Puckering the Planar Landscape of Fragments: Design and Synthesis of a 3D Cyclobutane Fragment Library

TY - JOUR

T1 - Puckering the Planar Landscape of Fragments

T2 - Design and Synthesis of a 3D Cyclobutane Fragment Library

AU - Hamilton, David J.

AU - Beemsterboer, Marieke

AU - Carter, Caroline M.

AU - Elsayed, Jasmina

AU - Huiberts, Rilana E.M.

AU - Klein, Hanna F.

AU - O'Brien, Peter

AU - de Esch, Iwan J.P.

AU - Wijtmans, Maikel

N1 - Funding Information: This work was funded by the European Union's Framework Programme for Research and Innovation Horizon 2020 (2014–2020) under the Marie‐Skłodowska‐Curie grant agreement number 675899 (“Fragment based drug discovery Network, FRAGNET”) and under the grant agreement number 777828 (“The best online drug discovery platform. Building the Ultimate chemical database for drug discovery”). We thank Robert Kiss and Attila Wootsch for helpful discussions and support. We would like to thank Bas de Boer, Florian van Vugt, Emylie Nguyen and Fariëlle Boldewijn for their involvement in synthesis. We are grateful to Hans Custers for HRMS and nephelometry measurements, Tom Dekker for assistance with radar plots and nephelometry, and Elwin Janssen for assistance with NMR analysis. Publisher Copyright: © 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.

PY - 2022/5/4

Y1 - 2022/5/4

N2 - Fragment-based drug discovery (FBDD) has a growing need for unique screening libraries. The cyclobutane moiety was identified as an underrepresented yet attractive three-dimensional (3D) scaffold. Synthetic strategies were developed via a key 3-azido-cyclobutanone intermediate, giving potential access to a range of functional groups with accessible growth vectors. A focused set of 33 novel 3D cyclobutane fragments was synthesised, comprising three functionalities: secondary amines, amides, and sulfonamides. This library was designed using Principal Component Analysis (PCA) and an expanded version of the rule of three (RO3), followed by Principal Moment of Inertia (PMI) analysis to achieve both chemical diversity and high 3D character. Cis and trans ring isomers of library members were generated to maximise the shape diversity obtained, while limiting molecular complexity through avoiding enantiomers. Property analyses of the cyclobutane library indicated that it fares favourably against existing synthetic 3D fragment libraries in terms of shape and physicochemical properties.

AB - Fragment-based drug discovery (FBDD) has a growing need for unique screening libraries. The cyclobutane moiety was identified as an underrepresented yet attractive three-dimensional (3D) scaffold. Synthetic strategies were developed via a key 3-azido-cyclobutanone intermediate, giving potential access to a range of functional groups with accessible growth vectors. A focused set of 33 novel 3D cyclobutane fragments was synthesised, comprising three functionalities: secondary amines, amides, and sulfonamides. This library was designed using Principal Component Analysis (PCA) and an expanded version of the rule of three (RO3), followed by Principal Moment of Inertia (PMI) analysis to achieve both chemical diversity and high 3D character. Cis and trans ring isomers of library members were generated to maximise the shape diversity obtained, while limiting molecular complexity through avoiding enantiomers. Property analyses of the cyclobutane library indicated that it fares favourably against existing synthetic 3D fragment libraries in terms of shape and physicochemical properties.

KW - Cyclobutane

KW - Drug design

KW - Fragment-based drug discovery (FBDD)

KW - Library design

KW - Three-dimensional (3D)

UR - http://www.scopus.com/inward/record.url?scp=85127516902&partnerID=8YFLogxK

U2 - 10.1002/cmdc.202200113

DO - 10.1002/cmdc.202200113

M3 - Article

C2 - 35277937

AN - SCOPUS:85127516902

SN - 1860-7179

VL - 17

JO - ChemMedChem

JF - ChemMedChem

IS - 9

M1 - e202200113

ER -