Claire Adcock

University of Sussex

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Hashim Javaid

GW Pharmaceuticals (United Kingdom)

Niall M.B. Martin

MRC Centre for Regenerative Medicine

Sylvie Gomez

University of Pamplona

Graeme C.M. Smith

Agios Pharmaceuticals (United States)

Keith Menear

GW Pharmaceuticals (United Kingdom)

Jan Drzewiecki

GW Pharmaceuticals (United Kingdom)

Louise Copsey

GW Pharmaceuticals (United Kingdom)

Xiaoling Cockcroft

GW Pharmaceuticals (United Kingdom)

Alessio Ciulli

University of Dundee

Jodie Manini

Novartis (United Kingdom)

Cooperative Institutions

Novartis (Switzerland)

GW Pharmaceuticals (United Kingdom)

Thermo Fisher Scientific (United Kingdom)

Novartis Institutes for BioMedical Research

Novartis (United Kingdom)

University of Sussex

University of East Anglia

Horsham Hospital

University of Dundee

AstraZeneca (United Kingdom)

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Solid-Phase Synthesis of Duocarmycin Analogues and the Effect of C-Terminal Substitution on Biological Activity

The Journal of Organic Chemistry (2015)

Michael J. Stephenson Lesley A. Howell Maria A. O’Connell Keith R. Fox Claire Adcock

The duocarmycins are potent antitumor agents with potential for use in the development of antibody-drug conjugates (ADCs) as well as being clinical candidates in their own right. In this article, we describe the synthesis of a duocarmycin monomer (DSA) that is suitably protected for utilization in solid-phase synthesis. The synthesis was performed on a large scale, and the resulting racemic protected Fmoc-DSA subunit was separated by supercritical fluid chromatography (SFC) into the single enantiomers; its application to solid-phase synthesis methodology gave a series of monomeric and extended duocarmycin analogues with amino acid substituents. The DNA sequence selectivity was similar to that in previous reports for both the monomeric and extended compounds. Substitution at the C-terminus of duocarmycin caused a decrease in antiproliferative activity for all of the compounds studied. An extended compound containing an alanine at the C-terminus was converted to the primary amide or to an extended structure containing a terminal tertiary amine, but this had no beneficial effects on biological activity.

Solid-Phase Synthesis

Amide

Peptide Synthesis

Alanine

10.1021/acs.joc.5b01373

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Citations (13)

7-Azaindole-3-acetic acid derivatives: Potent and selective CRTh2 receptor antagonists

Bioorganic & Medicinal Chemistry Letters (2009)

David A. Sandham Claire Adcock Kamlesh Bala Lucy Barker Zarin Brown

Chemotype

High-Throughput Screening

10.1016/j.bmcl.2009.06.042

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Citations (43)

Novel alkoxybenzamide inhibitors of poly(ADP-ribose) polymerase

Bioorganic & Medicinal Chemistry Letters (2008)

Keith Menear Claire Adcock Francisco Cuenca Alonso Kristel Blackburn Louise Copsey

Ribose

10.1016/j.bmcl.2008.06.025

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Citations (38)

Use of Aldehyde–Alkyne–Amine Couplings to Generate Medicinal Chemistry-Relevant Linkers

ACS Medicinal Chemistry Letters (2025)

Andrew McGown Vesna Vetma Damien Crépin Yan Lin Claire Adcock

Copper catalyzed aldehyde–alkyne–amine (A3) couplings lead to multifunctional, racemic, propargylic amines, many on a multigram scale. As part of an industrial collaboration, a selection of linkers was purified by chiral HPLC to afford single enantiomers, the absolute configuration of which was determined by vibrational circular dichroism (vCD). To show medicinal chemistry applications, selected linkers were further derivatized into potential cellular probes and (+)-JQ1 containing PROTACs (proteolysis targeting chimeras), which degraded their target protein BRD4.

Alkyne

10.1021/acsmedchemlett.4c00531

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4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1

Journal of Medicinal Chemistry (2008)

Keith Menear Claire Adcock Robert Boulter Xiaoling Cockcroft Louise Copsey

Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2 H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2 H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.

PARP inhibitor

Ribose

10.1021/jm8001263

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Citations (537)