Preferably, in the compound of formula (III),
each R16 independently denotes hydrogen,
wherein two adjacent R16 groups may together form -(CH)4-.
Preferably, in the compound of formula (III),
each R16 independently denotes hydrogen, halogen, OH, N02, C C4-alkyl, Ci-C4-alkoxy, C(0)ORc, C(0)N(Rb)2 or N(Rb)2.
Preferably, in the compound of formula (III),
each R16 independently denotes hydrogen, halogen, N02, CrC4-alkyl, or Ci-C4-alkoxy.
Preferably, in the compound of formula (III),
each R16 independently denotes hydrogen or Ci-C -alkyl.
Preferably, in the compound of formula (III),
each R16 independently denotes hydrogen.
Preferably, in the compound of formula (III),
R17 denotes hydrogen, halogen, C C4-alkyl, C C4-alkoxy, C(0)ORc, C(0)N(Rb)2, or N(Rb)2.
Preferably, in the compound of formula (III), R17 denotes hydrogen, halogen, C C4-alkyl, C C4-alkoxy, C(0)N(Rb)2, N(Rb)2, S02R, or S02N(Rb)2.
Preferably, in the compound of formula (III),
R17 denotes hydrogen, halogen, Ci-C4-alkyl, or Ci-C4-alkoxy
Preferably, in the compound of formula (III),
R17 denotes hydrogen.
Preferably, in the compound of formula (III),
each Rc denotes CrC4-alkyl.
Preferably, in the compound of formula (III),
Z" denotes CI", Br", HS04 ", S03NH2 ", H2P04 ", N03 ", acetate, propionate, succinate, glycolate, stearate, lactate, malate, tartarate, citrate, ascorbate, palmate, maleate, hydroxymaleate, phenylacetate, glutamate, benzoate, salicyclate, sulfanilate, 2-acetoxybenzoate, fumarate, toluenesulfonate, methanesulfonate, ethane disulphonate, trifluoromethanesulphonate, oxalate, or isethionate.
Preferably, in the compound of formula (III),
Z" denotes CI", Br", HS04 ", S03NH2 ", H2P04 ", N03 ", acetate, propionate, succinate, glycolate, stearate, lactate, malate, tartarate, citrate, ascorbate, palmate, maleate, hydroxymaleate, phenylacetate, glutamate, benzoate, salicyclate, sulfanilate, 2-acetoxybenzoate, fumarate, toluenesulfonate, methanesulfonate, ethane disulphonate, trifluoromethanesulphonate, oxalate, or isethionate.
Preferably, in the compound of formula (III),
Z" denotes CI", Br", HS04 ", S03NH2 ", H2P04 ", N03 ", acetate, propionate, succinate, glycolate, stearate, lactate, malate, tartarate, citrate, ascorbate, maleate, hydroxymaleate, glutamate, benzoate, salicyclate, fumarate, toluenesulfonate, or oxalate.
Preferably, in the compound of formula (III), Z~ denotes CP, ΒΓ, HS04 ~, acetate, propionate, succinate, glycolate, stearate, lactate, malate, tartarate, citrate, ascorbate, maleate, hydroxymaleate, glutamate, benzoate, fumarate, or oxalate.
Preferably, in the compound of formula (III),
the Au atom is Au(l).
When present in the compounds of the invention, the peptide group R may serve one of several roles. It could be an agonist or antagonist, or may serve as a biologically tolerable linking group to a co-active.
By "co-active" is meant a compound that is induces a biological response in a subject treated by the compound. A co-active can be therapeutically active (i.e. a drug).
In some embodiments, the peptide group is not linked to a co-active.
In some embodiments, R is an agonist or antagonist.
It is to be understood that where the preferred embodiments mentioned above are not mutually exclusive, they can be combined with one another. For example, the skilled person would understand that the above preferred
embodiments in which Ar1 denotes phenyl optionally substituted with one or more R can be combined with the preferred embodiments in which R denotes
independently denotes F, CI, CF3, OR1, C(=0)Y, C C4-alkyl or C C4-alkyl-phenyl. The same holds true for the other non-mutually exclusive preferred embodiments mentioned above. The skilled person would understand which embodiments where mutually exclusive and would thus readily be able to determine the combinations of preferred embodiments that are contemplated by the present application.
As used herein, "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "CrC6 alkyl" is intended to include Ci , C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.
By "haloalkyl" is meant both branched and straight chain saturated ali aliphatic hydrocarbon groups having the specified number of carbon atoms, wherein at least one of the hydrogen atoms has been replaced by F, CI, Br or I. Preferably, haloalkyl refers to perfluoralkyl. The term "cycloalkyl" refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl and the like. Branched cycloalkyl groups such as 1 -methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl".
As used herein, the term "aryl", is intended to mean an aromatic moiety containing, if specified, the specified number of carbon atoms; for example phenyl or naphthyl.
As used herein, the term "heteroaryl", is intended to mean an aromatic moiety containing, if specified, the specified number of atoms with at least one of the ring atoms being selected from N, O or S. Examples of heteroaryl rings include pyrrole, furan, thiophene, imidazole, pyrazole, 1 ,2,3-triazole, 1 ,2,4-triazole, tetrazole, thiazole, oxazole, isooxazole, benzofuran, isobenzofuran, indole, isoindole, benzothiophene, benzo[c]thiophene, benzimidazole, indazole, purine, benzoxazole, benzothiazole, pyridine, pyrimidine, pyrazine, pyrazidine, quinoline, isoquinoline, quinoxaline, quinazoline and cinnoline.
As described above, protecting groups may be present in the compounds of the present invention. The use of protecting groups is well known in the art (see for example, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Edn., John Wiley & Sons). The skilled person will be aware of particular groups available for protecting amine, amide, carboxylic acid and alcohol groups, and the conditions under which protection and deprotection can occur. Any suitable protecting groups may be present in the compounds of the invention, either to aid in the synthesis of the compounds of formula I, or to prevent unwanted side reactions occurring with reactive side groups in the compounds of formulae II and III.
Suitable protecting groups for an amine include carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC),
9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn) group, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP) group, tosyl (Ts), nosyl (Ns) and other sulfonamides.
Suitable protecting groups for a carboxylic acid include benzyl and alkyl esters, silyl esters, orthoesters and oxazoline.
Suitable protecting groups for an alcohol include acetyl (Ac) benzoyl, benzyl (Bn), β-methoxyethoxymethyl ether (MEM), dimethoxytrityl
[bis-(4-methoxyphenyl)phenylmethyl, DMT] methoxymethyl ether (MOM) methoxytrityl [(4-methoxyphenyl)diphenylmethyl, MMT), p-methoxybenzyl ether (PMB), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyranyl (THP), trityl (triphenylmethyl, Tr), silyl ethers such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tert-butyldimethylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), methyl ethers and ethoxyethyl ethers (EE).
The compounds of the invention which contain an amino acid derivative may be synthesised from suitable amino acids using a variety of synthetic strategies. For example, a typical synthetic routes are shown in the following schemes:
Figure imgf000036_0001
Scheme 1
The synthesis in Scheme 1 can be modified to introduce different functionalities onto the amino acid nitrogen atom, as shown in Schemes 2:
Figure imgf000037_0001
Figure imgf000037_0002
Scheme 2
Protection of the carboxylic acid can also allow functionalisation of the amino acid nitrogen to allow coordination to a metal centre, either directly (Scheme 3) or via a linker group (Scheme 4):
ethane nhydride, ine
Figure imgf000037_0003
Scheme 3 amino hydride
Figure imgf000038_0001
Scheme 4
The carboxylic acid moiety in the amino acid may also be removed (for example with lithium aluminium hydride (LAH)) to allow functionalisation with a phosphine moiety, as shown in Scheme 5:
Figure imgf000039_0001
Scheme 5
The methodology in Scheme 5 is in principle possible using any amino acid. However, it is preferable to use those an amino acid that does not contain a carboxylic acid in the side chain so as to avoid competing reactions in the final step.
An example of a typical synthetic route according to Scheme 5 is shown below in Scheme 6:
Figure imgf000039_0002
S02CI2, NEt3 (2 eq.)
DCM, -78 C (3h), RT (70h)
Figure imgf000039_0003
Figure imgf000039_0004
Scheme 6
In the above schemes, Ram corresponds to an amino acid side chain, which may be protected as necessary. While the above schemes are shown with respect to α-L-amino acids, the methodologies described would be equally applicable to β and/or D-amino acids. Likewise, the amino acids may be coupled to a suitable peptide R using standard methodology.
The skilled person would also know how to modify the above synthetic routes to incorporate other functionalities into the compounds of the invention. For example, while the AR moiety is typically shown to be derived from triflic acid, it would be trivial for the skilled person to adapt the above synthetic schemes to incorporate other functional groups at this position. Thus, using benzyl chloride in place of trifluoromethane sulfonic anhydride in Scheme 3 would functionalise the compound with AR denoting PhC=0 in place of CF3S02.
Compounds which do not contain an amino acid group may be synthesised using standard methodology, for example as described in Organic Letters, 2005, Vol. 7, No. 19, pp4133-4136.
The compounds of the invention, namely compounds of formula (I), (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), (lie) and (III) as well as the preferred embodiments of these compounds described herein, are therapeutically active.
Thus, the present invention relates to a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), (lie) or (III) for use in therapy.
Preferably, the present invention relates to a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), (lie) or (III) for use in treating cancer.
Preferably, the present invention relates to a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), (lie) or (III) for use in treating cancer, wherein the cancer cells are hyperpolarised.
Preferably, the present invention relates to a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), (lie) or (III) for use in treating cancer, wherein the cancer cells comprise hyperpolarised mitochondria.
Preferably, the present invention relates to compound of formula (I), (la), (lb), (Ic), (Id), (le), (If), (lla), (lib), (lie) or (III) for use in treating cancer, wherein the cancer cells are characterised by overexpressing thioredoxin reductase.
Preferably, the cancer is selected from adenocarcinoma, malignant mesothelioma, thyroid cancer, prostate cancer or colorectal cancer.
Preferably, the cancer is a slow growing cancer.
By "slow growing cancer" is meant a tumour with a doubling time (i.e. the time taken to double in size) of at least 250 days. Viewed another way, a "slow growing cancer" is a cancer with an S-phase fraction of less than 6% (i.e. less than 6% of the cells in the cancer are in the process of dividing). Viewed another way, a "slow growing cancer" has less than 3.5% of the cells Ki-67 positive. Ki-67 is a marker to determine the growth of human cells. Methods for staining and detecting Ki-67 are described below.
Methods to determine whether a cancer is slow growing are provided below.
Preferably, the present invention relates to compound of formula (I), (la), (lb), (lc), (Id), (le), (If), (Ma), (Mb), (lie) or (III) for use in modifying the activity of a selenosulphide protein, preferably thioredoxin reductase.
Preferably, the present invention relates to compound of formula (I), (la), (lb), (lc), (Id), (le), (If), (I la), (lib), (lie) or (III) for use in inhibiting a selenosulphide protein, preferably thioredoxin reductase.
