WO2003102538A2 - Bibliotheque chimique combinatoire ii - Google Patents

Bibliotheque chimique combinatoire ii Download PDF

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Publication number
WO2003102538A2
WO2003102538A2 PCT/US2003/016898 US0316898W WO03102538A2 WO 2003102538 A2 WO2003102538 A2 WO 2003102538A2 US 0316898 W US0316898 W US 0316898W WO 03102538 A2 WO03102538 A2 WO 03102538A2
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WIPO (PCT)
Prior art keywords
amino acid
side chain
alkylene
naturally occurring
independently
Prior art date
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PCT/US2003/016898
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English (en)
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WO2003102538A3 (fr
Inventor
Luis Serrano
Cayetano Gonzales
Luis Bejarano
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Europaisches Laboratorium fuer Molekularbiologie EMBL
WILLIAMS KATHLEEN M
Original Assignee
Europaisches Laboratorium fuer Molekularbiologie EMBL
WILLIAMS KATHLEEN M
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Priority to AU2003247435A priority Critical patent/AU2003247435A1/en
Publication of WO2003102538A2 publication Critical patent/WO2003102538A2/fr
Publication of WO2003102538A3 publication Critical patent/WO2003102538A3/fr
Anticipated expiration legal-status Critical
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/047—Simultaneous synthesis of different peptide species; Peptide libraries
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • J are the same or different and each J is independently CR I T R.2 ;. and
  • n is an integer from 0 to 10;
  • n is an integer from 0 to 10;
  • T 1 and T 2 are the same or different and each T 1 and each T 2 is independently one of the groups having the structures represented by the formulae:
  • p is an integer from 0 to 20;
  • J are the same or different and each J is independently CR l ⁇ R.2. ;
  • X are the same or different and each X is independently O, S, NR 4 or CR 4 R 4 ;
  • A are the same or different and each A is independently O, S or NR '
  • R 4 are the same or different and each R 4 is independently hydrogen, alkyl or a protecting group
  • protecting group refers to a group which reacts selectively with the desired functionality in good yield to give a derivative that is stable to the reactions for which protection is desired and can be selectively removed from the derivative to yield the desired functionality.
  • pharmaceutically acceptable salt refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic or organic acids and bases.
  • inorganic bases include metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium, and zinc.
  • Appropriate organic bases may be selected, for example, from N,N- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), and procaine.
  • G 1 are the same for each compound of the library of the invention and G 2 are the same for each compound of the library of the invention.
  • At least one group D preferably at least two, more preferably at least three, even more preferably at least four, still more preferably at least five groups D and particularly all groups D, except for any group D which is GR ⁇ T 1 or CT ! T 2 , are independently CR*R 2 wherein each R 1 and each R 2 is independently H, R 4 2 NCR 10 2 (CO)NR 4 -, R 4 O(CO)CR 10 2 NR 4 (CO)-, a side chain of a naturally occurring amino acid, a substituted side chain of a naturally occurring amino acid or a side chain of a naturally occurring amino acid protected by one or more protecting groups.
  • at least one of R 1 and R 2 is not H for each group D which is CR !
  • Each T 1 and each T 2 is independently one of the groups having the structures represented by the formulae:
  • each R is H.
  • p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • p is not 0. More preferably, p is 4, 5, 6, 7 or 8. Even more preferably, p is 5, 6 or 7, particularly 6.
  • R 3 is NR 4 or O, preferably NR 4 , particularly NH, and when T 1 or T 2 is the group having the structure represented by the formula
  • R is preferably -CX-, more preferably -CO-. This embodiment is particularly preferred when at least one Y is not an amino acid residue mimetic.
  • R 3 is a divalent radical of a side chain of a naturally occurring amino acid, a divalent radical of a substituted side chain of a naturally occurring amino acid or a divalent radical of a side chain of a naturally occurring amino acid protected by one or more protecting groups.
  • R 3 is a divalent radical of a side chain of a naturally occurring amino acid. This embodiment is particularly preferred when all Y are amino acid residue mimetics, for example -(CX)DA- or -AD(CX)-.
  • each T and each T is independently one of the groups having the structures represented by the formulae:
  • each R is H.
  • L 2 are the same or different and each L 2 is independently CR ⁇ 2 .
  • T 1 and T 2 are each independently one of the groups having the structures represented by the formula:
  • u is an integer from 0 to 20;
  • v is an integer from 0 to 20;
  • w is 0 or 1 ;
  • L are the same or different and each L is independently CR l ⁇ R>2
  • at least two groups D are independently CHT 1 .
  • one group T 1 is one of the groups having the structures represented by the formula:
  • one group T 1 is the group having the structure represented by the structure:
  • each R is H.
  • At least one group D is CHT 1 wherein T 1 is the group having the structure represented by the formula:
  • At least two groups D are independently CHT 1 , wherein in one group D which is CHT 1 , T 1 is the group having the structure represented by the formula:
  • T 1 is -NHCOCH 2 NH 2 .
  • u isO, 1,2,3,4,5,6,7,8,9,10,11,12,13, 14,15, 16,17, 18, 19 or 20.
  • u is not 0. More preferably, u is 1, 2, 3, 4 or 5, still more preferably 2, 3 or 4, particularly 3.
  • v is 0, 1, 2, 3, 4, 5, 6, 1, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • u is not 0. More preferably, v is 0, 1, 2, 3 or 4, still more preferably 1, 2 or 3, particularly 2.
  • w is 0 or 1, preferably 1.
  • u + v + w is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, more preferably 2, 3, 4, 5, 6, 7, 8 or 9, still more preferably 3, 4, 5, 6, 1, 8 or 9, still more preferably, 5, 6, 7, 8 or 9, still more preferably, 6, 7 or 8, particularly 7.
  • each group D is independently adjacent to a
  • O S NR 4 group which is O, S or NR and adjacent to another group which is ⁇ 1 ⁇ , ⁇ 1 ⁇ , or ⁇ 1 ⁇ .
  • each group D is separated from the nearest other group D by at least one group which is not D.
  • each group D is separated from the nearest other group D by two groups which are not D.
  • each group which is not D is independently O, S,
  • At least one group J preferably at least two, more preferably at least three, even more preferably at least four, still more preferably at least five groups J and particularly all groups J are independently CR J R 2 wherein each R 1 and each R 2 is independently H, a side chain of a naturally occurring amino acid, a substituted side chain of a naturally occurring amino acid or a side chain of a naturally occurring amino acid protected by one or more protecting groups.
  • at least one of R 1 and R 2 is not H for each group J.
  • each R 2 is H and each R 1 is independently a side chain of a naturally occurring amino acid, a substituted side chain of a naturally occurring amino acid or a side chain of a naturally occurring amino acid protected by one or more protecting groups.
