George Procopiou - Academia.edu (original) (raw)
Papers by George Procopiou
The Royal Society of Chemistry eBooks, Sep 6, 2018
This chapter covers the synthesis and the synthetic challenges associated with representative exa... more This chapter covers the synthesis and the synthetic challenges associated with representative examples of each of the following classes of transcription factor inhibitors: cyclin dependent kinase (synthesis of flavopiridol), STAT3 (phosphonodifluoromethyl isosteric analogue of a peptidomimetic including its pivaloyloxymethyl pro-drug), STAT5b (Stafib-1), c-Myc–Max (substituted benzanilide) and HIF-1 (Manassantin A). Synthetic approaches to pyrrolobenzodiazepines and diversity-orientated synthesis of transcription factor inhibitors are also discussed.
The Royal Society of Chemistry eBooks, Jul 15, 2019
The Royal Society of Chemistry eBooks, Jul 15, 2019
The CXI dimers [dimers containing, for example cyclopropapyrroloindole (CPI), cyclopropabenzindol... more The CXI dimers [dimers containing, for example cyclopropapyrroloindole (CPI), cyclopropabenzindole (CBI) or cyclopropathienoindole (CTI) moieties] first emerged in the late 1980s, and were composed of two units of the active pharmacophore present in duocarmycin natural products. They are among the most potent cytotoxic agents ever synthesised and have been successfully utilised by various groups as payloads for antibody–drug conjugates (ADCs). Their ability to cross-link DNA, selectively alkylating adenines in the minor groove, differentiates them from other known payload classes and even other cross-linking agents. This chapter reviews the various forms of CXI dimers that have been reported, including several examples where they have been shown to outperform approved ADCs both in vitro and in vivo.
Chemical Communications, 2014
Synlett, Jan 27, 2012
Both two-directional synthesis and tandem reactions are able to form several bonds in a single tr... more Both two-directional synthesis and tandem reactions are able to form several bonds in a single transformation, making them excellent reaction types to build molecular complexity. Over the past decade, we have had an ongoing interest in combining these two strategies in order to give access to complex molecular building blocks suitable for the synthesis of natural products in as efficient and concise a manner as possible. To date, we have successfully applied this strategy for the concise syntheses of anatoxin a, homoanatoxin, histrionicotoxin, alkaloid 223B and hippodamine (Figure 1), among others.1 Herein we report our investigations into the reaction of these keto dienoates with a range of primary amines, yielding azabicyclic structures pertinent to the synthesis of a range of frog alkaloids (e.g., alkaloid 275B2 and gephyrotoxin3) and the antitumour compounds, the lepadins.4
European Journal of Organic Chemistry, Jul 1, 2016
The first diastereoselective allylation reaction at the α-position of ketones by using tert-butan... more The first diastereoselective allylation reaction at the α-position of ketones by using tert-butanesulfinamide as a chiral auxiliary is explored. Excellent yields and high diastereomeric ratios were achieved under palladium catalysis in the
ChemInform, Nov 1, 2016
Palladium-Catalyzed Diastereoselective Cyclization of the Allylic Precursors. A Concise Synthetic... more Palladium-Catalyzed Diastereoselective Cyclization of the Allylic Precursors. A Concise Synthetic Route to 3-Azabicyclo[3.3.0]octane and Hydroisoindole Skeletons.-A useful variant for the palladiumcatalyzed synthesis of 1,1,2-trisubstituted cyclopentanes and cyclohexanes is given. The 1,2-diastereoselectivities are supposed to arise from the different steric effects of the anion stabilizing groups at the nucleophilic carbon atom.