As used herein, "treating" refers to the reduction, alleviation or elimination, preferably to normal levels, of one or more of the symptoms of said disease, disorder or condition which is being treated, e.g. normal blood pressure, cardiac function, etc., relative to the symptoms prior to treatment. Where not explicitly stated, treatment encompasses prevention. "Preventing" refers to absolute prevention, i.e. maintenance of normal levels with reference to the extent or appearance of a particular symptom (e.g. hypertension) or reduction or alleviation of the extent or timing (e.g. delaying) of the onset of that symptom.
The present invention also relates to pharmaceutical compositions comprising a compound according to formula (I), (la), (lb), (lc), (Id), (le), (If), (I la), (lib), (lie) or (III) and one or more pharmaceutically acceptable excipients and/or diluents.
By "pharmaceutically acceptable" is meant that the ingredient must be compatible with other ingredients in the composition as well as physiologically acceptable to the recipient.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. "Pharmaceutically acceptable anion" refers to negative ions in pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's
Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
"Therapeutically effective amount" is intended to include an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to treat cancer in a host. The amount of each compound of the combination may be selected so that when the combination is administered, the effect of the combination is effective to treat cancer in a host.
Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the
administration of many of the chemotherapeutic agents is described in the
"Physicians' Desk Reference" (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, NJ 07645-1742, USA); the disclosure of which is incorporated herein by reference thereto.
An embodiment of the present invention also encompasses a
pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the combinations of this invention, with or without pharmaceutically acceptable carriers or diluents. The pharmaceutical composition of this invention may additionally comprise an optional anti-proliferative cytotoxic agent or agents, an optional quiescence agent, and a pharmaceutically acceptable carrier.
The compositions of the present invention may further comprise one or more pharmaceutically acceptable additional ingredient(s) such as alum, stabilizers, antimicrobial agents, buffers, coloring agents, flavoring agents, adjuvants, and the like. The compounds of the combination of the present invention and compositions of the present invention may be administered orally or parenterally including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
For oral use, the compounds of the combination and compositions of this invention may be administered, for example, in the form of tablets or capsules, powders, dispersible granules, or cachets, or as aqueous solutions or suspensions. In the case of tablets for oral use, carriers which are commonly used include lactose, corn starch, magnesium carbonate, talc, and sugar, and lubricating agents such as magnesium stearate are commonly added. For oral administration in capsule form, useful carriers include lactose, corn starch, magnesium carbonate, talc, and sugar. When aqueous suspensions are used for oral administration, emulsifying and/or suspending agents are commonly added. In addition, sweetening and/or flavoring agents may be added to the oral compositions. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient(s) are usually employed, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of the solute(s) should be controlled in order to render the preparation isotonic. In another embodiment of the present invention, the compounds of the combination or pharmaceutically acceptable salts thereof are formulated with a sulfobutylether-7-β- cyclodextrin or a 2-hydroxypropyl-p-cyclodextrin for intravenous administration.
For preparing suppositories according to the invention, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously in the wax, for example by stirring. The molten homogeneous mixture is then poured into conveniently sized molds and allowed to cool and thereby solidify.
Liquid preparations include solutions, suspensions and emulsions. Such preparations are exemplified by water or water/propylene glycol solutions for parenteral injection. Liquid preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
Also included are solid preparations which are intended for conversion, shortly before use, to liquid preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the combination described herein may also be delivered transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
The combinations may also be used in conjunction with other well known therapies that are selected for their particular usefulness against the condition that is being treated.
If formulated as a fixed dose, the active ingredients of the combination compositions of this invention are employed within the dosage ranges known to one skilled in the art. Alternatively, the compounds of the combination may be administered separately in the appropriate dosage ranges.
The invention also extends to pharmaceutical compositions as described above for use as a medicament.
The precise dosage of the active compound to be administered and the length of the course of treatment will of course, depend on a number of factors including for example, the age and weight of the patient, the specific condition requiring treatment and its severity, and the route of administration.
Thus, viewed from a further aspect the present invention preferably provides a method of treating cancer, preferably as described hereinbefore, in a human or non-human animal wherein a compound of formula (I), (la), (lb), (lc), (Id), (le), (If), (I la), (lib), (lie) or (III) is administered to said animal.
Alternatively stated, the present invention preferably provides the use of a compound of formula (I), (la), (lb), (lc), (Id), (le), (If), (Ma), (Mb), (lie) or (III) for the preparation of a medicament for the treatment of cancer, preferably as described hereinbefore.
Alternatively stated, the present invention preferably provides the use of a compound of formula (I), (la), (lb), (lc), (Id), (le), (If), (Ma), (Mb), (lie) or (III) in treating cancer. Preferably, these methods and uses relate to the treatment of the preferred cancers described hereinbefore, e.g. slow growing cancers, adenocarcimas, and cancers associated with hyperpolarised cells (typically hyperpolarised
mitochondria).
The method of treatment according to the invention may advantageously be combined with administration of one or more active ingredients which are effective in treating the disorder or disease to be treated. Thus, pharmaceutical
compositions of the invention may additionally contain one or more of such active ingredients.
The following Examples are given by way of illustration only in which the Figures referred to are as follows:
Figure 1 - Cell viability in response to gold(l) complexes. Cell viability was determined by measuring the fluorescence of untreated ('Medium'), DMSO-treated ('Ο μΜ'), and gold(l) treated cells. The 'No cells' control was used as background subtraction. The normalized fluorescence was calculated as the background- subtracted fluorescence reading, divided by the background-subtracted
fluorescence reading of the DMSO-treated control. The error bars correspond to the standard deviation of the mean of four to eight replicates. ND- not done.
Figure 2 - Cell viability in response to gold(l) complex 7. Cell viability was determined by measuring the fluorescence of untreated ('Medium'), DMSO-treated ('Ο μΜ'), and gold(l) treated cells. The normalized fluorescence was calculated as the background-subtracted fluorescence reading, divided by the background- subtracted fluorescence reading of the DMSO-treated control. The error bars correspond to the standard deviation of the mean of four to eight replicates.
Figure 3 - IC50 estimation for compounds 1 and 2. Representative response curves for CV-1 control cells and the two cancer cells lines are shown. The IC50 values were estimated from curve-fitting using GraphPad. S.E. represents the standard error of the mean, calculated from n independent experiments. Figure 4 - Cell viability assays for the ligands of compounds 1 and 2 using the resazurin reductase activity assay on breast cancer cell line MDA-MB-231 and control epithelial cell line (CV-1 ). Cell viability was determined by measuring the fluorescence of DMSO-treated (Ό μΜ'), and ligand treated cells. The 'No cells' control was used for background subtraction. The normalized fluorescence was calculated as the background-substracted fluorescence reading, divided by the background-subtracted fluorescence reading of the DMSO-treated control. The error bars correspond to the standard deviation of the mean of three replicates.
Figure 5 - Nigericin sensitizes CV-1 cells to gold(l) compounds. CV-1 and MDA- MB-231 cell lines were treated with increasing concentrations of nigericin in addition to 4.28 or 5 μΜ gold(l) compound (black bars) or 0 μΜ gold(l), (la), DMSO- treatment (grey bars). Ethanol-only treatment of the cell lines (no gold(l) compounds) was used as 'Ethanol' control. 'No cells' control was used for background subtraction. The error bars represent standard deviation of the mean of three replicates.
Figure 6 - TrxR activity in vitro is inhibited by gold(l) complexes. Increasing concentrations of compounds 1 and 2 or 'ligand only' were added to TrxR and GR enzymes and their activity monitored by fluorescence. Normalized fluorescence values were calculated by taking the fluorescence value of the treated well and dividing it by the fluorescence value of 0 nM compound (DMSO-only treatment).
Examples
All reagents and solvents were used without further purification from commercially available sources unless otherwise stated. Triflic amide was prepared using the procedure reported by Burdon et al., J. Chem. Soc, 1957, 2574. Dry diethyl ether and tetrahydrofuran were distilled from sodium/benzophenone under an atmosphere of nitrogen. Dichloromethane, toluene, triethylamine, and diisopropylamine were distilled from calcium hydride under atmosphere of nitrogen. Under anhydrous conditions, all apparatus was flame-dried before either cooling under reduced pressure (0.3 mmHg) or under a continuous flow of nitrogen or argon. Evaporation under reduced pressure was performed on a Buchi rotary evaporator, using a diaphragm pump. Reduced pressure was achieved by using a Leybold static oil pump (0.05 mmHg) unless otherwise stated. The IR spectra were recorded on spectrometer Perkin Elmer FT-IR Spectrum One equipped with a diamond top plate. Mass spectra were obtained using VG Autospec Magnetic Sector MS and Bruker Daltonic FT-ICR-MS Ape III instruments, using electron impact (El) or fast atom bombardment (FAB). The 1H nuclear magnetic resonance spectra were recorded on a Varian 400 (400 MHz) or Varian 500 (500 MHz).
Chemical shifts are reported in parts per million (ppm) relative to residual CHCI3 (5 7.26 ppm), H20 (δ 4.80 ppm), DMSO (δ 2.50 ppm), CH3OH (δ 4.87 ppm). The following abbreviations are used to describe the multiplicity of given signals: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, sex = sextet, sept = septet, m = multiplet and br = broad. Coupling constants, J, are given wherever appropriate in Hertz. The 13C nuclear magnetic resonance spectra were recorded on a Varian 500 (126 MHz). Chemical shifts are reported in parts per million (ppm) relative to CDCI3 (central line of triplet δ 77.00 ppm), DMSO (central line of septet δ 39.51 ppm), CD3OD (central line of septet δ 49.15 ppm). The following
abbreviations are used to describe the given signals: C = quaternary, CH = methane, CH2 = methylene, CH3 =methyl. The 31P nuclear magnetic resonance spectra were recorded on a Varian 400 (162 MHz) and are referenced to 85% phosphoric acid in water (δ 0 ppm). The 19F nuclear magnetic resonance spectra were recorded on a Varian 400 (376 MHz). The units for the reported [a]D values are: [a] = degcm3g~1dm~1, c = cgdrrf3. All reactions were monitored, where appropriate, by T.L.C. using Macherey-Nagel plates with a 0.2 mm layer of 60 F254 silica gel containing a fluorescent indicator. Visualization was achieved with U.V. light (254 mm) followed by an ethanolic solution of phosphomolibdic acid or aqueous solution of potassium permanganate. Flash column chromatography was carried out using Apollo Zeoprep 60 Hyd 35-70 micron silica gel. Petroleum ether (PET) usually refers to the fraction distilled narrow alkene hydrocarbons distillate fraction from crude oil in the 40 to 60 °C range, unless otherwise stated, and was distilled prior to use.