  • each R 2 is H and each R 1 is independently a side chain of a naturally occurring positively charged amino acid, a side chain of a naturally occurring aromatic amino acid, a substituted side chain of a naturally occurring positively charged amino acid, a substituted side chain of a naturally occurring aromatic amino acid, a side chain of a naturally occurring positively charged amino acid protected by one or more protecting groups or a side chain of a naturally occurring aromatic amino acid protected by one or more protecting groups.
  • each R 2 is H and each R 1 is independently a side chain of a naturally occurring positively charged amino acid or a side chain of a naturally occurring aromatic amino acid.
  • at least one group J preferably at least two, more preferably at least three, even more preferably at least four, still more preferably at least five groups D and particularly all groups J which are C*R !
  • R 2 wherein C* is a stereogenic centie are at least 60%, more preferably at least 70%, even more preferably at least 80%, still more preferably at least 90%, still more preferably at least 95%, still more preferably at least 96%, still more preferably at least 97%, still more preferably at least 98%, particularly at least 99% C* of D-configuration.
  • at least one group J preferably at least two, more preferably at least three, even more preferably at least four, still more preferably at least five groups J and particularly all groups D which are C*R !
  • C* is a stereogenic centie are at least 60%, more preferably at least 70%), even more preferably at least 80%>, still more preferably at least 90%>, still more preferably at least 95%>, still more preferably at least 96%o, still more preferably at least 97%, still more preferably at least 98%>, particularly at least 99%o C* of L-configuration.
  • C* is substantially homochiral.
  • C* is substantially homochiral in the D-configuration.
  • C* is substantially homochiral in the L-configuration.
  • the group K is CR 1 wherein R 1 is H, a side chain of a naturally occurring amino acid, a substituted side chain of a naturally occurring amino acid or a side chain of a naturally occurring amino acid protected by one or more protecting groups.
  • R 1 is H or a side chain of a naturally occurring amino acid.
  • the group K is C*R J wherein C* is a stereogenic centie.
  • C* is at least 60%), more preferably at least 70%>, even more preferably at least 80%, still more preferably at least 90%, still more preferably at least 95%, still more preferably at least 96%>, still more preferably at least 97%, still more preferably at least 98%, particularly at least 99% C* of D- configuration.
  • C* is at least 60%), more preferably at least 70%>, even more preferably at least 80%), still more preferably at least 90%>, still more preferably at least 95%, still more preferably at least 96%, still more preferably at least 97%>, still more preferably at least 98%), particularly at least 99%) C* of L-configuration.
  • C* is substantially homochiral.
  • C* is substantially homochiral in the D-configuration.
  • C* is substantially homochiral in the L-configuration.
  • At least one group L 1 preferably at least two, more preferably at least three, even more preferably at least four, still more preferably at least five groups L and particularly all groups L 1 are independently CR ⁇ 2 wherein each R 1 and each R 2 is independently H, a side chain of a naturally occurring positively charged amino acid, a side chain of a naturally occurring aromatic amino acid, a substituted side chain of a naturally occurring positively charged amino acid, a substituted side chain of a naturally occurring aromatic amino acid, a side chain of a naturally occurring positively charged amino acid protected by one or more protecting groups or a side chain of a naturally occurring aromatic amino acid protected by one or more protecting groups
  • each R is H and each R 1 is independently a side chain of a naturally occurring positively charged amino acid, a side chain of a naturally occurring aromatic amino acid, a substituted side chain of a naturally occurring positively charged amino acid, a substituted side chain of a naturally occurring aromatic amino acid, a side chain of a naturally occurring positively charged amino acid protected by one or more protecting groups or a side chain of a naturally occurring aromatic amino acid protected by one or more protecting groups.
  • each R 2 is H and each R 1 is independently a side chain of a naturally occurring positively charged amino acid.
  • at least one group L 1 preferably at least two, more preferably at least three, even more preferably at least four, still more preferably at least five groups L 1 and particularly all groups L 1 which are C*R !
  • R 2 wherein C* is a stereogenic centre are at least 60%, more preferably at least 70%, even more preferably at least 80%), still more preferably at least 90%>, still more preferably at least 95%>, still more preferably at least 96%, still more preferably at least 97%, still more preferably at least 98%o, particularly at least 99%) C* of D-configuration.
  • at least one group L 1 preferably at least two, more preferably at least three, even more preferably at least four, still more preferably at least five groups L 1 and particularly all groups L 1 which are C*R !
  • At least one group L 2 preferably at least two, more preferably at least three, even more preferably at least four, still more preferably at least five groups L 2 and particularly all groups L 2 are independently CR ! R 2 wherein each R 1 and each R 2 is independently H, a side chain of a naturally occurring positively charged amino acid, a side chain of a naturally occurring aromatic amino acid, a substituted side chain of a naturally occurring positively charged amino acid, a substituted side chain of a naturally occurring aromatic amino acid, a side chain of a naturally occurring positively charged amino acid protected by one or more protecting groups or a side chain of a naturally occurring aromatic amino acid protected by one or more protecting groups. Even more preferably, each R 2 is H and each R 1 is independently a side chain of a naturally occurring aromatic amino acid.
  • At least one group L 2 preferably at least two, more preferably at least three, even more preferably at least four, still more preferably at least five groups L 2 and particularly all groups L 2 which are C*R L R 2 wherein C* is a stereogenic centie are at least 60%, more preferably at least 70%, even more preferably at least 80%, still more preferably at least 90%, still more preferably at least 95%, still more preferably at least 96%, still more preferably at least 97%o, still more preferably at least 98%>, particularly at least 99%) C* of L-configuration.
  • C* is substantially homochiral.
  • C* is substantially homochiral in the D- configuration.
  • C* is substantially homochiral in the L-configuration.
  • each compound of the library of the invention or the compound of the invention has independently a combination of groups G and G selected from the combinations shown in table 1 below.
  • G 1 and G 2 are the same for each compound of the library of the invention wherein the combination of G 1 and G 2 is selected from the combinations shown in table 1 above.
  • G 1 is CR ! R 2 wherein R 1 is -CH 2 CH(CH 3 ) 2 and R 2 is H and G 2 is CR ! R 2 wherein R 1 is -CH 2 (C 6 H 5 ) and R 2 is H is particularly preferred when no groups D are CR ⁇ or CT ! T 2 .
  • at least one of groups G 1 and G 2 more preferably both groups G 1 and G 2 which are C*R !
  • R 2 wherein C* is a stereogenic centie are at least 60%, more preferably at least 70%, even more preferably at least 80%>, still more preferably at least 90%, still more preferably at least 95%>, still more preferably at least 96%>, still more preferably at least 97%, still more preferably at least 98%o, particularly at least 99% C* of D-configuration.
  • groups G 1 and G 2 preferably both groups G 1 and G 2 which are C*R !