ChemInform, May 10, 2012
Combining Two-Directional Synthesis and Tandem Reactions. Part 17. Expedient Formation of Functio... more Combining Two-Directional Synthesis and Tandem Reactions. Part 17. Expedient Formation of Functionalized Azabicycles.-The TiCl4-mediated reaction of ketones (I) and (IV) with primary amines involves an enamine formation/Michael addition/aza-Michael addition sequence to give diastereomeric mixtures of azabicycles. For the sulfone substrate (IV), the major product is confirmed to be the trans isomer.-(AGGARWAL, P.;
The cycloaddition of chiral <i>tert-</i>butanesulfinimines with trimethylenemethane i... more The cycloaddition of chiral <i>tert-</i>butanesulfinimines with trimethylenemethane is found to give facile access to methylene-pyrrolidines with good yields and diastereoselectivities. The full scope of the cycloaddition is explored, and a range of transformations of the formed methylenepyrrolidines to give a range of functionalized chiral pyrrolidines is presented
Communications Biology
Antibody-Drug Conjugates (ADCs) are growing in importance for the treatment of both solid and hae... more Antibody-Drug Conjugates (ADCs) are growing in importance for the treatment of both solid and haematological malignancies. There is a demand for new payloads with novel mechanisms of action that may offer enhanced therapeutic efficacy, especially in patients who develop resistance. We report here a class of Cyclopropabenzindole-Pyridinobenzodiazepine (CBI-PDD) DNA cross-linking payloads that simultaneously alkylate guanine (G) and adenine (A) bases in the DNA minor groove with a defined sequence selectivity. The lead payload, FGX8-46 (6), produces sequence-selective G-A cross-links and affords cytotoxicity in the low picomolar region across a panel of 11 human tumour cell lines. When conjugated to the antibody cetuximab at an average Drug-Antibody Ratio (DAR) of 2, an ADC is produced with significant antitumour activity at 1 mg/kg in a target-relevant human tumour xenograft mouse model with an unexpectedly high tolerability (i.e., no weight loss observed at doses as high as 45 mg/kg...
Cytotoxic Payloads for Antibody–Drug Conjugates
The CXI dimers [dimers containing, for example cyclopropapyrroloindole (CPI), cyclopropabenzindol... more The CXI dimers [dimers containing, for example cyclopropapyrroloindole (CPI), cyclopropabenzindole (CBI) or cyclopropathienoindole (CTI) moieties] first emerged in the late 1980s, and were composed of two units of the active pharmacophore present in duocarmycin natural products. They are among the most potent cytotoxic agents ever synthesised and have been successfully utilised by various groups as payloads for antibody–drug conjugates (ADCs). Their ability to cross-link DNA, selectively alkylating adenines in the minor groove, differentiates them from other known payload classes and even other cross-linking agents. This chapter reviews the various forms of CXI dimers that have been reported, including several examples where they have been shown to outperform approved ADCs both in vitro and in vivo.
Cancer Research
Antibody-Drug Conjugates (ADCs) are a fast-growing class of targeted cancer therapeutic agents wi... more Antibody-Drug Conjugates (ADCs) are a fast-growing class of targeted cancer therapeutic agents with over ten approved and greater than 100 in various stages of clinical development. The pyridinobenzodiazepines (PDDs) are a new class of DNA-interactive sequence-selective Guanine mono-alkylating ADC payloads which contain a sequence recognition component with sufficient span to guide them to specific DNA sequences (e.g., transcription factor binding sites). A high potency PDD, FGX15-147, has been developed that contains a bi-aryl moiety capable of forming an intramolecular ‘sigma-hole’ interaction with DNA bases, thus providing the molecule with a unique sequence-selectivity profile when compared to other DNA-interactive agents. DNA footprinting data will be presented indicating that the molecule, which spans 8-9 DNA base pairs in the minor groove, has an increased sequence selectivity compared with related analogues, preferring DNA regions containing two guanines 2-4 base pairs apart...