(2S)-3-(4-hydroxyphenyl)-1 -methoxy-1 -oxopropan-2-aminium chloride
Figure imgf000048_0001
Thionyl chloride (0.48 mL, 6.62 mmol) was added dropwise to a solution of /.-tyrosine (0.60 g, 3.31 mmol) in methanol (22 mL). The reaction was heated to reflux with vigorous stirring for 24 h. After cooling, the reaction mixture was concentrated under reduced pressure and the residual methanol removed by azeotropic distillation with dichloromethane (10 mL) under reduced pressure to give the title compound as a white solid (0.65 g, 84%).[a]D 23 0 = -4.7 (c = 1.00 in water); 1H NMR (500 MHz, D20) δ = 7.08 (2H, d, J=7.7, 6, 7-H), 6.83 (2H, d, J=7.7, 8, 9-H), 4.31 (1 H, t, J=5.9, 2-H), 3.76 (3H, s, 1 1 -H), 3.24 - 3.02 (2H, m, 4-H); 13C NMR (126 MHz, D20) δ = 170.1 (3-C), 155.2 (10-C), 130.8 (6, 7-CH), 125.4 (5-C), 1 16.0 (8, 9- CH), 54.2 (2-CH), 53.5 (1 1 -CH3), 34.8 (4-CH2); IR (diamond, vMAx, cm"1) 3335 (NH st), 2877 (N+-H st), 1983 (Ar comb), 1741 (C=0 st), 1225 (CO-0 st as), 1 199 (C-0 st as); Acc. Mass (FAB) Ci0H14NO3 Found: 196.0962 m/z, Calculated: 196.0968 m/z.
(S)-methyl 3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-2- (trifluoromethylsulfonamido)propanoate
Figure imgf000048_0002
Triflic anhydride (0.56 ml_, 3.31 mmol) in dichloromethane (3.3 mL) was added dropwise to a solution of (2S)-3-(4-hydroxyphenyl)-1 -methoxy-1 -oxopropan-
2- aminium chloride (0.767 g, 3.31 mmol) and triethylamine (1 .38 mL, 9.93 mmol) in dichloromethane (12.8 mL) at -78 °C. The mixture was stirred for 24 h. at room temperature. Water (5 mL) was added and the pH adjusted to pH=5 using 32% hydrochloric acid. The aqueous layer was extracted with diethyl ether. The organics extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (diethyl ether) afforded the title compound as yellow solid (0.704 g, 49%). [a]D 25 5 = 17.1 (c = 1 .00 in dichloromethane); 1H NMR (500 MHz, CDCI3) δ = 7.29 - 7.22 (4H, m, 6, 7, 8, 9-H), 4.49 (1 H, t, J=6.0, 1 H, 2-H), 3.78 (3H, s, 1 1 -H), 3.23 - 3.13 (2H, m, 4-H); 13C NMR (126 MHz, CDCI3) δ = 170.4 (3-C), 149.2 (10-C), 134.8 (5-C), 131 .3 (6, 7-CH), 123.1 (12-CF), 121.8 (8, 9-CH), 120.6 (12-CF), 120.0 (12-CF), 1 18.0 (12- CF), 1 17.4 (12-CF), 1 15.8 (12-CF), 57.7 (2-CH), 53.2 (1 1 -CH3), 38.9 (4-CH2); IR (diamond, vMAx, cm"1) 3349 (O-H st), 3221 (NH st), 2176 (Ar comb), 1724 (C=0 st), 1238 (CO-0 st), 1 199 (S-0 st as), 1 141 (S-0 st sy); Acc. Mass (FAB) d4H10 F6N07S2 Found: 481.9778 m/z, Calculated: 481.9797 m/z.
Triphenylphosphine gold (S)-methyl
3- (4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-2-(trifluoromethylsulfonamido)pro panoate - Compound 1
Figure imgf000049_0001
Silver carbonate (42.1 mg, 0.153 mmol) was added to a solution of (S)- methyl 3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-2-
(trifluoromethylsulfonamido)propanoate (50 mg, 0.153 mmol) in dichloromethane (3.82 mL) and stirred for 5 min. under an atmosphere of nitrogen.
Triphenylphosphine gold chloride (75.6 mg, 0.153 mmol) was added and stirred for 1 .5 h. The reaction mixture was filtered through Celite and the filtrate concentrated under reduced pressure to give the corresponding compound as white solid (1 .548 g, 90%). [a]D 23 9 = 2.0 (c = 1 .00 in dichloromethane); 1H NMR (500 MHz, CDCI3) δ = 7.52 - 7.44 (15H, m, Ar), 7.27 (2H, d, J=9.6, 6, 7-H), 7.00 (2H, d, J=8.6, 2H, 8, 9- H), 4.91 (1 H, m, 2-H), 3.67 (3H, s, 1 1 -H), 3.26 - 3.16 (2H, m, 4-H); 13C NMR (126 MHz, CDCI3) δ = 170.8 (3-C), 148.4 (10-Ar), 137.0 (5-Ar), 134.2 (Ar), 134.1 (Ar), 132.01 (Ar), 131 .5 (6, 7-Ar), 129.3 (Ar), 129.2 (Ar), 121.0 (8, 9-Ar), 61.5 (2-CH), 52.0 (1 1 -CH3), 41 .7 (4-CH2); 31P NMR (162 MHz, CDCI3) δ = 31.30 (s); IR
(diamond, vMAx, cm-1) 2956 (O-H st), 2073 (Ar comb), 1738 (C=0 st), 1249 (CO-0 st), 1 176 (S-0 st as), 1 137 (S-0 st sy); Acc. Mass (FAB) C3oH25AuF6N07PS2 Found: 940.0383 m/z, Calculated: 940.0272 m/z.
(2 ?)-3-(1 H-indol-3-yl)-1 -methoxy-1 -oxopropan-2-aminium chloride
Figure imgf000050_0001
Thionyl chloride (0.72 mL, 9.87 mmol) was added dropwise to a solution of D-tryptophan (1.000 g, 4.89 mmol) in methanol (33 mL). The reaction was heated to reflux with vigorous stirring for 24 h. After cooling, the reaction mixture was concentrated under reduced pressure and residual methanol traces removed by azeotropic distillation with dichloromethane (10 mL) under reduced pressure to give the title compound as a white solid (1.070 g, 86%). [a]D 22 8 = -15.1 (c = 1 .00 in water); 1H NMR (500 MHz, D20) δ = 7.52 (1 H, d, J=7.9, 9-H), 7.46 (1 H, d, J=8.1 , 12-H), 7.26 - 7.10 (3H, m, 4, 5, 9-H), 4.37 (1 H, t, J=6.0, 2-H), 3.73 (3H, s, 13-H), 3.44 - 3.31 (2H, m, 4-H); 13C NMR (126 MHz, D20) δ = 170.4 (2-C), 136.3 (7-C), 126.4 (8-C), 125.4 (6-C), 122.3 (1 1 -CH), 1 19.6 (10-CH), 1 18.1 (9-CH), 1 12.1 (12- CH), 106.0 (5-C), 53.6 (13-CH3), 53.3 (2-CH), 25.7 (4-CH2); IR (diamond, vMAx, cm" 1) 3261 (NH st), 2870 (N+-H st), 2023 (Ar comb), 1748 (C=0 st), 1229, 121 1 (CO-0 st as), 1 181 (C-0 st as); Acc. Mass (FAB) Ci2H15N202 Found: 219.1120 m/z, Calculated: 219.1128 m/z. Methyl W-[(trifluoromethyl)sulfonyl]-D-tryptophanate
Figure imgf000051_0001
Triflic anhydride (0.83 mL, 4.89 mmol) in dichloromethane (4.9 mL) was added dropwise to a solution of (2R)-3-(1 H-indol-3-yl)-1 -methoxy-1 -oxopropan-2- aminium chloride (1 .073 g, 4.89 mmol) and triethylamine (2.05 mL, 14.69 mmol) in dichloromethane (18.9 mL) at -78 °C. The mixture was stirred for 24 h. at room temperature. Water (5 mL) was added and the pH was adjusted to pH=5 using 32% hydrochloric acid. The aqueous layer was extracted with diethyl ether. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (diethyl ether) afforded the title compound as brown-yellow solid (1.548 g, 90%).
[a]D 25 5 = -31.8 (c = 1 .00); 1H NMR (500 MHz, CDCI3) δ = 8.17 (1 H, s,1 -NH), 7.52 (1 H, d, J=7.9, 9-H), 7.37 (1 H, d, J=8.1 , 12-H), 7.24 - 7.19 (1 H, m, 10-H), 7.17 - 7.12 (1 H, m, 1 1 -H), 7.04 (1 H, d, J=2.3, 1 H, 6-H), 4.57 (1 H, t, J=5.0, 1 H, 2-H), 3.71 (3H, s, 13-H), 3.38 (2H, m, 4-H); 13C NMR (126 MHz, CDCI3) δ = 170.7 (3-C), 136.2 (7-C), 127.1 (8-C), 125.1 (14-CF), 124.6 (14-CF), 123.5 (6-CH), 123.3 (14-CF), 122.5 (1 1 -CH), 120.7 (14-CF), 120.0 (10-CH), 1 18.3 (9-CH), 1 18.2 (14-CF), 1 1 1 .4 (12-CH), 108.0 (5-C), 57.4 (2-CH), 53.0 (13-CH3), 29.3 (4-CH2); IR (diamond, vMAx, cm-1) 3402.9 (ar NH st ), 3261 .5 (NH st), 2197.0, 2157.2, 1031.4 (Ar comb), 1712.6 (C=0 st), 1230.6 (CO-0 st), 1 185.0 (S-0 st as), 1 145.5 (S-0 st sy); Acc. Mass (FAB)
Figure imgf000051_0002
Found: 373.0446 m/z, Calculated: 373.0440 m/z.
Triphenylphosphine gold methyl A/-[(trifluoromethyl)sulfonyl]-D-tryptophanate - Compound 2
Figure imgf000051_0003
Silver carbonate (38.6 mg, 0.143 mmol) was added to a solution of Methyl N-[(trifluoromethyl)sulfonyl]-D-tryptophanate (50 mg, 0.143 mmol) in
dichloromethane (3.6 mL) and stirred for 5 min. under an atmosphere of nitrogen. Triphenylphosphine gold chloride (70.6 mg, 0.143 mmol) was added and stirred for 1 .5 h. The reaction was filtered through Celite and the solvent evaporated under reduced pressure to give the corresponding compound as pale yellow solid (0.1 15 g, 99%). [a]D 23 7 = -42.4 (c = 1 .00 in dichloromethane); 1H NMR (500 MHz, CDCI3) δ = 7.58 - 6.97 (20H m, Ar), 5.06 (1 H, q, J=6.1 , 2-H), 3.65 (3H, s, 13-H), 3.39 (2H, ddd, J=5.7, 14.7, 21.2, 4-H); 13C NMR (126 MHz, CDCI3) δ = 174.1 (3-C), 135.9 (7- C), 134.2 (Ar), 134.10 (Ar), 131 .7 (Ar), 131.7 (Ar), 129.1 (Ar), 129.0 (Ar), 128.6 (Ar), 127.8 (8-CH), 123.7 (6-CH), 122.0 (1 1 -CH), 1 19.4 (10-CH), 1 19.0 (9-CH), 1 1 1 .1 (12-CH), 1 10.5 (5-C), 60.8 (2-CH), 52.0 (13-CH3), 31 .7 (4-CH); 31P NMR (162 MHz, CDCI3) 5 = 31.01 (s); IR (diamond, vMAx, cm-1) 3398 (ar NH st), 2180 (Ar comb), 1738 (C=0 st), 1212 (CO-0 st), 1 176 (S-0 st as), 1 101 (S-0 st sy); Acc. Mass (FAB) C3iH27AuF3N204PSNa Found: 831.0944 m/z, Calculated: 831.0939 m/z.