  • R 2 wherein C* is a stereogenic centie are at least 60%, more preferably at least 70%, even more preferably at least 80%, still more preferably at least 90%, still more preferably at least 95%, still more preferably at least 96%, still more preferably at least 97%, still more preferably at least 98%>, particularly at least 99% C* of L-configuration.
  • C* is substantially homochiral.
  • C* is substantially homochiral in the D-configuration.
  • C* is substantially homochiral in the L-configuration.
  • each X is independently O or NR 4 , more preferably O or NH. Particularly, X is O.
  • each A is independently O or NR 4 , more preferably O or NH.
  • A is H.
  • each Y is independently -(CX)DA-, -AD(CX)-, a divalent radical of a side chain of a naturally occurring amino acid, a divalent radical of a substituted side chain of a naturally occurring amino acid or a divalent radical of a side chain of a naturally occurring amino acid protected by one or more protecting groups.
  • each Y is independently -(CX)DA-, preferably -(CO)D(NR 4 )-, more preferably -(CO)D(NR 4 )-.
  • each Y is independently a divalent radical of a side chain of a naturally occurring amino acid.
  • each R 1 and each R 2 independently is R 4 2 NCR 10 2 (CO)NR 4 -, R 4 O(CO)CR 10 2 NR 4 (CO)-, a side chain of a naturally occurring amino acid, a substituted side chain of a naturally occurring amino acid or a side chain of a naturally occurring amino acid protected by one or more protecting groups. More preferably, each R 1 is independently a side chain of a naturally occurring amino acid and each R 2 is H.
  • each R 3 not comprising part of T 1 or T 2 is independently a single bond, a divalent radical of a side chain of a naturally occurring amino acid, a divalent radical of a substituted side chain of a naturally occurring amino acid or a divalent radical of a side chain of a naturally occurring amino acid protected by one or more protecting groups. More preferably, each R 3 is independently a single bond or a divalent radical of a side chain of a naturally occurring amino acid.
  • each R 3 comprising part of T 1 or T is independently a single bond, -O-, -S-,
  • a divalent radical of a side chain of a naturally occurring amino acid a divalent radical of a substituted side chain of a naturally occurring amino acid or a divalent radical of a side chain of a naturally occurring amino acid protected by one or more
  • O protecting groups more preferably a single bond, -O-, -NH-, ⁇ X ⁇ or a divalent radical of a side chain of a naturally occurring amino acid.
  • each R 4 is independently hydrogen or a protecting group. More preferably, each R 4 is hydrogen.
  • R 4 2 NCR 10 2 (CO)NR 4 - is R 4 2 NCH 2 (CO)NR 4 -, more preferably
  • R 4 O(CO)CR 10 2 NR 4 (CO> is R 4 O(CO)CH 2 NR 4 (CO)-, more preferably CH 3 (CO)O(CO)CH 2 NR 4 (CO)-
  • alkyl groups means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical.
  • the alkyl group is preferably C 3 to C ⁇ 2 , more preferably C 5 to C 10 , more preferably C 5 to C 7 .
  • the alkyl group is preferably Q to C 16 , more preferably d to C 4 , more preferably methyl.
  • Reference in the present specification to an alkoxy group means an alkyl-O- group.
  • alkoyl group means an alkyl-CO- group.
  • the alkyl groups may be substituted or unsubstituted, preferably unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent.
  • Substituents may include halogen atoms and halomethyl groups such as CF 3 and CC1 3 ; oxygen containing groups such as oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkoxy, alkoyl, alkoyloxy, aryloxy, aryloyl and aryloyloxy; nitiogen containing groups such as amino, amido, alkylamino, dialkylamino, cyano, azide, nitiato and nitro; sulphur containing groups such as thiol, alkylthiol, sulphonyl and sulphoxide; heterocyclic groups containing one or more, preferably one, heteroatom, such as thienyl, furanyl,
  • amino includes substituted or unsubstituted amino.
  • halogen means a fluorine, chlorine, bromine or iodine radical, preferably fluorine or chlorine radical.
  • a side chain of a naturally occurring amino acid means one of the side chains of the naturally occurring amino acids shown in table 2 below:
  • a side chain of a naturally occurring amino acid may not be the side chain of Cysteine.
  • a side chain of a naturally occurring amino acid may be substituted or unsubstituted, preferably unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent.
  • Substituents may include the side chains of the naturally occurring amino acids, T 1 groups as defined above, halogen atoms and halomethyl groups such as CF 3 and CC1 3 ; oxygen containing groups such as oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkoxy, alkoyl, alkoyloxy, aryloxy, aryloyl and aryloyloxy; nitiogen containing groups such as amino, amido, alkylamino, dialkylamino, cyano, azide, nitiato and nitro; sulphur containing groups such as thiol, alkylthiol, sulphonyl and sulphoxide; heterocyclic groups containing one or
  • Preferred substituents are the T 1 groups, particularly -NHCOCH 2 NH 2 .
  • a particularly preferred substituted side chain of a naturally occurring amino acid is the group having the formula represented by the structure:
  • the alkylene groups may be substituted or unsubstituted, preferably unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent.
  • Substituents may include halogen atoms and halomethyl groups such as CF 3 and CC1 3 ; oxygen containing groups such as oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkoxy, alkoyl, alkoyloxy, aryloxy, aryloyl and aryloyloxy; nitrogen containing groups such as amino, amido, alkylamino, dialkylamino, cyano, azide, nitrato and nitro; sulphur containing groups such as thiol, alkylthiol, sulphonyl and sulphoxide; heterocyclic groups containing one or more, preferably one, heteroatom, such as thienyl, furanyl, pyrrolyl,
  • a divalent radical of a side chain of a naturally occurring amino acid means a divalent radical (or trivalent radical in the case of the side chain of Proline) formed from a monovalent side chain (or divalent radical in the case of the side chain of Proline) of the naturally occurring amino acids set out above by the notional removal of one or more atoms.
  • divalent radicals of a side chain of a naturally occurring amino acid are notionally formed by the removal of H, OH or NH 2 .
  • divalent radicals of the side chains of the naturally occurring amino acids include, but are not limited to those shown in table 3 below:
  • the divalent radicals of the side chain are also attached to the N adjacent to the ⁇ carbon.
  • a divalent radical of a side chain of a naturally occurring amino acid may be substituted or unsubstituted, preferably unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent.
  • Substituents may include the side chains of the naturally occurring amino acids, T 1 groups as defined above, halogen atoms and halomethyl groups such as CF and CC1 3 ; oxygen containing groups such as oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkoxy, alkoyl, alkoyloxy, aryloxy, aryloyl and aryloyloxy; nitrogen containing groups such as amino, amido, alkylamino, dialkylamino, cyano, azide, nitiato and nitro; sulphur containing groups such as thiol, alkylthiol, sulphonyl and sulphoxide; heterocyclic groups containing one
  • Preferred substituents are the T 1 groups, particularly -NHCOCH 2 NH2.
