Article | Published:

A biomimetic polyketide-inspired approach to small-molecule ligand discovery

Nature Chemistry volume 4, pages 99104 (2012) | Download Citation

Abstract

The discovery of new compounds for the pharmacological manipulation of protein function often embraces the screening of compound collections, and it is widely recognized that natural products offer beneficial characteristics as protein ligands. Much effort has therefore been focused on ‘natural product-like’ libraries, yet the synthesis and screening of such libraries is often limited by one or more of the following: modest library sizes and structural diversity, conformational heterogeneity and the costs associated with the substantial infrastructure of modern high-throughput screening centres. Here, we describe the design and execution of an approach to this broad problem by merging principles associated with biologically inspired oligomerization and the structure of polyketide-derived natural products. A novel class of chiral and conformationally constrained oligomers is described (termed ‘chiral oligomers of pentenoic amides’, COPA), which offers compatibility with split-and-pool methods and can be screened en masse in a batch mode. We demonstrate that a COPA library containing 160,000 compounds is a useful source of novel protein ligands by identifying a non-covalent synthetic ligand to the DNA-binding domain of the p53 transcription factor.

  • Compound C7H11ClO2

    (R,E)-5-Chloro-2,4-dimethylpent-3-enoic acid

  • Compound C7H11ClO2

    (S,E)-5-Chloro-2,4-dimethylpent-3-enoic acid

  • Compound C7H8D3ClO2

    (S,E)-5-Chloro-2-(CD3)-methyl-4-methylpent-3-enoic acid

  • Compound C10H11NO2

    (R)-(-)-4-Benzyl-2-oxazolidinone

  • Compound C10H11NO2

    (S)-(+)-4-Benzyl-2-oxazolidinone

  • Compound C13H15NO3

    (S)-4-Benzyl-3-propionyl-2-oxazolidinone

  • Compound C13H15NO3

    (R)-4-Benzyl-3-propionyl-2-oxazolidinone

  • Compound C13H12D3NO3

    (R)-4-Benzyl-3-(CD3)-propionyl-2-oxazolidinone

  • Compound C4H6O

    Methacrolein

  • Compound C20H29NO4Si

    (4R)-4-Benzyl-3-[(2S,3R)-2,4-dimethyl-3-(trimethylsiloxy)pent-4-enoyl)]-oxazolidin-2-one

  • Compound C20H26D3NO4Si

    (4R)-4-Benzyl-3-[(2S,3R)-2-(CD3)-methyl-4-methyl-3-(trimethylsiloxy)pent-4-enoyl)]-oxazolidin-2-one

  • Compound C20H29NO4Si

    (4S)-4-Benzyl-3-[(2R,3S)-2,4-dimethyl-3-(trimethylsiloxy) pent-4-enoyl)]-oxazolidin-2-one

  • Compound C17H20ClNO3

    (4R)-4-Benzyl-3- [(R,S)-5-chloro-2,4-dimethylpent-3-enoyl] oxazolidin-2-one

  • Compound C17H17D3ClNO3

    (4R)-4-Benzyl-3-[(R,S)-5-chloro-2-(CD3)-methyl-4-methylpent-3-enoyl] oxazolidin-2-one

  • Compound C17H20ClNO3

    (4S)-4-Benzyl-3-[(R,E)-5-chloro-2,4-dimethylpent-3-enoyl]oxazolidin-2-one

  • Compound C4H9N

    Pyrrolidine

  • Compound C11H18ClNO

    1-(R,E)-5-Chloro-2,4-dimethylpent-3-enoyl-pyrrolidine

  • Compound C18H26N2O

    1-(R,E)-5-N-Benzylamino-2,4-dimethylpent-3-enoyl-pyrrolidine

  • Compound C25H35ClN2O2

    (R,E)-N-Benzyl-N-[(R,E)-2,4-dimethyl-5-oxo-5-(pyrrolidin-1-yl) pent-3-en-5-yl]-5-chloro-2,4-dimethylpent-3-enamide