(L)-(-).2-[(Diphenylphosphino)methyl]pyrrolidine
Figure imgf000052_0001
Deoxygenated 32% HCI (2 mL) was added to a round bottomed flask containing (S)-2-((diphenylphosphino)methyl)pyrrolidine-1 -sulfonic acid (100 mg, 0.30 mmol) under an atmosphere of nitrogen and stirred for 16 h. at 85 °C. After cooling, the pH was adjusted to pH=12 using potassium hydroxide and extracted with dichloromethane (3x7 mL). The reaction was concentrated under reduced pressure to give the title compound as yellow oil (53 mg, 65%). All data is identical to that reported: Tomioka Tetrahedron .Lett. 1999. 55. 3843
(S)-2-((diphenylphosphino)methyl)py ulfonic acid
Figure imgf000052_0002
(S)-hexahydropyrrolo[1 ,2-t)]isothiazole 1 ,1 -dioxide (0.850 g, 5.21 mmol) was added to a solution of diphenylphosphinelithium (5.21 mmol) in dry tetrahydrofuran (12.4 mL). The reaction was stirred for 3 h. and then quenched with 8 mL of water. The crude residue was extracted with dichloromethane (3x10 mL). The organic layers were combined and concentrated under reduced pressure. Purification by column chromatography (methanol : dichloromethane, [10:90]) afforded the title compound as white solid (1.648 g, 91 %). 1H NMR (500 MHz, CDCI3) δ = 7.94 - 6.95 (10H, m, Ar), 3.76 (1 H, s, 2-H), 3.32 - 2.80 (3H, m, 1 , 5-H), 2.03 (1 H, s, 1 -H), 1 .77 (1 H, s, 3-H), 1.52 (3H, s, 3, 4-H); 13C NMR (126 MHz, CDCI3) δ = 139.1 (s, Ar), 139.0 (s, Ar), 132.8 (s, Ar), 132.6 (s, Ar), 128.5 (s, Ar), 128.4 (s, Ar), 128.4 (s, Ar), 128.3 (s, Ar), 128.3 (s, Ar), 58.8 (d, J=21 .0, 2-CH), 50.2 (s, 5-CH2), 35.6 (s, 1 -CH2), 32.0 (s, 3-CH2), 24.3 (s, 4-CH2); 31P NMR (243 MHz, CDCI3) δ = -21 .26 (s); IR (diamond, vMAx, cm"1) 1433 (H-C-H st as), 1 174 (-S03 " st as), 1041 (-S03 " st sy); Acc. Mass (FAB): Ci7H20NaNO3PS Found: 372.0803 m/z Calculated: 372.0794 m/z.
Methyl 3-{(2S)-2-[(diphenylphosphino)methyl]pyrrolidin-1 -yl} propanoate
Figure imgf000053_0001
Methyl-3-bromopropionate (1.0 mL, 9.28 mmol) in dichloromethane (8.0 mL) was added dropwise to a solution of triethylamine (2.61 mL, 18.57 mmol) and (2S)- 2-[(diphenylphosphino)methyl]pyrrolidine (2.50 g, 9.28 mmol) in dichloromethane (27 mL). The resultant solution was stirred at 30 °C for 18 h. The reaction mixture was poured into water/dichloromethane (1 :1 , 200 mL). The aqeous phase was extracted with dichloromethane (100 mL) and the combined organic phases washed with water (100 mL) and brine (100 mL); dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (methanol : dichloromethane, [5:95]) afforded the title compound as a yellow cloudy viscous oil (1 .57 g, 47%). [a]D 25 5 = -78.2 (c = 1 .00 in
dichloromethane); 1H NMR (500 MHz, CDCI3) δ = 7.50 - 7.39 (4H, m, Ar), 7.37 - 7.28 (6H, m, Ar), 3.66 (3H, s, 9-H), 3.19 - 3.03 (2H, m, 5, 6-H), 2.54 (1 H, dt, J=3.3, 13.3, 4-H), 2.49 - 2.29 (4H, m, 6, 7-H), 2.15 - 2.06 (1 H, m, 5-H), 2.06 - 1.91 (2H, m, 1 , 3-H), 1.83 - 1.53 (3H, m, 3, 4-H); 13C NMR (126 MHz, CDCI3) δ = 172.7 (s, 8- C), 139.3 (d, J=12.1 , Ar), 138.5 (d, J=13.3, Ar), 133.0 (d, J=19.3, Ar), 132.6 (d, J=18.7, Ar), 128.7 (s, Ar), 128.5 (s, Ar), 128.4 (s, Ar), 128.4 (s, Ar), 128.3 (s, Ar), 128.3 (s, Ar), 62.1 (d, J=19.3, 2-CH), 53.4 (d, J=0.8, 5-CH2), 51 .5 (s, 9-CH3), 49.1 (s, 6-CH2), 33.6 (d, J=13.3, 1 -CH2), 33.5 (s, 7-CH2), 31 .7 (d, J=7.8, 3-CH2), 22.1 (d, J=0.6, 4-CH2); 31P NMR (162 MHz, CDCI3) δ = -21 .19 (s); IR (diamond, vMAx, cm 1) 2961 , 2802 (CH30 st), 1735 (C=0 st), 1433 (H-C-H st as), 1 175 (C-0 st as); Acc. Mass (FAB) C2iH27N02P Found: 356.1778, Calculated: 356.1774.
3-{(2S)-2-[(diphenylphosphino)methyl]pyrrolidin-1 -yl}propanoic acid
Figure imgf000054_0001
1 N sodium hydroxide (34.3 mL) was added to methyl 3-{(2S)-2- [(diphenylphosphino)methyl]pyrrolidin-1 -yl}propanoate (0.50 g, 1.41 mmol) in methanol (22.9 mL). After stirring for 20 h. at room temperature the reaction mixture was neutralized with 32% hydrochloric acid (3.5 mL). The resulting solution was lyophilized. The crude product was dissolved in methanol and the insoluble salts were removed by filtration. The resultant solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the corresponding compound as a yellow and cloudy viscous oil (0.57 g, 100%). [a]D 25 8 = -40.0 (c = 1 .00 in dichloromethane); 1H NMR (500 MHz, CDCI3) δ = 7.40 (10H, m, Ar), 3.70-3-80 (1 H, m, 5-H), 3.61 - 3.49 (1 H, m, 7-H), 3.06 - 2.72 (6H, m, 1 , 6, 7, 5-H), 2.64 (1 H, t, J=12.1 , 1 -H), 2.24 - 1.82 (m, 4H, 3, 4-H); 13C NMR (126 MHz, CDCI3) 5 = 173.2 (s, 8-C), 136.8 (d, J=1 1 .3, Ar), 136.1 (d, J=12.7, Ar), 133.0 (d, J=20.2, Ar), 132.5 (d, J=19.2, Ar), 129.6 (s, Ar), 129.1 (s, Ar), 128.9 (d, J=7.3, Ar), 128.7 (d, J=6.9, Ar), 66.9 (d, J=23.2, 2-CH), 52.8 (s, 5-CH2), 49.4 (s, 7-CH2), 31.1 (s, 6-CH2), 30.5 (d, J=7.4, 3-CH2), 29.6 (d, J=16.2, 1 -CH2), 21 .7 (s, 4-CH2); 31P NMR (162 MHz, CDCI3) δ = -20.61 (s), 30.40 (s, P=0, 5%); IR (diamond, vMAx, cm"1) 2956, 2547 (HO st), 1720 (C=0 st), 1432 (H-C-H st as); Acc. Mass (FAB) C20H25NO2P Found: 342.1608 m/z, Calculated: 342.1617 m/z. 3-{(2S)-2-[(diphenylphosphino)methyl]pyrrolidin
A/-[(trifluoromethyl)sulfonyl]propanamide
Figure imgf000055_0001
3-{(2S)-2-[(diphenylphosphino)methyl]pyrrolidin-1 -yl}propanoic acid (0.50 g, 1 .46 mmol), triflic amide (0.218 g, 1 .46 mmol) and HOBt*H20 (0.224 g, 1.46 mmol) were dissolved in dichloromethane (3.85 mL) and cooled to 0 °C under an atmosphere of nitrogen. EDC (0.233 g, 1 .50 mmol) was added and the mixture stirred for 15 min at 0 °C and then at room temperature for 18 h. The precipitate was removed by filtration and the filtrate concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and washed with 1 M citric acid (20 mL), saturated sodium bicarbonate (20 mL), brine (20 mL) and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (methanohdichloromethane, [5:95]) afforded the title compound as white solid (0.34 g, 49%). [a]D 25 7 = -27.7 (c = 1 .00 in dichloromethane); 1H NMR (500 MHz, (CD3)2SO) δ = 7.55 - 7.32 (10H, m, Ar), 3.75 - 3.45 (2H, m, 5, 6-H), 3.22 (1 H, s, 2-H,), 3.1 1 - 2.89 (3H, m, 1 ,5 ,6-H), 2.55 - 2.45 (2H, m, 7-H), 2.28 (1 H, t, J=12.1 , 1 -H), 2.07 (1 H, m, 3-H), 1.94 - 1.77 (2H, m, 4-H), 1 .67 (1 H, m, 3-H); 13C NMR (126 MHz, (CD3)2SO) δ = 174.3 (s, 8-C), 137.3 (d, J=12.2, Ar), 136.2 (d, J=13.2, Ar), 132.7 (d, J=19.9, Ar), 132.4 (d, J=19.6, Ar), 129.2 (d, J=33.7, Ar), 128.8 (d, J=7.1 , Ar), 128.6 (d, J=7.0, Ar), 124.1 (s, 9-CF), 121.5 (s, 9-CF), 1 18.9 (s, 9-CF), 1 16.4 (s, 9-CF), 66.1 (d, J=23.5, 2-CH), 52.8 (s, 5-CH2), 49.6 (s, 6-CH2), 34.3 (s, 7-CH2), 30.1 (s, 3-CH2), 28.9 (d, J=13.0, 1 -CH2), 21 .4 (s, 4- CH2); 31P NMR (162 MHz, DMSO) δ = -21 .76 (s); 19F NMR (376 MHz, (CD3)2SO) δ = -77.71 (s); IR (diamond, vMAx, cm"1) 3052, 2967 (NH st), 2192 (Ar comb), 1598 (C=0 st amide), 1431 (H-C-H st as), 1 176 (S-0 st as), 1 123 (S-0 st sy); Acc. Mass (FAB) C2i H24 F3N2Na03PS Found: 495.1117 m/z, Calculated: 495.1090 m/z; X- Ray: available see Appendix (benzene). 3-{(2S)-2-[(diphenylphosphino)methyl]pyrrolidin-1 -yl}-yV- [(trifluoromethyl)sulfonyl]propanamide gold chloride
Figure imgf000056_0001
3-{(2S)-2-[(diphenylphosphino)methyl]pyrrolidin-1 -yl}-/V-[(trifluoromet sulfonyl]propanamide (50 mg, 0.106 mmol) was dissolved in dry dichloromethane (1 mL) under an atmosphere of nitrogen. Dimethyl sulfide gold chloride (31 mg, 0.106 mmol) was added in one portion and the resultant mixture stirred for 3 h.