  • a particularly preferred substituted side chain of a naturally occurring amino acid is the group having the formula represented by the structure:
  • the positively charged amino acids are Lysine and Arginine.
  • the aromatic amino acids are Phenylalanine, Tyrosine, Tryptophan and Histidine.
  • L-configuration means the absolute configuration of the ⁇ carbon in the partial-structure of the compounds of the present invention as represented by the following formula:
  • D-configuration means the absolute configuration of the ⁇ carbon in the partial-structure of the compounds of the present invention as represented by the following formula:
  • n is selected from the integers 0 to 10;
  • n is selected from the integers 0 to 10;
  • Q 1 are the same or different and each Q 1 is independently CR ⁇ 2 ;
  • Q 2 are the same or different and each Q 2 is independently CR 1 ;
  • T 1 and T 2 are the same or different and each T 1 and each T 2 is independently one of the groups having the structures represented by the formulae:
  • u is an integer from 0 to 20;
  • w is 0 or 1;
  • L 1 are the same or different and each L 1 is independently CR ! R 2 ;
  • R 3 are the same or different and each R 3 is independently a single bond, alkylene,
  • a , A a divalent radical of a side chain of a naturally occurring amino acid, a divalent radical of a substituted side chain of a naturally occurring amino acid or a divalent radical of a side chain of a naturally occurring amino acid protected by one or more protecting groups;
  • R 4 are the same or different and each R 4 is independently hydrogen, alkyl or a protecting group
  • R 10 are the same or different and each R 10 is independently hydrogen or a side chain of a naturally occurring amino acid.
  • a preferred compound of the present invention, or pharmaceutically acceptable derivative thereof, has the structure represented by the formula II:
  • n is selected from the integers 0 to 10;
  • n is selected from the integers 0 to 10;
  • r is selected from the integers 0 to 10; Q 1 are the same or different and each Q 1 is independently CR J -R>2.
  • Q 2 are the same or different and each Q 2 is independently CR 1 ;
  • S' is R' or T 1
  • T 1 and T 2 are the same or different and each T 1 and each T 2 is independently one of the groups having the structures represented by the formulae:
  • u is an integer from 0 to 20;
  • w is 0 or 1;
  • L 1 are the same or different and each L 1 is independently CR R 2 ;
  • L are the same or different and each L is independently CR l ⁇ R ⁇ 2' .
  • Y are the same or different and each Y is independently -(CO)Q 1 (NR 4 )-, -(NR ⁇ Q ⁇ CO)-, a divalent radical of a side chain of a naturally occurring amino acid, a divalent radical of a substituted side chain of a naturally occurring amino acid or a divalent radical of a side chain of a naturally occurring amino acid protected by one or more protecting groups;
  • R 3 are the same or different and each R 3 is independently a single bond, alkylene,
  • a divalent radical of a side chain of a naturally occurring amino acid a divalent radical of a substituted side chain of a naturally occurring amino acid or a divalent radical of a side chain of a naturally occurring amino acid protected by one or more protecting groups;
  • R 4 are the same or different and each R 4 is independently hydrogen, alkyl or a protecting group
  • R , R , R and R are the same or different and are independently H or a side chain of a naturally occurring amino acid, wherein the combination of R 5 , R 6 , R 7 and R 8 is selected from the combinations shown in table 4 below:
  • R 5 are the same for each compound of the library of the invention
  • R 6 are the same for each compound of the library of the invention
  • R 7 are the same for each compound of the library of the invention
  • R 8 are the same for each compound of the library of the invention wherein the combination of R 5 , R 6 , R 7 and R s is selected from the combinations shown in table 4 above.
  • S 1 is T 1 .
  • S 2 i • s ⁇ TT>2.
  • S 1 and S 2 are the same for each compound of the library of the invention.
  • T 1 or T 2 is the group having the formula represented by the structure:
  • each R is H.
  • T 1 is the group having the structure represented by the formula:
  • each R 4 is H.
  • one of T 1 or T 2 is the group having the structure represented by the formula:
  • T is the group having the structure represented by the formula:
  • each compound of the library of the invention or the compound of the invention at least one group Q 1 , preferably at least two, more preferably at least three, even more preferably at least four, still more preferably at least five groups Q 1 and particularly all groups Q 1 are independently C ⁇ R 2 wherein each R 1 and each R 2 is independently H, R 4 2 NCR 10 2 (CO)NR 4 -, R 4 O(CO)CR 10 2 NR 4 (CO)-, a side chain of a naturally occurring amino acid, a substituted side chain of a naturally occurring amino acid or a side chain of a naturally occurring amino acid
  • each compound of the library of the invention or the compound of the invention at least one group Q 2 , preferably at least two, more preferably at least three, even more preferably at least four, still more preferably at least five groups Q 2 and particularly all groups Q 2 are independently CR ! R 2 wherein each R 1 and each R 2 is independently H, R 4 2 NCR 10 2 (CO)NR 4 -, R 4 O(CO)CR 10 2 NR 4 (CO)-, a side chain of a naturally occurring amino acid, a substituted side chain of a naturally occurring amino acid or a side chain of a naturally occurring amino acid protected by one or more protecting groups. More preferably, each R 2 is H and each R 1 is independently a side chain of a naturally occurring amino acid.
  • At least one group Q optionally at least two, optionally at least three, optionally at least four, optionally at least five and optionally all groups Q 2 are C*R* wherein C* is a stereogenic centre.
  • at least one group Q 2 preferably at least two, more preferably at least three, even more preferably at least four, still more preferably at least five groups Q 2 and particularly all groups Q 2 which are independently C ⁇ R 1 wherein C* is a stereogenic centre are at least 60%>, more preferably at least 70%>, even more preferably at least 80%>, still more preferably at least 90% still more preferably at least 95%, still more preferably at least 96%, still more preferably at least 97%o, still more preferably at least 98%>, particularly at least 99% C* of D-configuration.
  • At least one group Q 2 preferably at least two, more preferably at least three, even more preferably at least four, still more preferably at least five groups Q 2 and particularly all groups Q 2 which are C*R* wherein C* is a stereogenic centre are at least 60%, more preferably at least 70%, even more preferably at least 80%, still more preferably at least 90%), still more preferably at least 95%, still more preferably at least 96%>, still more preferably at least 97%, still more preferably at least 98%>, particularly at least 99%> C* of L-configuration.
  • C* is substantially homochiral.
  • C* is substantially homochiral in the D- configuration.
  • C* is substantially homochiral in the L-configuration.
  • any stereogenic carbon atoms between a carbonyl moiety and a nitrogen atom are in the D-configuration.