Cancer Research
Antibody-Drug Conjugates (ADCs) are rapidly growing in importance as a targeted cancer therapy, w... more Antibody-Drug Conjugates (ADCs) are rapidly growing in importance as a targeted cancer therapy, with over ten approved, and many currently undergoing clinical trials. ADCs comprise of a cytotoxic agent (i.e., the "payload") conjugated via a chemical linker to a tumor-targeting antibody. There is a demand for novel ADC payloads with unique mechanisms of action, enhanced tolerability profiles and improved physicochemical properties. Such payloads could lead to ADCs with therapeutic efficacy in patients resistant to other therapies, and payloads with reduced hydrophobicity should lead to improved conjugation, minimal aggregation, and higher Drug-Antibody Ratios (DARs). We report here, studies on a novel class of Cyclopropabenzindole-Pyridinobenzodiazepine (CBI-PDD) payloads, designed through molecular modeling, which form cross-links between Guanine and Adenine bases within the DNA minor groove with defined sequence specificity. Eleven novel analogs will be described which ha...
Cancer Research
Antibody-Drug Conjugates (ADCs) are a growing class of therapeutic agents for the treatment of ca... more Antibody-Drug Conjugates (ADCs) are a growing class of therapeutic agents for the treatment of cancer, with thirteen approved and over 100 others in clinical development. The pyridinobenzodiazepine (PDD) platform is a toolbox of sequence-selective, DNA Guanine mono-alkylating ADC payloads with varying potencies and biophysical properties, enabling a payload-based approach to targeting solid tumours and haematological malignancies. We recently reported the development of a lower potency DNA mono-alkylator, FGX20-75, with substantially superior in vivo properties to other DNA alkylating agents and an efficacy/tolerability profile on-par with a topoisomerase inhibitor-based ADC. This molecule is active in the low nanomolar range (i.e., median potency of 6 nM across a 15 cell-line screen), but is sufficiently hydrophilic to allow efficient conjugation to IgG antibodies with Drug Antobody Ratios (DARs) of up to 7. A maleimide-linked analogue of FGX20-75 has been conjugated to a number of...
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Cytotoxic Payloads for Antibody–Drug Conjugates, 2019
Antibody–drug conjugate (ADC) payloads are a relatively new class of potent and highly potent act... more Antibody–drug conjugate (ADC) payloads are a relatively new class of potent and highly potent active pharmaceutical ingredients (APIs), with cytotoxic activities often in the low picomolar range, due to mechanisms of action that include tubulin inhibition and DNA cleavage, cross-linking or mono-alkylation. The ability to conjugate such payloads to antibodies to make ADCs, represents a new area in the field of targeted cancer chemotherapy. The very high cytotoxicity of some ADC payloads, requires their manufacture and handling to be carefully managed and worker health and safety protected. Parties handling these materials must apply a systematic and scientific approach to occupational health and safety, including toxicological hazard assessment, exposure risk assessment, engineering control/containment, occupational hygiene and related management systems.
Small-molecule Transcription Factor Inhibitors in Oncology, 2018
This chapter covers the synthesis and the synthetic challenges associated with representative exa... more This chapter covers the synthesis and the synthetic challenges associated with representative examples of each of the following classes of transcription factor inhibitors: cyclin dependent kinase (synthesis of flavopiridol), STAT3 (phosphonodifluoromethyl isosteric analogue of a peptidomimetic including its pivaloyloxymethyl pro-drug), STAT5b (Stafib-1), c-Myc–Max (substituted benzanilide) and HIF-1 (Manassantin A). Synthetic approaches to pyrrolobenzodiazepines and diversity-orientated synthesis of transcription factor inhibitors are also discussed.
Synlett, 2018
The pyrrolidine-catalysed formation of novel diastereomeric C11-acetone adducts was observed duri... more The pyrrolidine-catalysed formation of novel diastereomeric C11-acetone adducts was observed during the chromatographic purification of pyrrolobenzodiazepine (PBD) compounds in the presence of acetone. The mechanism of this reaction was explored and the adducts obtained fully characterised. Talirine, the cytotoxic payload element of the antibody-drug conjugate (ADC) vadastuximab talirine, was also found to form a bis-adduct under similar conditions. A cellular cytotoxicity evaluation of the modified PBD compounds confirmed their lack of cytotoxicity, consistent with loss of the DNA-interactive N10–C11 imine functionality. As well as the new chemistry reported here, given the number of PBD-based ADCs presently in the clinic, this observation may be important for the larger-scale manufacture of PBD-based products.