Concentration of the reaction mixture under reduced pressure afforded the title compound as a white solid (70 mg, 94%). [a]D 26 1 = -26.1 (c = 1 .00); 1H NMR (500 MHz, CDCI3) δ = 7.92 (2H, dd, J=7.1 , 13.6, Ar), 7.80 (2H, dd, J=7.1 , 13.4, Ar), 7.59 - 7.42 (6H , m, Ar), 4.26 (1 H, m, 5-H), 3.86 - 3.58 (2H, m, 6-H), 3.53 - 3.37 (2H , m, 1 -H), 3.02 - 2.90 (2H, m, 5,6-H), 2.83 - 2.55 (2H, m, 7-H), 2.19 - 1 .91 (3H, m, 3,4- H), 1 .80 - 1 .67 (1 H, m, 3-H); 13C NMR (126 MHz, CDCI3) δ = 175.6 (s, 8-C), 134.1 (d, J=14.3, Ar), 133.1 (d, J=13.6, Ar), 132.6 (dd, J=2.1 , 52.4, Ar), 129.5 (dd, J=6.8, 12.1 , Ar), 128.6 (d, J=63.1 , Ar), 127.9 (d, J=61 .7, Ar), 124.12(s, 9-CF), 121 .5 (s, 9- CF), 1 19.0 (s, 9-CF), 1 16.4 (s, 9-CF), 67.7 (s, 2-CH), 54.6 (s, 5-CH2), 52.3 (s, 6- CH2), 34.5 (s, 7-CH2), 30.4 (s, 3-CH2), 29.1 (d, J=38.9, 1 -CH2), 21 .9 (s, 4-CH2); 31P NMR (162 MHz, CDCI3) δ = 26.38 (s); 19F NMR (376 MHz, CDCI3) δ = -78.34 (s). IR (diamond, vMAx, cm"1) 3055 (NH st), 2191 (Ar comb), 1610 (C=0 st amide), 1437 (H-C-H st as), 1 173 (S-0 st as), 1 124 (S-0 st sy); Acc. Mass (FAB) C2i H24 AuCIF3N2Na03PS Found: 727.0440 m/z, Calculated: 727.0444 m/z. bis(3-{(2S)-2-[(diphenylphosphino)methyl]pyrrolidin-1 -yl}-yV- [(trifluoromethyl)sulfonyl]propanamide) di-gold - Compound 3
Figure imgf000056_0002
3-{(2S)-2-[(diphenylphosphino)methyl]pyrrolidin-1 -yl}-/V- [(trifluoromethyl)sulfonyl] propanamide (100 mg, 0.212 mmol) was dissolved in dry dichloromethane (2.1 mL) in a flame dried flask, under an atmosphere of nitrogen. Dimethyl sulfide gold chloride (62 mg, 0.212 mmol) was added in one portion and the mixture stirred for 15 min. Silver carbonate (58 mg, 0.212 mmol) was added in one portion and the resultant mixture stirred for 18 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give the title compound as a yellow solid (139 mg, 98%). [a]D 23 5 = -21 .2 (c = 1 .00); 1H NMR (500 MHz, CDCI3) δ = 7.91 - 7.37 (10H m, Ar), 3.36 - 1.23 (13H m, 1 -7-H); 13C NMR (126 MHz, CDCI3) δ = 176.6 (s, 8-C), 133.6 (s, Ar), 133.0 (s, Ar), 132.2 (s, Ar), 129.9 (s, Ar), 129.4 (s, Ar), 129.3 (s, Ar), 125.4 (s, 9-CF), 122.1 (s, 9-CF), 1 18.7 (s, 9-CF), 1 15.5 (s, 9-CF), 61 .8 (s, 2-CH), 53.4 (s, 5-CH2), 50.04 (s, 6-CH2), 37.4 (s, 7-CH2), 33.2 (s, 3-CH2), 31 .9 (s, 1 -CH2), 22.8 (s, 4-CH2); 31P NMR (162 MHz, CDCI3) δ = 21 .92 (s), 20.81 (s); IR (diamond, vMAx, cm"1) 2962 (NH st), 2168 (Ar comb), 1683 (C=0 st amide), 1437 (H-C-H st as), 1 177 (S-0 st as), 1 121 (S-0 st sy); Acc. Mass (FAB) C42H47Au2F6N406P2S2 Found: 1337.1704 m/z, Calculated: 1337.1704 m/z.
3-{(2S)-2-[(diphenylphosphino)methyl]pyrrolidin-1 -yl}-yV- [(trifluoromethyl)sulfonyl]propanamide gold bis(trifluoromethanesulfonate) - Compound 4
Figure imgf000057_0001
Bistriflic amide (26 mg, 0.092 mmol) and silver carbonate (25.5 mg, 0.092 mmol) in dry dichloromethane (2 mL) was stirred for 5 min. under an atmosphere of nitrogen. Triphenylphosphine gold chloride (65.2 mg, 0.092 mmol) in
dichloromethane (0.31 mL) was added and stirred for 2 h. excluding light. The mixture was filtered through Celite and concentrated under reduced pressure to give the title compound as an off white solid with (70.5 mg, 80%). [a]D 26'1 = -23.6 (c = 1 .00 in dichloromethane); 1H NMR (500 MHz, CDCI3) δ = 8.17 - 6.96 (10H, m, Ar), 4.33 -2.89 (9H, m, 1 ,5,6,7-H), 2.22 - 1 .75 (3H, m, 3,4-H), 1 .47 - 1 .21 (1 H , m, 3-H); 13C NMR (126 MHz, CDCI3) δ = 174.8 (s, C-8), 134.9 (d, J=14.0, Ar), 133.8 (s, Ar), 132.2 (s, Ar), 131 .7 (d, J=12.2, Ar), 130.0 (s, Ar), 129.6 (s, Ar), 129.4 (d, J=1 1 .7, Ar), 123.4 (s, CF), 120.9 (s, CF), 1 18.3 (s, CF), 1 15.7 (s, CF), 64.4 (s, 2- CH), 52.8 (s, 5-CH2), 44.9 (s, 6-CH2), 29.5, 29.1 (s, 1 , 3, 7-CH2), 20.8 (s, 4-CH2); 31P NMR (162 MHz, CDCI3) δ = 26.78 (s); 19F NMR (376 MHz, CDCI3) δ = -76.56 (s), -78.68 (s). IR (diamond, vMAx, cm"1) 2178 (Ar comb), 1669 (C=0 st amide), 1439 (H-C-H st as), 1 178 (S-0 st as), 1 128 (S-0 st sy).
(S)-4-((1 -methoxy-4-(methylthio)-1 -oxobutan-2-yl)amino)-4-oxobutanoic acid
Figure imgf000058_0001
L-methionine methyl ester hydrochloride (250 mg, 1 .25 mmol) was suspended in dichloromethane (12.5 mL) under an atmosphere of nitrogen.
Triethylamine (0.26 mL, 1 .88 mmol) was added and the suspension stirred for 10 min. 4-dimethylaminopyridine (15 mg, 0.12 mmol) and succinic anhydride (125 mg, 1 .25 mmol) were added and the reaction stirred for 16 h. The reaction mixture was shaken with 3 x 20 mL portions of hydrochloric acid (2 M) and the aqueous washings extracted with diethyl ether (3x20 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield the title compound as a white solid (0.199 g, 60%).
[a]D 25-4 = 29.3 (c = 1 .05 in dichloromethane); 1H NMR (500 MHz, CDCI3) δ = 10.6 (1 H, s, 12-H), 6.44 (1 H, d, J=7.8, 7-NH), 4.73 (1 H, td, J=7.3, 5.4, 3-H), 3.77 (3H, s, 1 -H), 2.66 - 2.81 (2H, m, 9-H), 2.57 (2H, t, J=6.8, 10-H), 2.49 - 2.54 (2H, m, 5-H), 2.13 - 2.22 (1 H, m, 4-H), 2.10 (3H, s, 6-H), 1 .94 - 2.06 (1 H, m, 4-H); 13C NMR(126 MHz, CDCI3) δ = 176.9(1 1 -C=0), 172.5(2-C=0), 171 .9 (8-C=0), 52.8 (1 -CH3), 51 .6 (3-CH), 31 .5 (4-CH2), 30.5 (10-CH2), 29.9 (5-CH2), 29.3 (9-CH2), 15.4 (6-CH3); IR (diamond, vMAx, cm"1) 3309, 3104 (O-H st), 2923, 1746 (C=0 st), 1715 (C=0 st), 1651 (C=0 st), 1533, 1410.1 , 1227 (CO-0 st) 1204, 1 159 (C-OC); Acc. Mass (FAB) Ci0H17NNaO5S, Found: 286.0726 m/z, Calculated: 286.0720 m/z. (S)-methyl 4-(methylthio)-2-(4-oxo-4
(trifluoromethylsulfonamido)butanamido)butanoate
Figure imgf000059_0001
(S)-4-((1 -methoxy-4-(methylthio)-1 -oxobutan-2-yl)amino)-4-oxobutanoic acid (0.53 g, 2.01 mmol) and triflic amide (0.3 g, 2.01 mmol) were dissolved in dichloromethane (7.5 mL) and cooled to 0 °C under an atmosphere of nitrogen. EDC (0.36ml, 2.06 mmol) was added and the reaction mixture stirred at 0 °C for 15 min., and then at room temperature for 48 h. The reaction mixture was
concentrated under reduced pressure and the residue dissolved in ethyl acetate (10 mL). The solution was washed with citric acid (sat.), sodium hydrogen carbonate (sat.) and brine. The combined aqueous washings were then extracted with diethyl ether using continuous extraction equipment for 24 h. The organic phase was separated and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield a yellow oil. The crude oil was purified by column chromatography using a gradient solvent system (0-5% methanol in diethyl ether) to yield the title compound as a pale yellow oil (0.18 g, 23%). [a]D 26 0 = 22.1 (c = 1 .085 in dichloromethane); 1H NMR (500 MHz, CDCI3) δ = 6.83 (1 H, d, J=8.3, 7-NH), 4.70 - 4.77 (1 H, m, 3-H), 3.77 (3H, s, 1 -H), 2.87 - 2.79 (2H, m, 10-H), 2.66 - 2.75 (2H, m, 9-H), 2.45 - 2.55 (2H, m, 5-H), 2.16 (1 H, m, 4-H), 2.09 (3H, s, 6-H), 1.95 - 2.05 (1 H, m, 4-H); 13C NMR (126 MHz, CDCI3) δ = 172.4 (2-C=0), 171 .9 (8-C=0), 169.4 (1 1 -C=0), 52.8 (1 -CH3), 52.0 (3-CH), 32.2 (10-CH2), 31.0(4-CH2), 29.8(5-CH2), 29.7 (9-CH2), 15.4 (6-CH3); IR (diamond, vMAx, cm"1) 3371 , 2919.4, 1734.5 (C=0), 1649.6, 1537.7, 1441.2, 1387.2, 1201 .6 + 1 134.8 + 1096.8 (C-O); Acc. Mass (FAB) CiiH18F3N206S2 Found: 395.0544 m/z, Calculated: 395.0553. Triphenylphosphine gold (S)-methyl 4-(methylthio)-2-(4-oxo-4
(trifluoromethylsulfonamido)butanamido)butanoate - Compound 5
Figure imgf000060_0001
(S)-methyl 4-(methylthio)-2-(4-oxo-4
(trifluoromethylsulfonamido)butanamido)butanoate 54 (48.9 mg, 0.12 mmol) was dissolved in dichloromethane (2.5 mL). Ag2C03 (0.034g, 0.12 mmol) was added and the mixture stirred for 5 min. excluding light, under an atmosphere of nitrogen. Triphenylphosphine gold chloride (0.061 g, 0.12 mmol) was added in one portion and the reaction stirred for 1 .5 h. The reaction mixture was diluted with
dichloromethane (10ml), filtered through Celite and concentrated under reduced pressure to afford the title compound as an off white solid (90.3 mg, 85%). [a]D 26 2 = 6.4 (c = 1 .025 in dichloromethane); 1H NMR (500 MHz, CDCI3) δ = 7.57 - 7.45 (15H, m, Ar), 6.49 (1 H, d, J=8.3, 7-NH), 4.7 (1 H, m, 3-H), 3.72 (3H, s, 1 -H), 3.17 - 3.02 (2H, m, 10-H), 2.59 - 2.53 (4H, m, 9,5-H), 2.20 - 2.13 (1 H, m, 4-H), 2.08 (3H, s, 6-CH3), 1.98 (1 H, m, 4-CH2); 13C NMR (126 MHz, CDCI3) δ = 177.35(1 1 -C=0), 172.2(2-C=0), 171 .7(8-C=0), 134.2(Ar), 134.1 (Ar), 132.1 (Ar), 132.1 (Ar), 129.4(Ar), 129.3(Ar), 52.4(1 -CH3), 51.5(3-CH), 33.9(10-CH2), 31.8(4-CH2), 31 .3(9-CH2), 30.2(5-CH2), 15.8 (6-CH3); 31P NMR(162Mhz, CDCI3) δ = 30.5 (s); IR (diamond, VMAX, cm"1) 2933, 1737, 1671 , 1436, 1354, 1 174, 1 138, 1 101 ; Acc. Mass (FAB) C29H3iAuF3N2Na06PS2 Found: 875.0871 m/z, Calculated: 875.0819 m/z. pyridinium-2-yl(trifluoromethylsulfonyl)amide