  • X 1 , X 2 , X 3 and X are the same or different and each X , X , X 3 and X 4 is independently a residue of a naturally occurring amino acid;
  • a "naturally occurring amino acid” means an amino acid selected from those shown in table 5 below:
  • a naturally occurring amino acid may not be Cysteine.
  • the amino acid residues of the compounds of the library are at least 60%, more preferably at least 70%, even more preferably at least 80%>, still more preferably at least 90%, still more preferably at least 95%>, still more preferably at least 96%, still more preferably at least 97%, still more preferably at least 98%, particularly at least 99%> C* in the D- configuration.
  • a preferred library of the present invention comprises two or more different compounds, or zwitterions or salts thereof, each compound independently having a structure represented by the formula:
  • R 9 are the same of different and each R 9 is independently a side chain of a naturally occurring amino acid
  • R 5 is a side chain of a naturally occurring amino acid
  • R 7 is a side chain of a naturally occurring amino acid.
  • a particularly preferred library of the present invention comprises two or more different compounds, or zwitterions or salts thereof, each compound independently having a structure represented by the formula:
  • R 9 are the same of different and each R 9 is independently a side chain of a naturally occurring amino acid
  • R 5 is a side chain of a naturally occurring amino acid
  • R 7 is a side chain of a naturally occurring amino acid.
  • R 5 and R 7 are selected from the combinations shown in table 4 above.
  • R are the same for each compound of the library of the invention and R are the same for each compound of the library of the invention.
  • Preferred compounds of the present invention are the compounds having structures represented by the following formulae:
  • R 9 are the same of different and each R 9 is independently a side chain of a naturally occurring amino acid
  • R 5 is a side chain of a naturally occurring amino acid
  • R 7 is a side chain of a naturally occurring amino acid.
  • Particularly preferred compounds of the present invention are the compounds having structures represented by the following formulae:
  • R 5 is a side chain of a naturally occurring amino acid
  • R 7 is a side chain of a naturally occurring amino acid.
  • Libraries and compounds of the invention maybe prepared by standard solution phase or solid phase methods in which subunits are added stepwise to growing oligomers until a desired oligomer size is reached.
  • Cyclisation may be effected either by end to end coupling of the peptide backbone, side chain to side chain coupling of side chains of the residues or residue side chain to end of peptide backbone coupling (P. Rovero, Homodetic Cyclic Peptide in Solid-Phase Synthesis: A Practical Guide (S.A. Kates and F. Albericio Eds.), Marcel Dekker, Inc., New York, USA (2000), pages 331 - 364).
  • the libraries and of the invention comprise at least one bioactive compound.
  • the compounds of the invention are bioactive.
  • each library having mutually exclusive compounds contained therein, wherein each library possesses a constant portion which is the same for all the compounds contained in the two or more libraries, and a variable portion, the variable portion of each library being constant for the compounds of that library, but variable between the two or more libraries;
  • the steps set out above can be repeated iteratively using different variable or constant portions at each iteration.
  • Such a repetition allows the progressive determination of the most preferred groups for each portion and therefore the most active compound or compounds of the library.
  • the constant and variable portions are selected from the groups D, T , T , J, X, A, Y, E, F, G 1 , G 2 , R 1 , R 2 , R 3 and R 4 , as defined herein.
  • the constant and variable portions are selected from the amino acid residue mimetics -(CX)G 1 A- (e.g. -(CO)CR 5 R 6 NR 4 -) , -(CX)G 2 A- (e.g. -(CO)CR 7 R 8 NR 4 )-, - (CX)DA- (e.g. -(CO)Q 1 NR 4 -), -EDY- (e.g. -NR 4 QT 1 Y-), -YDF- (e.g. -YQT 2 (CO)-), and -(CX)JA- (e.g. -(CO)JNR 4 -).
  • bioactive compounds of the invention have utility in the treatment of one or more of the following: neoplasms, including cancer, brain tumour, glioma, bone tumour, lung tumour, breast tumour, prostate tumour, colon tumour, hemangioma, melanoma, lung, colorectal, breast, pancreas, head and neck and other solid tumours, myeloproliferative disorders, such as leukemia, non-Hodgkin lymphoma, leukopenia, thrombocytopenia, Kaposis' sarcoma, angiogenesis disorders, inflammatory diseases (e.g.
  • allergies and inflammatory bowel disease hematological disease, neutropenia, autoimmune disease, thrombocytopenia, angiogenesis disorders, dermatological disease, ageing, wounds, burns, fibrosis, arthritis, psoriasis, respiratory tract inflammation, asthma, disorders associated with organ transplantation, cardiovascular disease, hypertension, oedema, angina, atherosclerosis, thrombosis, sepsis, disorders relating to aberrant angiogenesis, shock, reperfusion injury, ischemia, central nervous system disease,
  • Alzheimer's disease brain injury and amyotrophic lateral sclerosis, pain, renal disease, diabetes mellitus, osteoporosis, restensosis, heart disease, myeloid cell disorders, lymphoid cell disorders, peripheral vascular disease, coronary artery disease, oedema, thromboembolism, dysmenorrhea, endometiiosis, pre-eclampsia, lung disease, COPD, asthma, bone disease, renal disease, glomerulonephritis, liver disease, Crohn's disease, gastritis, ulcerative colitis, ulcer, immune disorder, autoimmune disease, arthritis, rheumatoid arthritis, psoriasis, epidermolysis bullosa, systemic lupus erythematosus, ankylosing spondylitis, Lyme disease, multiple sclerosis, neurodegeneration, stroke, brain/spinal cord injury, Parkinson's disease, motor neurone disease, neuromuscular disease, ocular
  • a bioactive compound of the invention may alternatively or additionally exhibit one or more of the following activities or effects; promotion of wound healing; effecting biorhythms or circadian cycles or rhythms; effecting the fertility of male or female subjects; effecting the metabolism, catabolism, anabolism, processing, utilization, storage or elimination, of dietary fat, lipid, protein, carbohydrate, vitamins, minerals, co-factors or other nutritional factors or component(s); effecting behavioural characteristics, including, without limitation, appetite, libido, stress, cognition (including cognitive disorders), hormonal or endocrine activity; and, in the case of enzymes, correcting deficiencies of the enzyme and treating deficiency-related diseases.
  • the bioactive compounds of the invention may be useful in treating an infectious disease.
  • Niruses are one example of an infectious agent.