Tetrahedron Letters, 2017
The Royal Society of Chemistry eBooks, Sep 6, 2018
This chapter covers the synthesis and the synthetic challenges associated with representative exa... more This chapter covers the synthesis and the synthetic challenges associated with representative examples of each of the following classes of transcription factor inhibitors: cyclin dependent kinase (synthesis of flavopiridol), STAT3 (phosphonodifluoromethyl isosteric analogue of a peptidomimetic including its pivaloyloxymethyl pro-drug), STAT5b (Stafib-1), c-Myc–Max (substituted benzanilide) and HIF-1 (Manassantin A). Synthetic approaches to pyrrolobenzodiazepines and diversity-orientated synthesis of transcription factor inhibitors are also discussed.
The Royal Society of Chemistry eBooks, Jul 15, 2019
The Royal Society of Chemistry eBooks, Jul 15, 2019
The CXI dimers [dimers containing, for example cyclopropapyrroloindole (CPI), cyclopropabenzindol... more The CXI dimers [dimers containing, for example cyclopropapyrroloindole (CPI), cyclopropabenzindole (CBI) or cyclopropathienoindole (CTI) moieties] first emerged in the late 1980s, and were composed of two units of the active pharmacophore present in duocarmycin natural products. They are among the most potent cytotoxic agents ever synthesised and have been successfully utilised by various groups as payloads for antibody–drug conjugates (ADCs). Their ability to cross-link DNA, selectively alkylating adenines in the minor groove, differentiates them from other known payload classes and even other cross-linking agents. This chapter reviews the various forms of CXI dimers that have been reported, including several examples where they have been shown to outperform approved ADCs both in vitro and in vivo.
Chemical Communications, 2014
Synlett, Jan 27, 2012
Both two-directional synthesis and tandem reactions are able to form several bonds in a single tr... more Both two-directional synthesis and tandem reactions are able to form several bonds in a single transformation, making them excellent reaction types to build molecular complexity. Over the past decade, we have had an ongoing interest in combining these two strategies in order to give access to complex molecular building blocks suitable for the synthesis of natural products in as efficient and concise a manner as possible. To date, we have successfully applied this strategy for the concise syntheses of anatoxin a, homoanatoxin, histrionicotoxin, alkaloid 223B and hippodamine (Figure 1), among others.1 Herein we report our investigations into the reaction of these keto dienoates with a range of primary amines, yielding azabicyclic structures pertinent to the synthesis of a range of frog alkaloids (e.g., alkaloid 275B2 and gephyrotoxin3) and the antitumour compounds, the lepadins.4
European Journal of Organic Chemistry, Jul 1, 2016
The first diastereoselective allylation reaction at the α-position of ketones by using tert-butan... more The first diastereoselective allylation reaction at the α-position of ketones by using tert-butanesulfinamide as a chiral auxiliary is explored. Excellent yields and high diastereomeric ratios were achieved under palladium catalysis in the
ChemInform, Nov 1, 2016
Palladium-Catalyzed Diastereoselective Cyclization of the Allylic Precursors. A Concise Synthetic... more Palladium-Catalyzed Diastereoselective Cyclization of the Allylic Precursors. A Concise Synthetic Route to 3-Azabicyclo[3.3.0]octane and Hydroisoindole Skeletons.-A useful variant for the palladiumcatalyzed synthesis of 1,1,2-trisubstituted cyclopentanes and cyclohexanes is given. The 1,2-diastereoselectivities are supposed to arise from the different steric effects of the anion stabilizing groups at the nucleophilic carbon atom.