Figure imgf000060_0002
2-aminopyridine (0.5 g, 5.3 mmol) and pyridine (0.43 mL, 5.3 mol) were dissolved in dichloromethane (9.75 mL) under an atmosphere of nitrogen. The reaction mixture was cooled to -78 °C and a solution of triflic anhydride (0.89 mL, 5.3 mmol) in dichloromethane (1.8 mL) was added dropwise via cannula over 20 min. with vigorous stirring, after which the mixture was stirred at -78 °C for 2 h. and then at room temperature for 19 h. The reaction was quenched with water (30 mL). The aqueous layer was extracted with chloroform (4x50 mL) and the combined organic layers washed with water (50 mL), 10% NaOH (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate. The pH of the aqueous layer was brought down to 8 by adding dilute hydrochloric acid dropwise and further extracted with diethyl ether (3x50 mL). The organic layer was dried over anhydrous magnesium sulphate and filtered. The chloroform and ether solutions were combined and concentrated under reduced pressure to leave a pale brown solid. The solid was recrystallised from methanol to yield the title compound as an off white solid (0.19 g, 16%). 1H NMR (400MHz, CD3OD) δ = 8.05 (1 H, ddd, J=9.0, 7.1 , 1 .5), 7.98 (1 H, d, J=6.4), 7.72 (1 H, d, J=9.3), 7.1 1 (1 H, t, J=6.6) 13C NMR (126 MHz, CD3OD) δ = 1 15.0, 1 18.0, 136.8, 144.4; IR (diamond, νΜΑχ, cm"1) 777.29, 1 128.94, 1 155.04, 1323.58, 1357.99, 1540.07, 1614.62, 1632.61 ; Acc. Mass (FAB) C6H5F3N2Na02S Found: 248.9918 m/z, Calculated: 248.9916 m/z.
Triphenylphosphine gold pyridinium-2-yl(trifluoromethylsulfonyl)amide - Compound 6
Figure imgf000061_0001
2-(/V-triflyl)pyridine (50mg, 0.2 mmol) was dissolved in of dry
dichloromethane (2.2 mL) under an atmosphere of nitrogen. Silver carbonate (66 mg, 0.2 mmol) and subsequently triphenylphosphine gold chloride (0.108 g, 0.2 mmol) were added and the reaction mixture stirred for 19 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure to yield the title compound as a white crystalline solid. 0.133 g (87%). 1H NMR (400 MHz, (CD3)2SO) δ = 8.26 (1 H, d, J=4.4), 7.87 (1 H, t, J=7.8), 7.48 - 7.80 (16H, m), 7.08 (1 H, t, J=5.9). 13C NMR (126 MHz, (CD3)2SO) δ = 141 .1 , 134.1 , 133.9, 132.31 , 132.29, 129.6, 129.5, 128.3, 127.8, 1 16.6, 1 16.3; 31P NMR (162 MHz, (CD3)2SO) δ = 29.6 (s); Acc. Mass (FAB): C24H2oAuF3N202PS, Found: 685.0658 m/z,
Calculated: 685.0595 m/z. Compound 7 was synthesised using methodology previously described in the art.
Tf
Ph3P Au N /
\ Tf 7
Cell culture
The breast cancer cell lines MDA-MB-231 and MDA-MB-468 as well as green monkey kidney epithelial cells (CV1 ) were obtained from Cancer Research UK. Cells were grown in 25 ml Dulbecco's modified medium (DMEM, 21969; Gibco) supplemented with 12% fetal calf serum (16010-159; lot 1014583; PAA), 1 % penicillin/streptomycin and 1 % L-glutamate in 75 cm3 cell culture flasks (Corning). The media and supplements were obtained from Gibco/invitrogen. Cell cultures were maintained at 37°C and 5% C02. Cells were split every 3-4 days, cells never reached a confluency greater than 95% to avoid cells growing on top of each other. Prior to trypsinization of cells in preparation for splitting, cells were inspected on a standard light microscope and only propagated further or used in assays if they appeared 'normal' (not floating) and were not contaminated (e.g. by bacteria or yeast). A maximum of 25 passages were carried out.
Trypsinization.
Cells were washed twice in 13 mis of phosphate buffered saline (pH 7.25). Cells were trypsinized with 2.5 mg trypsin (27250-018; GIBCO)/ml phosphate buffered saline (pH 7.25) for 5 min. at 37°C and 5% C02. The trypsin was removed from the cells adding 10 ml of DMEM, supplemented as above ("Cell Culture") to the culture flask and then adding the cell suspension to a 30 ml tube (201 150, Greiner Bio One). The cells were centrifuged at1500 rpm in a Rotina 38R (Hettich) for 5 min. (room temperature, -21 °C) and the supernatant was aspirated before cells were resuspended in 10mls of DMEM, supplemented as above.
Haemocytometer counts were carried out at this stage to determine 'cell concentration'.
Cell viability assay
Cell viability was determined using the CellTiter-Blue® Cell Viability Assay (G8080, Promega) following the instructions by the supplier. It was found that confluency of the cells prior to incubation with the gold(l) complexes influenced cell viability. Therefore, cells were initially grown to a 'cell concentration' between 2 χ 105 to 5 x 105 cells/ml, as determined by haemocytometer counts after trypsinization of the cells (see above). At this 'cell concentration', cells were healthy and no substantial level of 'floating', detached cells were noticed. Moreover, cell viability was substantially higher after treatment with the gold(l) complexes within this range, compared to higher, commonly-used concentrations (or confluencies leading to higher concentrations using the cell concentration measure defined above).
After trypsinization, cells were resuspended in phenol red free DMEM (VX1053028; Fisher) to prevent interactions of the gold compounds and phenol red. This was supplemented as described above for the standard DMEM. ~ 5000 cells were then seeded into wells of 96-well black-walled, clear bottomed plates (655090; Greiner). The plates were incubated for 24 hours, as described above, to allow cells to adhere to the well. The gold(l) compounds were prepared from powder immediately prior to use by dissolving the compound in undiluted (-100%) DMSO to give a stock concentration of 100 mM. This stock was further diluted with 10% (v/v, diluted in sterile, distilled water) DMSO to yield a 1 mM solution in 10.9% DMSO. Gold compounds were added to each well in the indicated concentrations, keeping the final concentration of DMSO constant at 0.109% (v/v), except for the [Bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(l) experiments where the final concentration was 0.209% (v/v) DMSO. 3-8 replicates were made each time. A DMSO-only control (0.1 % v/v), a medium-only control (no DMSO and no drug), and no-cells control (media only) were added to the plate. The final volume of each well was 100 μΙ.
The plates were incubated for a further 44 hours, at 37°C and 5% C02 (in the dark). After 44 hours, 20 μΙ of CellTiter-Blue® was added to each well of the plate and the plate incubated for a further 4 hours at 37 C and 5% C02 (in the dark). Fluorescence readings from each well were then measured at 560nm/590nm using a Promega Glomax multi detection system. Cell viability was determined as follows. Fluorescence of each well was recorded as total fluorescence'.
'Background fluorescence' (determined by the mean value of the 'no-cells' control) was subtracted from 'total fluorescence' to yield 'adjusted fluorescence'.
'Normalized fluorescence' was calculated as adjusted fluorescence' divided by the 'adjusted fluorescence' of the mean of the DMSO-only (no drug, or 0 μΜ) treated cells. We observed no significant differences between DMSO-only treated cells (0.1 % or 0.2% v/v) and media-only treated cells (Figures 2 and Figure 4).
Curve fitting and IC5o determination.
IC50 concentrations for complexes 1 and 2 were determined using
GraphPad Prism. The nonlinear regression curve fit model was chosen using the log(inhibitor) vs. response-variable response (four parameter) equation. Outliers were identified using the Grubbs test.
Treatment with nigericin.
Cell viability in response to nigericin (N7143, Sigma) and treatment with compounds 1 and 2 were carried out as above, except the cells were treated with nigericin at the indicated final concentration or ethanol-only (CV1 0.1 %, MDA-MB- 231 0.3-1 % ethanol) for 30 minutes prior to the addition of compound 1 or 2 (final concentration 4.28 μΜ or 5 μΜ respectively, or DMSO-only).
Thioredoxin reductase and Glutathione reductase assays
The in vitro thioredoxin reductase and glutathione reductase activity were measured using abeam thioredoxin reductase and glutathione reductase assay kits (ab83463 and ab83461 , respectively) following the instructions by the supplier. Briefly, thioredoxin reductase (T9698, Sigma) or glutathione reductase (G9297, sigma) both at concentrations of 0.0005 units/μΙ were treated with increasing concentrations of compound 1 , compound 2, or the indicated ligands. The absorbance was measured on a BIO-TEK synergy HT plate reader at 405 nm, every 30 seconds for up to 20 minutes. TrxR and GR activities were calculated as nmol TNB■ min"1 ■ ml"1 sample volume.