  • viruses include, but are not limited to the following D ⁇ A and R ⁇ A viruses and viral families: Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Birnaviridae, Bunyaviridae, Caliciviridae, Circoviridae, Coronaviridae, Dengue, EBN, HIV, Flaviviridae, Hepadnaviridae (Hepatitis), Herpesviridae (such as, Cytomegalovirus, Herpes Simplex, He ⁇ es Zoster), Mononegavims (e.g., Paramyxoviridae, Morbillivirus, Rhabdoviridae), Orthomyxoviridae (e.g., Influenza A, Influenza B, and parainfluenza), Papiloma virus, Papovaviridae, Parvoviridae,
  • Viruses falling within these families can cause a variety of diseases or symptoms, including, but not limited to: arthritis, bronchiollitis, respiratory syncytial virus, encephalitis, eye infections (e.g., conjunctivitis, keratitis), chronic fatigue syndrome, hepatitis (A, B, C, E, Chronic Active, Delta), Japanese B encephalitis, Junin, Chikungunya, Rift Valley fever, yellow fever, meningitis, opportunistic infections (e.g., AIDS), pneumonia, Burkitt's Lymphoma, chickenpox, hemorrhagic fever, Measles, Mumps,
  • a bioactive compound of the invention may be used to treat one (or more) of these diseases.
  • Bacteria and fungi are further examples of infectious agents.
  • a bioactive compound having utility in the tieatment of an infection caused by, the following Gram-Negative and Gram-positive bacteria and bacterial families and fungi: Actinomycetales (e.g., Corynebacterium, Mycobacterium, Norcardia), Cryptococcus neoformans, Aspergillosis, Bacillaceae (e.g., Anthrax, Clostiidium), Bacteroidaceae, Blastomycosis, Bordetella, Borrelia (e.g., Borrelia burgdorferi, Brucellosis, Candidiasis, Campylobacter, Coccidioidomycosis, Cryptococcosis, Dermatocycoses, E.
  • Actinomycetales e.g., Corynebacterium, Mycobacterium, Norcardia
  • Cryptococcus neoformans Aspergillosis
  • Enterobacteriaceae Klebsiella, Salmonella (e.g., Salmonella typhi, and Salmonella paratyphi), Serratia, Yersinia), Erysipelothrix, Helicobacter, Legionellosis, Leptospirosis, Listeria, Mycoplasmatales, Mycobacterium leprae, Vibrio cholerae, Neisseriaceae (e.g., Acinetobacter, Gonorrhea, Menigococcal), Meisseria meningitidis, Pasteurellacea Infections (e.g., Actinobacillus, Heamophilus (e.g., Heamophilus influenza type B), Pasteurella), Pseudomonas, Rickettsiaceae, Chlamydiaceae, Syphilis, Shigella spp.,
  • bacterial or fungal families can cause the following diseases or symptoms, including, but not limited to: bacteremia, endocarditis, eye infections (conjunctivitis, tuberculosis, uveitis), gingivitis, opportunistic infections (e.g., AIDS related infections), paronychia, prosthesis-related infections, Reiter's Disease, respiratory tract infections, such as Whooping Cough or Empyema, sepsis, Lyme Disease, Cat-Scratch Disease, Dysentery, Paratyphoid Fever, food poisoning, Typhoid, pneumonia, Gonorrhea, meningitis (e.g., mengitis types A and B), Chlamydia, Syphilis, Diphtheria, Leprosy, Paratuberculosis, Tuberculosis, Lupus, Botulism, gangrene, tetanus, impetigo, Rheumatic Fever, Scarlet Fever, sexually
  • parasitic agents causing diseases include, but not limited to, the following families or class: Amebiasis, Babesiosis, Coccidiosis, Cryptosporidiosis, Dientamoebiasis, Dourine, Ectoparasitic, Giardiasis, Helminthiasis, Leishmaniasis, Theileriasis, Toxoplasmosis, Trypanosomiasis, and Trichomonas and Sporozoans (e.g., Plasmodium virax, Plasmodium falciparium, Plasmodium malariae and Plasmodium ovale).
  • families or class Amebiasis, Babesiosis, Coccidiosis, Cryptosporidiosis, Dientamoebiasis, Dourine, Ectoparasitic, Giardiasis, Helminthiasis, Leishmaniasis, Theileriasis, Toxoplasmosis, Trypanosomiasis, and Trichomonas and Sporozoans
  • a bioactive compound of the invention may be used to treat one (or more) of these diseases.
  • a bioactive compound of the invention may be effective in adult and pediatiic oncology including in solid phase tumours/malignancies, locally advanced tumours, human soft tissue sarcomas, metastatic cancer, including lymphatic metastases, blood cell malignancies including multiple myeloma, acute and chronic leukemias, and lymphomas, head and neck cancers including mouth cancer, larynx cancer and thyroid cancer, lung cancers including small cell carcinoma and non-small cell cancers, breast cancers including small cell carcinoma and ductal carcinoma, gastrointestinal cancers including esophageal cancer, stomach cancer, colon cancer, colorectal cancer and polyps associated with colorectal neoplasia, pancreatic cancers, liver cancer, urologic cancers including bladder cancer and prostate cancer, malignancies of the female genital tract including ovarian carcinoma, uterine (including endometiial) cancers, and solid tumour in the ovarian follicle, kidney cancers including renal cell carcinoma, brain cancers including intrinsic brain tumours
  • compositions comprising a bioactive compound of the invention can be administered in therapeutically effective dosages alone or in combination with adjuvant cancer therapy such as surgery, chemotherapy, radiotherapy, thermotherapy, and laser therapy, and may provide a beneficial effect, e. g. reducing tumour size, slowing rate of tumour growth, inhibiting metastasis, or otherwise improving overall clinical condition, without necessarily eradicating the cancer.
  • adjuvant cancer therapy such as surgery, chemotherapy, radiotherapy, thermotherapy, and laser therapy
  • a bioactive compound of the invention could also be administered in therapeutically effective amounts as a portion of an anti-cancer cocktail.
  • An anti-cancer cocktail is a mixture of a bioactive compound of the invention with one or more anti-cancer drugs in addition to a pharmaceutically acceptable carrier for delivery.
  • a bioactive compound of the invention may be used for prophylactic tieatment of cancer.
  • hereditary conditions and/or environmental situations e.g. exposure to carcinogens
  • In vitro models can be used to determine the efficacy of, and/or effective dose, of a bioactive compound of the invention as a potential cancer treatment.
  • tumour cells in Boyden Chamber assays as described in Pilkington et al., Anticancer Res., 17: 4107-9 (1997)
  • angiogenesis assays such as induction of vascularization of the chick chorioallantoic membrane or induction of vascular endothelial cell migration as described in Ribatta et al., Intl. J. Dev. Biol., 40 : 1189-97 (1999) and Li et al., Clin. Exp. Metastasis, 17 : 423-9 (1999), respectively.
  • Suitable tumour cells lines are available, e. g. from American Type Tissue Culture Collection catalogs.
  • a bioactive compound of the invention may have utility in the tieatment of malignancies and related disorders such as leukemia (including acute leukemias (e.g., acute lymphocytic leukemia, acute myelocytic leukemia
  • Assays for determining the efficacy of a library of the invention, a compound of the library of the invention or a compound of the invention in tieating one of the above-mentioned conditions will be known, or can be readily devised by, persons skilled in the art. Such assays may be in vivo, ex vivo or in vitro assays.