ChemInform, May 10, 2012
Combining Two-Directional Synthesis and Tandem Reactions. Part 17. Expedient Formation of Functio... more Combining Two-Directional Synthesis and Tandem Reactions. Part 17. Expedient Formation of Functionalized Azabicycles.-The TiCl4-mediated reaction of ketones (I) and (IV) with primary amines involves an enamine formation/Michael addition/aza-Michael addition sequence to give diastereomeric mixtures of azabicycles. For the sulfone substrate (IV), the major product is confirmed to be the trans isomer.-(AGGARWAL, P.;
The cycloaddition of chiral <i>tert-</i>butanesulfinimines with trimethylenemethane i... more The cycloaddition of chiral <i>tert-</i>butanesulfinimines with trimethylenemethane is found to give facile access to methylene-pyrrolidines with good yields and diastereoselectivities. The full scope of the cycloaddition is explored, and a range of transformations of the formed methylenepyrrolidines to give a range of functionalized chiral pyrrolidines is presented
Communications Biology
Antibody-Drug Conjugates (ADCs) are growing in importance for the treatment of both solid and hae... more Antibody-Drug Conjugates (ADCs) are growing in importance for the treatment of both solid and haematological malignancies. There is a demand for new payloads with novel mechanisms of action that may offer enhanced therapeutic efficacy, especially in patients who develop resistance. We report here a class of Cyclopropabenzindole-Pyridinobenzodiazepine (CBI-PDD) DNA cross-linking payloads that simultaneously alkylate guanine (G) and adenine (A) bases in the DNA minor groove with a defined sequence selectivity. The lead payload, FGX8-46 (6), produces sequence-selective G-A cross-links and affords cytotoxicity in the low picomolar region across a panel of 11 human tumour cell lines. When conjugated to the antibody cetuximab at an average Drug-Antibody Ratio (DAR) of 2, an ADC is produced with significant antitumour activity at 1 mg/kg in a target-relevant human tumour xenograft mouse model with an unexpectedly high tolerability (i.e., no weight loss observed at doses as high as 45 mg/kg...
Cytotoxic Payloads for Antibody–Drug Conjugates
The CXI dimers [dimers containing, for example cyclopropapyrroloindole (CPI), cyclopropabenzindol... more The CXI dimers [dimers containing, for example cyclopropapyrroloindole (CPI), cyclopropabenzindole (CBI) or cyclopropathienoindole (CTI) moieties] first emerged in the late 1980s, and were composed of two units of the active pharmacophore present in duocarmycin natural products. They are among the most potent cytotoxic agents ever synthesised and have been successfully utilised by various groups as payloads for antibody–drug conjugates (ADCs). Their ability to cross-link DNA, selectively alkylating adenines in the minor groove, differentiates them from other known payload classes and even other cross-linking agents. This chapter reviews the various forms of CXI dimers that have been reported, including several examples where they have been shown to outperform approved ADCs both in vitro and in vivo.
Cancer Research
Antibody-Drug Conjugates (ADCs) are a fast-growing class of targeted cancer therapeutic agents wi... more Antibody-Drug Conjugates (ADCs) are a fast-growing class of targeted cancer therapeutic agents with over ten approved and greater than 100 in various stages of clinical development. The pyridinobenzodiazepines (PDDs) are a new class of DNA-interactive sequence-selective Guanine mono-alkylating ADC payloads which contain a sequence recognition component with sufficient span to guide them to specific DNA sequences (e.g., transcription factor binding sites). A high potency PDD, FGX15-147, has been developed that contains a bi-aryl moiety capable of forming an intramolecular ‘sigma-hole’ interaction with DNA bases, thus providing the molecule with a unique sequence-selectivity profile when compared to other DNA-interactive agents. DNA footprinting data will be presented indicating that the molecule, which spans 8-9 DNA base pairs in the minor groove, has an increased sequence selectivity compared with related analogues, preferring DNA regions containing two guanines 2-4 base pairs apart...
Cancer Research
Antibody-Drug Conjugates (ADCs) are rapidly growing in importance as a targeted cancer therapy, w... more Antibody-Drug Conjugates (ADCs) are rapidly growing in importance as a targeted cancer therapy, with over ten approved, and many currently undergoing clinical trials. ADCs comprise of a cytotoxic agent (i.e., the "payload") conjugated via a chemical linker to a tumor-targeting antibody. There is a demand for novel ADC payloads with unique mechanisms of action, enhanced tolerability profiles and improved physicochemical properties. Such payloads could lead to ADCs with therapeutic efficacy in patients resistant to other therapies, and payloads with reduced hydrophobicity should lead to improved conjugation, minimal aggregation, and higher Drug-Antibody Ratios (DARs). We report here, studies on a novel class of Cyclopropabenzindole-Pyridinobenzodiazepine (CBI-PDD) payloads, designed through molecular modeling, which form cross-links between Guanine and Adenine bases within the DNA minor groove with defined sequence specificity. Eleven novel analogs will be described which ha...