In vitro assessment of antiproliferative effects on gold(l) complexes on two breast cancer cell lines
The complexes 1-7 were tested for antiproliferative effects on two commonly-used breast cancer cell lines (MDA-MB-231 and MDA-MB-468) as well as CV-1 cells from normal, African green monkey kidney epithelial cells (control), using a range of concentrations that spanned two orders of magnitude. This initial screen revealed that all of the compounds exhibited marked cytotoxic effects, with preferential inhibition of the two cancer cell lines (Figures 1 and 2). The MDA-MB- 468 cell line was consistently more sensitive to the gold(l) complexes compared to the MDA-MB-231 . Compounds 1 , 2, 3 and 6 were comparable to auranofin in the inhibition of the MDA-MB-231 cell line. Relative to the inhibition of the CV-1 cell line, compounds 4 and 5 inhibited MDA-MB-231 as well as auranofin. Further analysis of compounds 1 and 2 revealed IC50 values in the low and even sub- micromolar ranges (Figure 3).
To determine whether the effects on cell viability was at least in part due to the gold-amide bond containing the derivatized amino acid ligand, the effect of the two precursor compounds (Me2SAuCI and Ph3PAuCI) was tested. The CV-1 cells were unaffected by either precursor at concentrations up to 50 μΜ. Only at concentrations above 30 μΜ was a slight effect on the MDA-MB-231 observed, and at 50 μΜ, the IC50 had not yet been reached for either precursor. These data show that the gold-amide ligand effects are substantial and that the derived ligands significantly influence the efficacy of the gold(l) complexes in mediating cellular toxicity. Importantly, the ligands alone were not sufficient to induce cell toxicity (Figure 4).
Preferential sensitization of CV-1 cells to gold(l) complexes with treatment of nigericin
Mitochondrial hyperpolarization of adenocarcinomas from which the two cell lines used in this study are derived is hypothesized to be the cause of the selective inhibition of cell proliferation due to enhanced accumulation of gold(l) in the mitochondria. This predicts that hyperpolarizing the mitochondrial membranes of CV-1 cells with the K7H+ ionophore, nigericin, should sensitize them further to the gold complexes. To test this, CV-1 cells were treated with increasing
concentrations of nigericin in addition to 0 or 4.28 μΜ of compound 1 or 0 or 5 μΜ of compound 2. Although nigericin treatment alone caused a concentration- dependent decrease in cell viability; in combination with compound 1 or 2, nigericin caused a marked, further sensitization to the gold(l) complexes (Figure 5). In contrast, although MDA-MB-231 cells also showed a degree of sensitivity to nigericin, addition of compounds 1 or 2 caused no further decrease in cell viability (Figure 5). Compounds 1 and 2 inhibit TrxR but not GR in vitro
Increasing concentrations of complexes 1 and 2 inhibited TrxR in the nM range (Figure 6). Furthermore, treatment with solely the ligands did not inhibit TrxR, demonstrating that the gold(l) is required for the inhibition of TrxR. The related protein, glutathionone reductase (GR), which contains a cysteine was unaffected, suggesting that the gold(l) complexes inhibit selenol-containing proteins.
Method for measuring tumour doubling time
Tumour doubling time can be estimated using computed tomography, as described by Henschke et al. in Thracic and Cardiovascular Surgery, 2005, 17(2) pp99-106. This methodology is particularly useful for measuring tumour sizes of lung cancer.
Methods of measuring S-phase fraction
The numbe of cells in S-phase can be determined using fluorescence- activated cell sorting, such as the technique described by Pinto et al. in j. Clin Pathol, 2001 , 54, pp543-549 (see section headed DNA Flow Cytometry). As used herein, the S-phase fraction is:
(Total number of cells in all S-phases / Total number of cells) x 100
Methods for detecting Ki-67
Methods for staining and detection Ki-67 are described by Cowen et al. in Clinical Cancer Research, 2002, 8, pp1 148-1 154.

Claims

Claims
1 . A compound of formula (I) for use in therapy
G
L Au N /
\ A
\ R
(I)
wherein
L denotes a phosphine or N-heterocyclic carbene ligand;
A denotes S02 or C(=0);
R denotes hydrogen, alkyl, or haloalkyl; or optionally substituted
(hetero)aryl; and
G denotes hydrogen, alkyl, cydoalkyi, (hetero)aryl, A-R, or a group deriving from an a- or β-amino acid,
wherein optionally L may derive from a G substituent in an identical compound of formula (I), such that a macrocycle containing two Au atoms is formed, with the L substituent on each Au metal atom deriving from the G substituent on the corresponding compound of formula (I).
2. A compound according to claim 1 , wherein the compound has formula (la)
Figure imgf000067_0001
(la)
wherein
L denotes P(R1)3 or N /
N
each R1 independently denotes Ci-C4-alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 Ra
Figure imgf000068_0001
R2 denotes H, (CH2)kC(0)NR3R3;
k denotes an integer from 0 to 4;
each R3 independently denotes hydrogen, d-C4-alkyl, S02R;
each R4 independently denotes CrC4-alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 Ra;
A denotes S02 or C(=0);
R denotes hydrogen, CrC6-alkyl or CrC6-fluoroalkyl; phenyl optionally substituted with 1 to 5 Ra; or a pyridinyl which is optionally quaternized with hydrogen or methyl;
G denotes hydrogen, CrC6-alkyl, C3-C6-cycloalkyl; phenyl optionally substituted with 1 to 5 Ra; naphthyl optionally substituted with 1 to 5 Ra; C5-Ci0- heteroaryl optionally substituted with 1 to 5 Ra; A-R, or G1-CHRxRy;
G1 denotes a bond, -C(=0)(CH2)u- or -C(=0)-(CH2)t-G2;
G2 denotes (C(=0))vNR9; or
G2 and CHRxRy together denote
Figure imgf000068_0002
t denotes an integer from 1 to 4; u denotes 0 or 1 ;
v denotes 0 or 1 ;
Rx denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
CH(OR5)CH3, (CH2)4OR5, CH2SR6, CH2CH2SCH3, (CH2)4NR7R8,
(CH2)3NHC(NH)(NH2), CH2C02Rc, CH2CH2C02Rc, CH2CONR9R10,
CH2CH 9R10,
Figure imgf000069_0001
Ry denotes (CH2)uC(0)Rp or (CH2)uC02Rc when G1 denotes a bond;
Ry denotes (CH2)uC(0)Rp, (CH2)uC02Rc or CH2P(R14)2 when G1 and G2 together denote -C(=0)(CH2)t(C(=0))vNR9;
Ry denotes NHRP or N(Rb)2 when G1 denotes -C(=0)(CH2)u-;
Rz denotes C(0)Rp, C02Rc or CH2P(R14)2;
each Ra independently denotes halogen, OH, N02, CrC4-alkyl, d-C4-alkoxy or N(Rb)2;
each Rb independently denotes hydrogen, CrC4-alkyl, -CH2C6H5,
(CH2)1-4C02Rc. phenyl or PGam;
each Rc independently denotes hydrogen, CrC4-alkyl, or PGac;
R9 denotes hydrogen or CrC4-alkyl;
R5 denotes hydrogen, C C4-alkyl, OS02C C6-alkyl, OS02-C C6-fluoroalkyl; OS02-phenyl optionally substituted with 1 to 5 Ra; or PGal;
R6 denotes hydrogen or CrC4-alkyl;
R7 and R8 independently denote Rb;
R9 and R10 independently denote hydrogen or CrC4-alkyl;
R11 denotes hydrogen, CrC4-alkyl or CrC4-alkylene-P(R14)2;
R12 denotes hydrogen, CrC4-alkyl or CrC4-alkylene-P(R14)2;
R13 denotes hydrogen, OH, C C4-alkoxy, OS02C C6-alkyl,
OS02-C C6-fluoroalkyl; OS02-phenyl optionally substituted with 1 to 5 Ra;
R14 denotes CrC4-alkyl, cyclohexyl, adamantyl, or phenyl optionally substituted with 1 to 5 Ra; Rp denotes a peptide optionally linking the compound of formula (I) to a active;
PGac denotes a protecting group for a carboxylic acid;
PGam denotes a protecting group for an amine; and
PGal denotes a protecting group for an alcohol,
wherein optionally L may derive from a G substituent in an identical compound of formula (la), such that a macrocycle containing two Au atoms is formed, with the L substituent on each Au metal atom deriving from the G substituent on the corresponding compound of formula (la).
3. A compound according to claim 2, wherein the compound has formula (lb)
Figure imgf000070_0001
(lb)
wherein
L denotes P(R1)3 or
Figure imgf000070_0002
each R1 independently denotes CrC4-alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 Ra; or
Figure imgf000070_0003
R2 denotes H, -(CH2)kC(0)NR3R3;
k denotes an integer from 0 to 4;
each R3 independently denotes H, CrC4-alkyl, S02R;
A denotes S02 or C(=0);
R denotes hydrogen, d-C6-alkyl or CrC6-fluoroalkyl; phenyl optionally substituted with 1 to 5 Ra; or a pyridinyl which is optionally quaternized with hydrogen or methyl;
G1 denotes a bond, -C(=0)(CH2)u- or -C(=0)-(CH2)t-G2;
G2 denotes (C(=0))vNR9; or
G2 and CHRxRy together denote
Figure imgf000071_0001
t denotes an integer from 1 to 4;
u denotes 0 or 1 ;
v denotes 0 or 1 ;
Rx denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl, CH(OR5)CH3, (CH2)4OR5, CH2SR6, CH2CH2SCH3, (CH2)4NR7R8,
(CH2)3NHC(NH)(NH2), CH2C02Rc, CH2CH2C02Rc, CH2CONR9R10,
CH2CH 9R10,
Figure imgf000071_0002
er denote -C(=0)(CH2)t(C(=0))vNR9;
Ry denotes NHRP or N(Rb)2 when G1 denotes -C(=0)(CH2)u- Rz denotes C(0)Rp, C02Rc or CH2P(R14)2; each Ra independently denotes halogen, OH, N02, CrC4-alkyl, CrC4-alkoxy or N(Rb)2;
each Rb independently denotes hydrogen, d-C4-alkyl, -CH2C6H5,
(CH2)1-4C02Rc, phenyl or PGam;
each Rc independently denotes hydrogen, CrC4-alkyl, or PGac;
R9 denotes hydrogen or CrC4-alkyl;
R5 denotes hydrogen, C C4-alkyl, OS02C C6-alkyl, OS02-C C6-fluoroalkyl; OS02-phenyl optionally substituted with 1 to 5 Ra; or PGal;
R6 denotes hydrogen or CrC4-alkyl;
R7 and R8 independently denote Rb;
R9 and R10 independently denote hydrogen or CrC4-alkyl;
R11 denotes hydrogen, CrC4-alkyl or CrC4-alkylene-P(R14)2;
R12 denotes hydrogen, CrC4-alkyl or CrC4-alkylene-P(R14)2;
R13 denotes hydrogen, OH, C C4-alkoxy, OS02C C6-alkyl,
OS02-C C6-fluoroalkyl; OS02-phenyl optionally substituted with 1 to 5 Ra;
R14 denotes CrC4-alkyl, cyclohexyl, adamantyl, or phenyl optionally substituted with 1 to 5 Ra;
Rp denotes a peptide optionally linking the compound of formula (I) to a co- active;
PGac denotes a protecting group for a carboxylic acid;
PGam denotes a protecting group for an amine; and
PGal denotes a protecting group for an alcohol.