  • Compound C25H35ClN2O2

    (S,E)-N-Benzyl-N-[(R,E)-2,4-dimethyl-5-oxo-5-(pyrrolidin-1-yl) pent-3-en-5-yl] -5-chloro-2,4-dimethylpent-3-enamide

  • Compound C93H114D9BrN10O18

    (2S,E)-N-((16S,17E,22S,23E)-1-Amino-20-benzyl-8-(4-bromophenethyl)-14-(3-isopropoxypropyl)-11-(3-methoxypropyl)-16,18,22,24-tetramethyl-6,9,12,15,21-pentaoxo-5-(2-oxo-2-((2-oxotetrahydrofuran-3-yl)amino)ethyl)-5,8,11,14,20-pentaazapentacosa-17,23-dien-25-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-5-((R,E)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-5-((benzo[d][1,3]dioxol-5-ylmethyl)amino)-2,4-dimethylpent-3-enamido)-2,4-dimethylpent-3-enamide

  • Compound C90H96N8O19S

    5-(3-(((4E,6R,10E,12S,16E,18S,22E,24S,32R)-1-(Benzo[d][1,3]dioxol-5-yl)-8,14-bis(benzo[d][1,3]dioxol-5-ylmethyl)-20-benzyl-32-carbamoyl-4,6,10,12,16,18,22,24-octamethyl-7,13,19,25,30-pentaoxo-2,8,14,20,26,31-hexaazatritriaconta-4,10,16,22-tetraen-33-yl)thio)-2,5-dioxopyrrolidin-1-yl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

  • Compound C90H96N8O19S

    5-(3-(((4E,6R,10E,12S,16E,18S,22E,24R,32R)-1-(Benzo[d][1,3]dioxol-5-yl)-8,14-bis(benzo[d][1,3]dioxol-5-ylmethyl)-20-benzyl-32-carbamoyl-4,6,10,12,16,18,22,24-octamethyl-7,13,19,25,30-pentaoxo-2,8,14,20,26,31-hexaazatritriaconta-4,10,16,22-tetraen-33-yl)thio)-2,5-dioxopyrrolidin-1-yl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

  • Compound C90H96N8O19S

    5-(3-(((4E,6R,10E,12S,16E,18R,22E,24S,32R)-1-(Benzo[d][1,3]dioxol-5-yl)-8,14-bis(benzo[d][1,3]dioxol-5-ylmethyl)-20-benzyl-32-carbamoyl-4,6,10,12,16,18,22,24-octamethyl-7,13,19,25,30-pentaoxo-2,8,14,20,26,31-hexaazatritriaconta-4,10,16,22-tetraen-33-yl)thio)-2,5-dioxopyrrolidin-1-yl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

  • Compound C90H96N8O19S

    5-(3-(((4E,6R,10E,12R,16E,18S,22E,24S,32R)-1-(Benzo[d][1,3]dioxol-5-yl)-8,14-bis(benzo[d][1,3]dioxol-5-ylmethyl)-20-benzyl-32-carbamoyl-4,6,10,12,16,18,22,24-octamethyl-7,13,19,25,30-pentaoxo-2,8,14,20,26,31-hexaazatritriaconta-4,10,16,22-tetraen-33-yl)thio)-2,5-dioxopyrrolidin-1-yl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

  • Compound C90H96N8O19S

    5-(3-(((4E,6S,10E,12S,16E,18S,22E,24S,32R)-1-(Benzo[d][1,3]dioxol-5-yl)-8,14-bis(benzo[d][1,3]dioxol-5-ylmethyl)-20-benzyl-32-carbamoyl-4,6,10,12,16,18,22,24-octamethyl-7,13,19,25,30-pentaoxo-2,8,14,20,26,31-hexaazatritriaconta-4,10,16,22-tetraen-33-yl)thio)-2,5-dioxopyrrolidin-1-yl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