  • a library of the invention, a compound of the library of the invention or a compound of the present invention can be used in assays to test for one or more biological activities. If the compound exhibits activity in a particular assay, it is likely that the compound may useful in treating a disease associated with the biological activity.
  • kits comprising two or more separate libraries of the present invention.
  • a compound of the present invention for use in a method of tieatment, particularly in a method of tieatment of one or more of the conditions mentioned above.
  • the term "tieatment” includes prophylactic treatment.
  • the term “tieating” should be construed accordingly.
  • the therapy is the treatment of bacterial infection.
  • the bacteria may be gram-t ⁇ or gram-.
  • a method of treating a condition comprising administering to a patient in need of such treatment an effective dose of a compound of the present invention.
  • the condition is a bacterial infection.
  • the compounds of the invention will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension.
  • dosage levels used may vary over quite a wide range depending upon the compound used, the severity of the symptoms exhibited by the patient and the patient's body weight.
  • Figure 1 shows the results of a mortality assay on 3T3 cells using libraries of the invention.
  • Figure 2 shows the results of a mortality assay on oncogenic OCM-1 cells using libraries of the invention.
  • Figure 3 shows the results of a mortality assay on E. coli cells using libraries of the invention.
  • Figure 4 shows a comparison of the mortality assays on 3T3 cells, OCM-1 cells and E. coli cells using libraries of the invention.
  • Figures 5 A and 5B show the concentration effect of the positive and negative control libraries on E. coli growth.
  • Figure 8 shows the percentage of living and dead NIH/3T3 cells after 24 hour culture in the presence of libraries of the invention.
  • Figure 9 shows the results of a mortality assay on Listeria cells using libraries of the invention.
  • Figure 10 shows a comparison of the mortality assays on Listeria cells and E. coli cells using libraries of the invention.
  • Figures 11A - 1 IN show the growth curve of Listeria monocytogenes, Sigella flexneri and E. coli with libraries of the present invention.
  • Figure 12 shows the antibacterial activity against E. coli of a library containing compounds without a tail moiety
  • a library kit consisting of 361 libraries in separate vials, was compiled with each library being synthesised on solid support, with conventional solid phase methods, using orthogonal protecting groups that allow side chain to side chain cyclisation on the resin.
  • each R 01 and R 02 were independently selected from the side chains of the natural llyy ooccccuurrririnngg aammiinnoo aacciiddss eexxcceejpt Cysteine such that R 01 and R 02 were together uniquely defined and constant for each library.
  • R x were variable between the compounds of the library and were randomly selected from the side chains of the naturally occurring amino acids except Cysteine. Accordingly, for each R x , each side chain of the naturally occurring amino acids was present in a substantially equimolar amount.
  • each library vial consists a total of 19 4 different peptides, that is 130231 compounds.
  • NIH/3T3 cells were cultured in MEM supplemented with 10%o foetal bovine serum, ImM L-glutamine, 10 U/ml Penicillin and 10 ⁇ g/ml Streptomycin, at 37 °C in a 5%> CO 2 atmosphere.
  • Example 2 Mortality assay on onco genie OCM-1 cells
  • OCM-l(l,2) Malignant coroid human cell medium was cultured in RPMI supplemented with 5% foetal bovine serum, 10 U/ml Penicillin and 10 ⁇ g/ml Streptomycin, at 37 °C in a 5%> CO2 atmosphere.
  • Figures 1 and 2 summarise the effect that the different libraries had on eukaryotic cell viability.
  • all libraries having peptides with a positively charged residue, Lys or Arg, at any of the two defined positions induce cell death, while having negative residues, Asp and Glu, do not compromise cell viability.
  • aromatic residues, Tyr, Phe and T ⁇ tend to have on average higher mortality rate than hydrophobic or neutral polar residues. It is interesting to note that a much higher mortality rate is observed in the cancer cell line (OCM-1), than in NIH/3T3 cells.
  • Example 3 Mortality assay on E. coli cells
  • the numbers are assigned in the same way as in examples 1 - 3. For eukaryotic cells the numbering goes from 1 (no effect) to 5 (all dead). In the case of bacteria the numbers indicate cell culture OD (0 for no growth and 10 (denoted as #) for maximum growth).
  • the density of the cell culture was monitored every hour for a total period of 12 hours using a Tecan Spectia (TECAN Deutschland GmbH) and Delta Soft III software Ver 2.24 (Dr Bechtold and Biometallics Inc.) by following the OD of the cell culture at 600 nm.
  • FIGS 5 A and 5B The results of the analysis are shown in figures 5 A and 5B.
  • the Ref+ lines show the growth curve of the contiol without peptide and the Ref- lines show the control without bacteria.
  • Figures 5 A and 5B show that the positive control library Arg-Leu prevents bacteria growth at all concentiations tested, while the negative control library Asp-Asp does not affect growth at all concentiations tested.
  • Example 6 Titration effect of the library Leu-Phe on E. coli growth
  • the results of the analysis are shown in figure 6.
  • the Ref+ line shows the growth curve of the contiol without peptide and the Ref- line shows the contiol without bacteria.
  • Figure 6 demonstrates the concentration effect on the inhibition effect of the Leu-Phe library. It can be seen that the library is still active at very low active concentiations, for example 2.5 nM, and completely abolishes bacterial growth at 7 nM.
  • FIGS 7 A - 7N The results of the analysis are shown in figures 7 A - 7N.
  • the Ref+ line shows the growth curve of the control without peptide and the Ref- line shows the control without bacteria, hi each figure, the left graph shows the initial bacterial growth, while the right one shows the bacterial growth after washing and dilution. If the cells have acquired resistance, a normal growth curve should be observed on the right graph. However, if the problem is peptide degradation, we should see the same growth pattern in both the left and right graphs.
  • the behaviour of the cell culture with a peptide dose allowing partial cell growth is a repetition of the first incubation. Accordingly, bacterial growth after long incubation periods can be attributed to peptide degradation.
  • a cell culture of 3T3 cells were infected with 10 ⁇ l of an overnight culture of E. coli diluted 1000 times. At intervals of 3, 6, 9 and 12 hours, an aliquot of the cell medium was taken, diluted 1000 times and plated on Agar plated. The plates were incubated for 12 hours at 37 °C and the number of colonies counted. Cell mortality was also examined through visual inspection of the cells. In all cases, except with the Arg-Leu library that killed both bacteria and cells, and in the other contiol, library Asp- Asp, that did not prevent bacterial growth, the cells looked healthy and viable and could be cultured longer. The results of this analysis are shown in table 10 below:
  • Table 10 Relative bactericidal activity of the active selected libraries. For some of the libraries, for example, Ile-Val, Leu-Gly, Tyr-Gly, it was found that the bacteria start growing after a certain period of time, suggesting cell division arrest. In other libraries, some growing, followed by a decline in the number of viable cells, was observed, suggesting cell death. It therefore appears that different peptides prevent bacterial death by different mechanisms.