4. A compound according to claim 3, wherein the compound has formula (Ic') or (Ic")
Figure imgf000072_0001
(IC) (Ic") wherein
L denotes P(R1)3 or R4
Figure imgf000073_0001
each R1 independently denotes Ci-C4-alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 Ra;
each R4 independently denotes CrC4-alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 Ra;
Rx denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
CH(OR5)CH3, (CH2)4OR5, CH2SR6, CH2CH2SCH3, (CH2)4NR7R8,
(CH2)3NHC(NH)(NH2), CH2C02Rc, CH2CH2C02Rc, CH2CONR9R10,
9R10,
Figure imgf000073_0002
RN denotes NHRP or NRbRd;
Rd denotes Rb; or
Rd and Rx may together form -(CH2)3-;
u denotes 0 or 1 ; and
A, R, R5, R6, R7, R8, R9, R10, R11, R12, R13, Ra, Rb, Rc and Rp are as defined for the compound of claim 3.
5. A compound according to claim 3, wherein the compound has formula (Id') or (Id")
Figure imgf000074_0001
')
Figure imgf000074_0002
(Id")
wherein
L denotes P(R1)3 or
Figure imgf000074_0003
each R1 independently denotes Ci-C4-alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 Ra;
each R4 independently denotes CrC4-alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 Ra;
R9 denotes Rb;
Rx denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl,
CH(OR5)CH3, (CH2)4OR5, CH2SR6, CH2CH2SCH3, (CH2)4NR7R8,
(CH2)3NHC(NH)(NH2)., CH2C02Rc, CH2CH2C02Rc, CH2CONR9R10,
CH2CH2CONR9R10,
Figure imgf000075_0001
R9 and Rx may together form -(CH2)3-;
u denotes 0 or 1 ;
v denotes 0 or 1 ; and
A, R, R5, R6, R7, R8, R9, R10, R11, R12, R13, Ra, Rb, Rc, Rz, and t are as defined in claim 3.
6. A compound according to claim 3, wherein the compound has formula (le') or (le")
Figure imgf000075_0002
wherein
L denotes P(R1)3 or
Figure imgf000075_0003
each R1 independently denotes CrC4-alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 Ra; each R4 independently denotes Ci-C4-alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 Ra;
Rx denotes methyl, ethyl isopropyl, sec-butyl, 2-methyl-propyl, CH(OR5)CH3, (CH2)4OR5, CH2SR6, CH2CH2SCH3, (CH2)4NR7R8, (CH2)3NHC(NH)(NH2),
CH c, CH2CH2C02Rc, CH2CONR9R10, CH2CH2CONR9R10,
Figure imgf000076_0001
7. A compound according to claim 2, wherein the compound has formula (If)
G
L Au N /
\ A
\ R
(if)
wherein
L denotes P(R1)3 or
R4
Figure imgf000076_0002
each R1 independently denotes CrC4-alkyl, cyclohexyl, adamantyl; or phenyl optionally substituted with 1 to 5 Ra; each R4 independently denotes Ci-C4-alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 Ra;
A denotes S02 or C(=0);
R denotes hydrogen, d-C6-alkyl or CrC6-fluoroalkyl; phenyl optionally substituted with 1 to 5 Ra; or a pyridinyl which is optionally quaternized with hydrogen or methyl;
G denotes hydrogen, CrC6-alkyl, C3-C6-cycloalkyl, phenyl optionally substituted with 1 to 5 Ra; naphthyl optionally substituted with 1 to 5 Ra; C5-Ci0- heteroaryl optionally substituted with 1 to 5 Ra; or A-R;
each Ra independently denotes halogen, OH, N02, CrC4-alkyl, CrC4-alkoxy or N(Rb)2;
each Rb independently denotes hydrogen, CrC4-alkyl, (CH2)i-4C02Rc or p Gam.
each Rc independently denotes hydrogen, CrC4-alkyl, or PGac;
PGac denotes a protecting group for a carboxylic acid; and
PGam denotes a protecting group for an amine.
8. A compound according to claim 2, wherein the compound has formula (lla') or (ll ")
Figure imgf000077_0001
(lla') (lla")
wherein
Y denotes
Figure imgf000077_0002
w denotes an integer from 1 to 4;
u denotes 0 or 1 ;
RN denotes NHRP or NRbRb and
A, R, R2, R3, R14, Rb and Rp are as defined in claim 3.
9. A compound according to claim 2, wherein the compound has formula (lib') or (lib")
Figure imgf000078_0001
(lib')
Figure imgf000078_0002
(lib")
wherein
t denotes an integer from 1 to 4;
v denotes 0 or 1 ;
Rz denotes C(0)Rp or C02Rc;
Y is as defined for the compound of formula (I la); and
A, R, Rb, Rc, Rp, and u are as defined in claim 3.
10. A compound according to claim 2, wherein the compound has formula (lie') or (lie")
Figure imgf000079_0001
')
Figure imgf000079_0002
(lie")
wherein
u denotes 0 or 1 ;
v denotes 0 or 1 ;
R9 denotes Rb;
Rx denotes methyl, ethyl, isopropyl, sec-butyl, 2-methyl-propyl, CH(OR5)CH3, (CH2)4OR5, CH2SR6, CH2CH2SCH3, (CH2)4NR7R8, (CH2)3NHC(NH)(NH2), CH2C02Rc, CH2CH2C02Rc, CH2CONR9R10, CH2CH2CONR9R10,
Figure imgf000079_0003
R9 and Rx may together form -(CH2)3-; and t, A, R, R\ R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, Rb and Rc are as defined in claim 3.
1 1 . A compound having formula (III) for use in therapy
Figure imgf000080_0001
(III)
wherein
L denotes P(R1)3 or
R4
Figure imgf000080_0002
each R1 independently denotes Ci-C4-alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 Ra;
each R4 independently denotes CrC4-alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 Ra;
each Ra independently denotes halogen, OH, N02, CrC4-alkyl, CrC4-alkoxy or N(Rb)2;
each Rb independently denotes hydrogen, CrC4-alkyl, or (CH2)i-4C02Rc; each Rc independently denotes hydrogen or CrC4-alkyl;
n denotes and integer from 0 to 4,
R15 denotes N-AR;
A denotes S02 or C(=0); and
R denotes hydrogen, d-C6-alkyl or CrC6-fluoroalkyl; or phenyl optionally substituted with 1 to 5 Ra.
12. A compound according to any preceding claim, wherein the Au is Au(l).
13. A compound according to any preceding claim, wherein R denotes
CrC6-alkyl, CrC6-fluoroalkyl; or phenyl optionally substituted with 1 to 5 Ra.
14. A compound according to any preceding claim, wherein R denotes S02CH3, S02Ci-C6-perfluoroalkyl, S02C6H5Me, SO2C6H5NO2 or COC6H5Br.
15. A compound according to any preceding claim, wherein L denotes P(R1 )3-
16. A compound according to any preceding claim, wherein L denotes P(CH3)3, P(C2H5)3 or PPh3.
17. A compound according to any of claims 2, 3, 4, 5, 6 or 10, wherein R5
denotes hydrogen, C C4-alkyl, S02CH3, S02CF3, S02C6H5Me, or
S02C6H5N02.
18. A compound according to any of claims 2, 3, 5, 8 or 10, wherein
v denotes 1 ; and
t denotes 2.
19. A compound according to any of claims 2, 3, 5, 8 or 10, wherein
v denotes 0.
20. A compound according to any of claims 2 to 19, wherein
Rb denotes hydrogen, C C4-alkyl, -CH2C6H5, (CH2)1-4C02CH3 or phenyl.
21 . A compound according to any of claims 2 to 20, wherein
Rc denotes hydrogen or Ci-C4-alkyl.
22. A compound according to any of claims 2 to 21 , wherein u denotes 0.
23. A compound according to any of claims 2 to 22, wherein Rp denotes a
peptide containing 1 to 50 amino acids.
24. A compound of formula (III), for use in therapy
Figure imgf000082_0001
(III)
wherein
each of Xi, X2, X4 and X5 denotes N, CR15 or CR16,
X3 denotes N, CR15, CR16 or O, providing that
and X2 do not both denote N,
X4 and X5 do not both denote N,
when X3 denotes O, X2 and X4 denote CR16, and
only one of Xi, X2, X3, X4 and X5 denotes CR15;
L denotes P(R1)3 or
Figure imgf000082_0002
each R1 independently denotes CrC4-alkyl, cyclohexyl, adamantyl, phenyl optionally substituted with 1 to 5 Ra;
each R4 independently denotes CrC4-alkyl, cyclohexyl or adamantyl; or phenyl optionally substituted with 1 to 5 Ra;
R15 denotes O" C02 ", NRb ", N-AR", A-N-A-R", ANRb " or R17, providing that when R15 denotes R17, the compound of formula (III) is accompanied by a counterion Z~;
A denotesS02 or C(=0);
R denotes hydrogen, d-C6-alkyl or CrC6-fluoroalkyl; or phenyl optionally substituted with 1 to 5 Ra;
each R16 independently denotes hydrogen, halogen, OH, N02, CrC4-alkyl, CrC4-alkoxy, C(0)ORc, C(0)N(Rb)2, N(Rb)2, S02R, S02OR or S02N(Rb)2, wherein two adjacent R16 groups may together form -(CH)4-, -N(CH)3-, -CHN(CH)2-, -NN(CH)2-,-NCHNCH-, -N(CH)2N-, -CHNHCH-, -NH(CH)2-, -NHCHN-, -NHNCH-;
each Ra independently denotes halogen, OH, N02, Ci-C4-alkyl, Ci-C4-alkoxy or N(Rb)2;
each Rb independently denotes hydrogen, Ci-C4-alkyl, -CH2C6H5, or (CH2)1-4C02Rc, or phenyl;
each Rc independently denotes hydrogen or Ci-C4-alkyl;
R17 denotes hydrogen, halogen, Ci-C4-alkyl, Ci-C4-alkoxy, C(0)ORc, C(0)N(Rb)2, N(Rb)2, S02R, S02OR or S02N(Rb)2; and
Z~ denotes a pharmaceutically acceptable anion.
25. A compound according to any preceding claim, for use in treating cancer.
26. A compound according to claim 25, wherein the cancer cells are
hyperpolarised.
27. A compound according to claim 25, wherein the cancer cells are
characterised by overexpressing thioredoxin reductase.
28. A compound according to claim 25, wherein the cancer is a slow growing cancer.
29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 and one or more pharmaceutically acceptable excipients and/or diluents.
30. Use of a compound according to any one of claims 1 to 24 for the
manufacture of a medicament for use in treating cancer.
31 . A compound according to any one of claims 1 -24, for use in inhibiting a selenosulphide protein, preferably thioredoxin reductase.
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