  • Compound C13H20ClNO3

    (R,E)-5-Chloro-2,4-dimethylpent-3-enoyl-(L)-proline methyl ester

  • Compound C13H20ClNO3

    (S,E)-5-Chloro-2,4-dimethylpent-3-enoyl-(L)-proline methyl ester

  • Compound C79H127D3BrN11O15

    (6E,8R,12E,14R,18E,20R,24E,26S)-16-(2-Acetamidoethyl)-41-amino-34-(4-bromophenethyl)-10,22-diisopentyl-28-(3-isopropoxypropyl)-31-(3-methoxypropyl)-6,8,12,14,18,20,24,26-octamethyl-9,15,21,27,30,33,36-heptaoxo-37-(2-oxo-2-((2-oxotetrahydrofuran-3-yl)amino)ethyl)-4,10,16,22,28,31,34,37-octaazahentetraconta-6,12,18,24-tetraen-1-oic acid

  • Compound C76H103N9O16S

    (2R,10S,11E,16R,17E,22R,23E,28R,29E)-20-(2-Acetamidoethyl)-1-amino-2-(((1-(3-carboxy-4-(6-hydroxy-3-oxo-3H-xanthen-9-yl)phenyl)-2,5-dioxopyrrolidin-3-yl)thio)methyl)-14,26-diisopentyl-10,12,16,18,22,24,28,30-octamethyl-1,4,9,15,21,27-hexaoxo-3,8,14,20,26,32-hexaazapentatriaconta-11,17,23,29-tetraen-35-oic acid

  • Compound C83H118D3BrN10O18

    (6E,8R,12E,14R)-29-Amino-22-(4-bromophenethyl)-10-(2-carboxyethyl)-19-(3-hydroxypropyl)-16-(3-isopropoxypropyl)-4-((R,E)-5-((S,E)-N-(4-methoxybenzyl)-5-((4-methoxybenzyl)amino)-2,4-dimethylpent-3-enamido)-2,4-dimethylpent-3-enoyl)-6,8,12,14-tetramethyl-9,15,18,21,24-pentaoxo-25-(2-oxo-2-((2-oxotetrahydrofuran-3-yl)amino)ethyl)-4,10,16,19,22,25-hexaazanonacosa-6,12-dien-1-oic acid

  • Compound C81H96N8O19S

    5-(3-(((4E,6S,10E,12R,16E,18R,22E,24R,32R)-32-Carbamoyl-14,20-bis(2-carboxyethyl)-8-(4-methoxybenzyl)-1-(4-methoxyphenyl)-4,6,10,12,16,18,22,24-octamethyl-7,13,19,25,30-pentaoxo-2,8,14,20,26,31-hexaazatritriaconta-4,10,16,22-tetraen-33-yl)thio)-2,5-dioxopyrrolidin-1-yl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

  • Compound C81H123D3BrN13O15

    (2R,E)-N-(2-Acetamidoethyl)-N-((16R,17E,22S,23E,28R,29E)-26-(2-acetamidoethyl)-1-amino-20-benzyl-8-(4-bromophenethyl)-14-(3-isopropoxypropyl)-11-(3-methoxypropyl)-16,18,22,24,28,30-hexamethyl-6,9,12,15,21,27-hexaoxo-5-(2-oxo-2-((2-oxotetrahydrofuran-3-yl)amino)ethyl)-5,8,11,14,20,26-hexaazahentriaconta-17,23,29-trien-31-yl)-5-((2-acetamidoethyl)amino)-2,4-dimethylpent-3-enamide

  • Compound C78H99N11O16S

    5-(3-(((8E,10R,14E,16R,20E,22S,26E,28R,36R)-12,18-Bis(2-acetamidoethyl)-24-benzyl-36-carbamoyl-8,10,14,16,20,22,26,28-octamethyl-2,11,17,23,29,34-hexaoxo-3,6,12,18,24,30,35-heptaazaheptatriaconta-8,14,20,26-tetraen-37-yl)thio)-2,5-dioxopyrrolidin-1-yl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

