Total syntheses of cyclohelminthol I-IV reveal a new cysteine-selective covalent reactive group

TY - JOUR

T1 - Total syntheses of cyclohelminthol I-IV reveal a new cysteine-selective covalent reactive group

AU - Paulsen, Thomas T

AU - Kiib, Anders E

AU - Wørmer, Gustav J

AU - Hacker, Stephan M

AU - Poulsen, Thomas B

N1 - This journal is © The Royal Society of Chemistry.

PY - 2025/1/29

Y1 - 2025/1/29

N2 - Biocompatible covalent reactive groups (CRGs) play pivotal roles in several areas of chemical biology and the life sciences, including targeted covalent inhibitor design and preparation of advanced biologic drugs, such as antibody-drug conjugates. In this study, we present the discovery that the small, chlorinated polyketide natural product cyclohelminthiol II (CHM-II) acts as a new type of cysteine/thiol-targeting CRG incorporating both reversible and irreversible reactivity. We devise the first syntheses of four simple cyclohelminthols, (±)-cyclohelminthol I-IV, with selective chlorinations (at C 2 and C 5) and a Ni-catalyzed reductive cross coupling between an enone, a vinyl bromide and triethylsilyl chloride as the key steps. Unbiased biological profiling (cell painting) was used to discover a putative covalent mechanism for CHM-II in cells with subsequent validation experiments demonstrating mechanistic similarity to dimethyl fumarate (DMF) - a known (covalent) drug used in the treatment of multiple sclerosis. Focused biochemical experiments revealed divergent thiol-reactivity inherent to the CHM-II scaffold and through further chemical derivatization of CHM-II we applied activity-based protein profiling (ABPP)-workflows to show exclusive cysteine-labelling in cell lysate. Overall, this study provides both efficient synthetic access to the CHM-II chemotype - and neighboring chemical space - and proof-of-concept for several potential applications of this new privileged CRG-class within covalent chemical biology.

AB - Biocompatible covalent reactive groups (CRGs) play pivotal roles in several areas of chemical biology and the life sciences, including targeted covalent inhibitor design and preparation of advanced biologic drugs, such as antibody-drug conjugates. In this study, we present the discovery that the small, chlorinated polyketide natural product cyclohelminthiol II (CHM-II) acts as a new type of cysteine/thiol-targeting CRG incorporating both reversible and irreversible reactivity. We devise the first syntheses of four simple cyclohelminthols, (±)-cyclohelminthol I-IV, with selective chlorinations (at C 2 and C 5) and a Ni-catalyzed reductive cross coupling between an enone, a vinyl bromide and triethylsilyl chloride as the key steps. Unbiased biological profiling (cell painting) was used to discover a putative covalent mechanism for CHM-II in cells with subsequent validation experiments demonstrating mechanistic similarity to dimethyl fumarate (DMF) - a known (covalent) drug used in the treatment of multiple sclerosis. Focused biochemical experiments revealed divergent thiol-reactivity inherent to the CHM-II scaffold and through further chemical derivatization of CHM-II we applied activity-based protein profiling (ABPP)-workflows to show exclusive cysteine-labelling in cell lysate. Overall, this study provides both efficient synthetic access to the CHM-II chemotype - and neighboring chemical space - and proof-of-concept for several potential applications of this new privileged CRG-class within covalent chemical biology.

UR - http://www.scopus.com/inward/record.url?scp=85216974107&partnerID=8YFLogxK

U2 - 10.1039/d4sc08667h

DO - 10.1039/d4sc08667h

M3 - Journal article

C2 - 39886435

SN - 2041-6520

SP - 3916

EP - 3927

JO - Chemical Science

JF - Chemical Science

ER -