Cancer Research
Antibody-Drug Conjugates (ADCs) are a growing class of therapeutic agents for the treatment of ca... more Antibody-Drug Conjugates (ADCs) are a growing class of therapeutic agents for the treatment of cancer, with thirteen approved and over 100 others in clinical development. The pyridinobenzodiazepine (PDD) platform is a toolbox of sequence-selective, DNA Guanine mono-alkylating ADC payloads with varying potencies and biophysical properties, enabling a payload-based approach to targeting solid tumours and haematological malignancies. We recently reported the development of a lower potency DNA mono-alkylator, FGX20-75, with substantially superior in vivo properties to other DNA alkylating agents and an efficacy/tolerability profile on-par with a topoisomerase inhibitor-based ADC. This molecule is active in the low nanomolar range (i.e., median potency of 6 nM across a 15 cell-line screen), but is sufficiently hydrophilic to allow efficient conjugation to IgG antibodies with Drug Antobody Ratios (DARs) of up to 7. A maleimide-linked analogue of FGX20-75 has been conjugated to a number of...
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Cytotoxic Payloads for Antibody–Drug Conjugates, 2019
Antibody–drug conjugate (ADC) payloads are a relatively new class of potent and highly potent act... more Antibody–drug conjugate (ADC) payloads are a relatively new class of potent and highly potent active pharmaceutical ingredients (APIs), with cytotoxic activities often in the low picomolar range, due to mechanisms of action that include tubulin inhibition and DNA cleavage, cross-linking or mono-alkylation. The ability to conjugate such payloads to antibodies to make ADCs, represents a new area in the field of targeted cancer chemotherapy. The very high cytotoxicity of some ADC payloads, requires their manufacture and handling to be carefully managed and worker health and safety protected. Parties handling these materials must apply a systematic and scientific approach to occupational health and safety, including toxicological hazard assessment, exposure risk assessment, engineering control/containment, occupational hygiene and related management systems.
Small-molecule Transcription Factor Inhibitors in Oncology, 2018
This chapter covers the synthesis and the synthetic challenges associated with representative exa... more This chapter covers the synthesis and the synthetic challenges associated with representative examples of each of the following classes of transcription factor inhibitors: cyclin dependent kinase (synthesis of flavopiridol), STAT3 (phosphonodifluoromethyl isosteric analogue of a peptidomimetic including its pivaloyloxymethyl pro-drug), STAT5b (Stafib-1), c-Myc–Max (substituted benzanilide) and HIF-1 (Manassantin A). Synthetic approaches to pyrrolobenzodiazepines and diversity-orientated synthesis of transcription factor inhibitors are also discussed.
Synlett, 2018
The pyrrolidine-catalysed formation of novel diastereomeric C11-acetone adducts was observed duri... more The pyrrolidine-catalysed formation of novel diastereomeric C11-acetone adducts was observed during the chromatographic purification of pyrrolobenzodiazepine (PBD) compounds in the presence of acetone. The mechanism of this reaction was explored and the adducts obtained fully characterised. Talirine, the cytotoxic payload element of the antibody-drug conjugate (ADC) vadastuximab talirine, was also found to form a bis-adduct under similar conditions. A cellular cytotoxicity evaluation of the modified PBD compounds confirmed their lack of cytotoxicity, consistent with loss of the DNA-interactive N10–C11 imine functionality. As well as the new chemistry reported here, given the number of PBD-based ADCs presently in the clinic, this observation may be important for the larger-scale manufacture of PBD-based products.
Tetrahedron Letters, 2017