  • Compound C85H132D3BrN14O15

    (6E,8R,12E,14R,18E,20S,24E,26R)-22-(3-(1H-Imidazol-1-yl)propyl)-41-amino-34-(4-bromophenethyl)-28-(3-isopropoxypropyl)-31-(3-methoxypropyl)-6,8,12,14,18,20,24,26-octamethyl-9,15,21,27,30,33,36-heptaoxo-37-(2-oxo-2-((2-oxotetrahydrofuran-3-yl)amino)ethyl)-16-(3-(2-oxopyrrolidin-1-yl)propyl)-10-(3-(pyrrolidin-1-yl)propyl)-4,10,16,22,28,31,34,37-octaazahentetraconta-6,12,18,24-tetraen-1-oic acid

  • Compound C82H106N12O17S

    (2R,10R,11E,16S,17E,22R,23E,28S,29E)-14-(3-(1H-Imidazol-1-yl)propyl)-1-amino-2-(((1-(3-carboxy-4-(6-hydroxy-3-oxo-3H-xanthen-9-yl)phenyl)-2,5-dioxopyrrolidin-3-yl)thio)methyl)-10,12,16,18,22,24,28,30-octamethyl-1,4,9,15,21,27-hexaoxo-20,26-bis(3-(2-oxopyrrolidin-1-yl)propyl)-3,8,14,20,26,32-hexaazapentatriaconta-11,17,23,29-tetraen-35-oic acid

  • Compound C79H125D3BrN13O16

    (6E,8S,12E,14R)-4-((R,E)-5-((R,E)-N-(2-Acetamidoethyl)-2,4-dimethyl-5-((3-(2-oxopyrrolidin-1-yl)propyl)amino)pent-3-enamido)-2,4-dimethylpent-3-enoyl)-29-amino-10-(3-aminopropyl)-22-(4-bromophenethyl)-16-(3-isopropoxypropyl)-19-(3-methoxypropyl)-6,8,12,14-tetramethyl-9,15,18,21,24-pentaoxo-25-(2-oxo-2-((2-oxotetrahydrofuran-3-yl)amino)ethyl)-4,10,16,19,22,25-hexaazanonacosa-6,12-dien-1-oic acid

  • Compound C76H101N11O17S

    (2R,10R,11E,16S,17E)-20-((R,E)-5-((R,E)-N-(2-Acetamidoethyl)-2,4-dimethyl-5-((3-(2-oxopyrrolidin-1-yl)propyl)amino)pent-3-enamido)-2,4-dimethylpent-3-enoyl)-1-amino-14-(3-aminopropyl)-2-(((1-(3-carboxy-4-(6-hydroxy-3-oxo-3H-xanthen-9-yl)phenyl)-2,5-dioxopyrrolidin-3-yl)thio)methyl)-10,12,16,18-tetramethyl-1,4,9,15-tetraoxo-3,8,14,20-tetraazatricosa-11,17-dien-23-oic acid

  • Compound C84H124D3BrN12O16

    (8R,E)-4-((S,E)-5-((R,E)-5-((R,E)-N-(3-(1H-Imidazol-1-yl)propyl)-5-((benzo[d][1,3]dioxol-5-ylmethyl)amino)-2,4-dimethylpent-3-enamido)-N-isopentyl-2,4-dimethylpent-3-enamido)-2,4-dimethylpent-3-enoyl)-23-amino-16-(4-bromophenethyl)-10-(3-isopropoxypropyl)-13-(3-methoxypropyl)-6,8-dimethyl-9,12,15,18-tetraoxo-19-(2-oxo-2-((2-oxotetrahydrofuran-3-yl)amino)ethyl)-4,10,13,16,19-pentaazatricos-6-en-1-oic acid

  • Compound C81H100N10O17S

    (4E,6R,10E,12R,16E,18S)-8-(3-(1H-Imidazol-1-yl)propyl)-20-((4R,E)-5-((4-(((2R)-1-amino-3-((1-(3-carboxy-4-(6-hydroxy-3-oxo-3H-xanthen-9-yl)phenyl)-2,5-dioxopyrrolidin-3-yl)thio)-1-oxopropan-2-yl)amino)-4-oxobutyl)amino)-2,4-dimethyl-5-oxopent-2-en-1-yl)-1-(benzo[d][1,3]dioxol-5-yl)-14-isopentyl-4,6,10,12,16,18-hexamethyl-7,13,19-trioxo-2,8,14,20-tetraazatricosa-4,10,16-trien-23-oic acid