  • Example 9 3T3 cell survival in the presence of the active antibiotic peptides.
  • NIH/3T3 cells were cultured in MEM supplemented with 10% ⁇ foetal bovine serum, 1 mM L-glutamine, 10 U/ml Penicillin and 10 ⁇ g/ml Streptomycin, at 37 °C in a 5 % CO2 atmosphere. The day before the experiment, the cells were spread on a 96 glass bottom well plate at 30%) confluency and 150 ⁇ l of media per well. The media was removed and fresh media was added (150 ⁇ l/well). Then, 15 ⁇ l of a selected vial was added to reach a final active peptide concentration of 14 nM.
  • the Live/Dead assay was made using the LIVE/DEAD Viability/Cytotoxicity Kit (L3224) from Molecular Probes, following the protocol supplied by the manufacturer.
  • the cells were incubated in a 2 ⁇ M Calcein AM and 4 ⁇ M Ethidium homodimer-1 in D-PBS for 20 min at room temperature. Then the cells were observed using a DMIRBE Leica photomicroscope and photographed with a COHU high performance CCD camera.
  • As a negative control (dead culture) one of the wells was treated with 3.7%> formaldehyde for 20 min at room temperature, prior to the staining with the Live/Dead assay.
  • the antibiotic properties of the selected libraries were tested on the pathogenic strains Sigella flexneri SC301, Listeria monocytogenes 10403s and E. coli.
  • Example 12 Comparison of mortality assays on Listeria and E. coli
  • Figure 10 shows a comparison of the mortality effects produced using a total of 5 ⁇ l of each selected peptide library at a concentration of 14 nM on E. coli (right columns) after 12 hours and on Listeria (left columns) after 18 hours.
  • the cell density was measured by recording the absorbance at 600 nm after 18 hours.
  • 6 groups were made, ranging from 10 to 0. "10" corresponds to the OD of the control without peptide and "1" to that after incubating the cells with Kanamycin (30 ⁇ g/ml), Ampicillin (100 ⁇ g/ml), Tetiacyclin (12.5 ⁇ g/ml) or Streptomycin (25 ⁇ g/ml).
  • Example 13 Titration effect of selected libraries on prokaryote growth
  • R 01 is the side chain of the amino acid Leucine and R 02 is the side chain of the amino acid Phenylalanine.

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Abstract

La présente invention a trait à une bibliothèque chimique comportant un ou des composés mimétiques de peptides cycliques différents présentant chacun indépendamment une structure représentée par la formule (I). L'invention a trait également à des composés individuels à partir desquels la bibliothèque est constituée. La bibliothèque chimique est utile pour le criblage de composés pharmaceutiquement actifs, notamment des composés antibactériens.
PCT/US2003/016898 2002-05-30 2003-05-30 Bibliotheque chimique combinatoire ii Ceased WO2003102538A2 (fr)

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US8859723B2 (en) 2010-08-13 2014-10-14 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US8889632B2 (en) 2007-01-31 2014-11-18 Dana-Farber Cancer Institute, Inc. Stabilized p53 peptides and uses thereof
US8927500B2 (en) 2012-02-15 2015-01-06 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US8987414B2 (en) 2012-02-15 2015-03-24 Aileron Therapeutics, Inc. Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles
US9096684B2 (en) 2011-10-18 2015-08-04 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US9604919B2 (en) 2012-11-01 2017-03-28 Aileron Therapeutics, Inc. Disubstituted amino acids and methods of preparation and use thereof
US10023613B2 (en) 2015-09-10 2018-07-17 Aileron Therapeutics, Inc. Peptidomimetic macrocycles as modulators of MCL-1
US10253067B2 (en) 2015-03-20 2019-04-09 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
US10301351B2 (en) 2007-03-28 2019-05-28 President And Fellows Of Harvard College Stitched polypeptides
US10471120B2 (en) 2014-09-24 2019-11-12 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
US10905739B2 (en) 2014-09-24 2021-02-02 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and formulations thereof

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US6008058A (en) * 1993-06-18 1999-12-28 University Of Louisville Cyclic peptide mixtures via side chain or backbone attachment and solid phase synthesis
US5916872A (en) * 1996-07-24 1999-06-29 Intrabiotics Pharmaceuticals, Inc. Cyclic peptides having broad spectrum antimicrobial activity
US6248864B1 (en) * 1997-12-31 2001-06-19 Adherex Technologies, Inc. Compounds and methods and modulating tissue permeability

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US9527896B2 (en) 2007-01-31 2016-12-27 Dana-Farber Cancer Institute, Inc. Stabilized p53 peptides and uses thereof
US8889632B2 (en) 2007-01-31 2014-11-18 Dana-Farber Cancer Institute, Inc. Stabilized p53 peptides and uses thereof
US10301351B2 (en) 2007-03-28 2019-05-28 President And Fellows Of Harvard College Stitched polypeptides
US9957299B2 (en) 2010-08-13 2018-05-01 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US8859723B2 (en) 2010-08-13 2014-10-14 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US10308699B2 (en) 2011-10-18 2019-06-04 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US9522947B2 (en) 2011-10-18 2016-12-20 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US9096684B2 (en) 2011-10-18 2015-08-04 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US10213477B2 (en) 2012-02-15 2019-02-26 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US8987414B2 (en) 2012-02-15 2015-03-24 Aileron Therapeutics, Inc. Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles
US10227380B2 (en) 2012-02-15 2019-03-12 Aileron Therapeutics, Inc. Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles
US8927500B2 (en) 2012-02-15 2015-01-06 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US9505804B2 (en) 2012-02-15 2016-11-29 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US9845287B2 (en) 2012-11-01 2017-12-19 Aileron Therapeutics, Inc. Disubstituted amino acids and methods of preparation and use thereof
US9604919B2 (en) 2012-11-01 2017-03-28 Aileron Therapeutics, Inc. Disubstituted amino acids and methods of preparation and use thereof
US10669230B2 (en) 2012-11-01 2020-06-02 Aileron Therapeutics, Inc. Disubstituted amino acids and methods of preparation and use thereof
US10471120B2 (en) 2014-09-24 2019-11-12 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
US10905739B2 (en) 2014-09-24 2021-02-02 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and formulations thereof
US10253067B2 (en) 2015-03-20 2019-04-09 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
US10023613B2 (en) 2015-09-10 2018-07-17 Aileron Therapeutics, Inc. Peptidomimetic macrocycles as modulators of MCL-1

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