  • Compound C80H128BrN13O15

    (6E,8R,12E,14R)-4-((R,E)-5-((R,E)-N-(3-(1H-Imidazol-1-yl)propyl)-5-(isopentylamino)-2,4-dimethylpent-3-enamido)-2,4-dimethylpent-3-enoyl)-10-(2-acetamidoethyl)-29-amino-22-(4-bromophenethyl)-16-(3-isopropoxypropyl)-19-(3-methoxypropyl)-6,8,12,14-tetramethyl-9,15,18,21,24-pentaoxo-25-(2-oxo-2-((2-oxotetrahydrofuran-3-yl)amino)ethyl)-4,10,16,19,22,25-hexaazanonacosa-6,12-dien-1-oic acid

  • Compound C77H101N11O16S

    (2R,10R,11E,16R,17E)-20-((R,E)-5-((R,E)-N-(3-(1H-Imidazol-1-yl)propyl)-5-(isopentylamino)-2,4-dimethylpent-3-enamido)-2,4-dimethylpent-3-enoyl)-14-(2-acetamidoethyl)-1-amino-2-(((1-(3-carboxy-4-(6-hydroxy-3-oxo-3H-xanthen-9-yl)phenyl)-2,5-dioxopyrrolidin-3-yl)thio)methyl)-10,12,16,18-tetramethyl-1,4,9,15-tetraoxo-3,8,14,20-tetraazatricosa-11,17-dien-23-oic acid

  • Compound C56H95BrN12O14

    20-Amino-4-(2-(2-(N-(3-aminopropyl)-2-((3-aminopropyl)amino)acetamido)-N-isopentylacetamido)acetyl)-13-(4-bromophenethyl)-7-(3-isopropoxypropyl)-10-(3-methoxypropyl)-6,9,12,15-tetraoxo-16-(2-oxo-2-((2-oxotetrahydrofuran-3-yl)amino)ethyl)-4,7,10,13,16-pentaazaicosan-1-oic acid

  • Compound C79H109BrN14O20S

    (2R)-1-Amino-6-(4-aminobutyl)-18-(2-(2-(N-(3-aminopropyl)-2-((3-aminopropyl)amino)acetamido)-N-isopentylacetamido)acetyl)-9-(4-bromophenethyl)-2-(((1-(3-carboxy-4-(6-hydroxy-3-oxo-3H-xanthen-9-yl)phenyl)-2,5-dioxopyrrolidin-3-yl)thio)methyl)-15-(3-isopropoxypropyl)-12-(3-methoxypropyl)-1,4,7,10,13,16-hexaoxo-3,6,9,12,15,18-hexaazahenicosan-21-oic acid

  • Compound C64H103BrN12O16

    29-Amino-22-(4-bromophenethyl)-7-isopentyl-16-(3-isopropoxypropyl)-19-(3-methoxypropyl)-6,9,12,15,18,21,24-heptaoxo-25-(2-oxo-2-((2-oxotetrahydrofuran-3-yl)amino)ethyl)-10,13-bis(3-(2-oxopyrrolidin-1-yl)propyl)-4,7,10,13,16,19,22,25-octaazanonacosan-1-oic acid

  • Compound C87H117BrN14O22S

    (2R)-1-Amino-6-(4-aminobutyl)-9-(4-bromophenethyl)-2-(((1-(3-carboxy-4-(6-hydroxy-3-oxo-3H-xanthen-9-yl)phenyl)-2,5-dioxopyrrolidin-3-yl)thio)methyl)-24-isopentyl-15-(3-isopropoxypropyl)-12-(3-methoxypropyl)-1,4,7,10,13,16,19,22,25-nonaoxo-18,21-bis(3-(2-oxopyrrolidin-1-yl)propyl)-3,6,9,12,15,18,21,24,27-nonaazatriacontan-30-oic acid

  • Compound C67H99BrN12O18

    20-Amino-4-(2-(2-(2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)-N-(3-(2-oxopyrrolidin-1-yl)propyl)acetamido)-N-(3-(2-oxopyrrolidin-1-yl)propyl)acetamido)acetyl)-13-(4-bromophenethyl)-7-(3-isopropoxypropyl)-10-(3-methoxypropyl)-6,9,12,15-tetraoxo-16-(2-oxo-2-((2-oxotetrahydrofuran-3-yl)amino)ethyl)-4,7,10,13,16-pentaazaicosan-1-oic acid

  • Compound C90H113BrN14O24S

    (2R)-1-Amino-6-(4-aminobutyl)-18-(2-(2-(2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)-N-(3-(2-oxopyrrolidin-1-yl)propyl)acetamido)-N-(3-(2-oxopyrrolidin-1-yl)propyl)acetamido)acetyl)-9-(4-bromophenethyl)-2-(((1-(3-carboxy-4-(6-hydroxy-3-oxo-3H-xanthen-9-yl)phenyl)-2,5-dioxopyrrolidin-3-yl)thio)methyl)-15-(3-isopropoxypropyl)-12-(3-methoxypropyl)-1,4,7,10,13,16-hexaoxo-3,6,9,12,15,18-hexaazahenicosan-21-oic acid

  • Compound C64H100BrN13O16

    N-(2-Acetamidoethyl)-2-(2-(N-(2-acetamidoethyl)-2-((2-morpholinoethyl)amino)acetamido)-N-(4-methoxybenzyl)acetamido)-N-(16-amino-9-(4-bromophenethyl)-3-(3-isopropoxypropyl)-6-(3-methoxypropyl)-2,5,8,11-tetraoxo-12-(2-oxo-2-((2-oxotetrahydrofuran-3-yl)amino)ethyl)-3,6,9,12-tetraazahexadecyl)acetamide

  • Compound C87H114BrN15O22S

    5-(3-(((R)-18,24-Bis(2-acetamidoethyl)-6-(4-aminobutyl)-9-(4-bromophenethyl)-2-carbamoyl-15-(3-isopropoxypropyl)-21-(4-methoxybenzyl)-12-(3-methoxypropyl)-29-morpholino-4,7,10,13,16,19,22,25-octaoxo-3,6,9,12,15,18,21,24,27-nonaazanonacosyl)thio)-2,5-dioxopyrrolidin-1-yl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

  • Compound C70H100BrN13O14

    2-((3-(1H-Imidazol-1-yl)propyl)amino)-N-(22-amino-3-benzyl-15-(4-bromophenethyl)-9-(3-isopropoxypropyl)-6-(4-methoxybenzyl)-12-(3-methoxypropyl)-2,5,8,11,14,17-hexaoxo-18-(2-oxo-2-((2-oxotetrahydrofuran-3-yl)amino)ethyl)-3,6,9,12,15,18-hexaazadocosyl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)acetamide

  • Compound C93H114BrN15O20S

    5-(3-(((R)-6-(4-Aminobutyl)-21-benzyl-9-(4-bromophenethyl)-2-carbamoyl-30-(1H-imidazol-1-yl)-15-(3-isopropoxypropyl)-18-(4-methoxybenzyl)-12-(3-methoxypropyl)-4,7,10,13,16,19,22,25-octaoxo-24-(3-(2-oxopyrrolidin-1-yl)propyl)-3,6,9,12,15,18,21,24,27-nonaazatriacontyl)thio)-2,5-dioxopyrrolidin-1-yl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

  • Compound C59H96BrN13O16

    4-(2-(2-(N-(2-Acetamidoethyl)-2-((3-aminopropyl)amino)acetamido)-N-(3-(2-oxopyrrolidin-1-yl)propyl)acetamido)acetyl)-20-amino-13-(4-bromophenethyl)-7-(3-isopropoxypropyl)-10-(3-methoxypropyl)-6,9,12,15-tetraoxo-16-(2-oxo-2-((2-oxotetrahydrofuran-3-yl)amino)ethyl)-4,7,10,13,16-pentaazaicosan-1-oic acid

  • Compound C82H110BrN15O22S

    (2R)-18-(2-(2-(N-(2-Acetamidoethyl)-2-((3-aminopropyl)amino)acetamido)-N-(3-(2-oxopyrrolidin-1-yl)propyl)acetamido)acetyl)-1-amino-6-(4-aminobutyl)-9-(4-bromophenethyl)-2-(((1-(3-carboxy-4-(6-hydroxy-3-oxo-3H-xanthen-9-yl)phenyl)-2,5-dioxopyrrolidin-3-yl)thio)methyl)-15-(3-isopropoxypropyl)-12-(3-methoxypropyl)-1,4,7,10,13,16-hexaoxo-3,6,9,12,15,18-hexaazahenicosan-21-oic acid

  • Compound C13H15NO4

    (R)-Ethyl 4-benzyl-2-oxooxazolidine-3-carboxylate

  • Compound C62H79N9O8

    (R,E)-N-(2-((2-((2-((2-Amino-2-oxoethyl)(4-aminobutyl)amino)-2-oxoethyl)(3-methoxypropyl)amino)-2-oxoethyl)(benzyl)amino)-2-oxoethyl)-N-benzyl-5-(N-benzyl-2-(N-benzyl-2-(benzylamino)acetamido)acetamido)-2,4-dimethylpent-3-enamide

  • Compound C84H116BrN11O10

    (2R,E)-N-(3-(1H-Imidazol-1-yl)propyl)-N-((13R,14E,19S,20E)-1-amino-17-benzyl-8-(3-isopropoxypropyl)-13,15,19,21-tetramethyl-6,9,12,18-tetraoxo-5-(2-oxo-2-((2-oxotetrahydrofuran-3-yl)amino)ethyl)-11-phenethyl-5,8,11,17-tetraazadocosa-14,20-dien-22-yl)-5-((S,E)-5-((4-bromobenzyl)amino)-2,4-dimethyl-N-phenethylpent-3-enamido)-2,4-dimethylpent-3-enamide

  • Compound C59H71N5O10

    (S,E)-N-((S,E)-5-Amino-2,4-dimethyl-5-oxopent-2-en-1-yl)-5-((S,E)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-5-((R,E)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-5-((benzo[d][1,3]dioxol-5-ylmethyl)amino)-2,4-dimethylpent-3-enamido)-2,4-dimethylpent-3-enamido)-N-benzyl-2,4-dimethylpent-3-enamide

  • Compound C70H64N8O19S

    5-(3-(((R)-1-(Benzo[d][1,3]dioxol-5-yl)-5,8-bis(benzo[d][1,3]dioxol-5-ylmethyl)-11-benzyl-20-carbamoyl-4,7,10,13,18-pentaoxo-2,5,8,11,14,19-hexaazahenicosan-21-yl)thio)-2,5-dioxopyrrolidin-1-yl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

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Acknowledgements

G.C.M. acknowledges financial support from the Fidelity Biosciences Research Initiative, the Scripps Research Institute, Scripps Florida. T.K. acknowledges support from the NHLBI (N01-HV-00242).

Author information

Affiliations

  1. Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA

    • Claudio Aquino
    • , Mohosin Sarkar
    • , Kimberly Mendes
    • , Thomas Kodadek
    •  & Glenn C. Micalizio
  2. Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA

    • Mohosin Sarkar
    • , Kimberly Mendes
    •  & Thomas Kodadek
  3. Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA

    • Michael J. Chalmers

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Contributions

G.C.M. and T.K. conceived and directed the project. C.A. and M.S. contributed equally to the execution of this work. C.A. prepared acid 1 and conducted all solution-phase chemistry. M.S. and C.A. conducted all solid-phase experiments, library synthesis, decoding experiments and biochemical evaluation of the hits. M.S. purified the p53–DBD, which was cloned and expressed by K.M., and conducted the biochemical characterization of the hit. M.C. developed the ETD-based method for compound decoding. G.C.M. and T.K. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Thomas Kodadek or Glenn C. Micalizio.

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DOI

https://doi.org/10.1038/nchem.1200

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