Three-component assembly and structure-function relationships of (–)-gukulenin A.
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| Title: | Three-component assembly and structure-function relationships of (–)-gukulenin A. |
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| Authors: | Gupta, Vaani (AUTHOR), Wang, Zechun (AUTHOR), Combs, Joshua B. (AUTHOR), Wright, Timothy (AUTHOR), Chen, Lei (AUTHOR), Lin, Boxu (AUTHOR), Holmes, Ryan (AUTHOR), Qin, Bo (AUTHOR), Oh, Joonseok (AUTHOR), Crawford, Jason M. (AUTHOR), Herzon, Seth B. (AUTHOR) |
| Source: | Science. 12/11/2025, Vol. 390 Issue 6778, p1-9. 9p. |
| Subjects: | Chemical synthesis, Structure-activity relationships, Metabolites, Alkaloids, Cytotoxins, Marine organisms, Antineoplastic agents |
| Abstract: | α-Tropolones comprise an unsaturated seven-membered ring bearing a hydroxyl substituent adjacent to a polarized carbon-oxygen π bond. This polarization imparts a permanent molecular dipole and aromatic stabilization to the ring, resulting in distinct physical properties, including affinity for divalent metals and ambiphilic reactivity. Among secondary metabolites that contain α-tropolones, the pseudodimeric isolate (–)-gukulenin A (7) stands out for its complexity and has shown promise in treating mouse models of ovarian cancer. In this study, we describe an enantioselective synthesis of (–)-gukulenin A (7). Key steps include a directed C–H arylation, a tandem Grob fragmentation–alkylation, an innovative synthesis of methyl tropolone ethers, a multicomponent cross-coupling, and a thermal carbonyl-ene reaction. Structure-function studies establish the dimeric tropolone and aldehyde substructures as drivers of cytotoxicity. Editor's summary: Gukulenin A, an organic compound isolated from a marine sponge, has attracted fundamental interest on account of the pair of seven-carbon tropolone ring motifs in its framework. Preliminary studies have also highlighted the compound's anticancer activity in mouse models. Gupta et al. report the synthesis of this compound in 24 steps, hinging in particular on the use of a tin reagent that was custom developed to couple the two tropolone fragments in a manner that differentiates their subtly distinct substituents. The route also enabled the preparation of 15 analogs to study the structural factors underlying the previously reported cytotoxicity. —Jake S. Yeston INTRODUCTION: α-Tropolones are aromatic seven-membered rings that contain hydroxyl and carbonyl substituents in a 1,2-relationship. Their aromatic resonance stabilization energy has been estimated as ~47 kcal/mol, ~10 kcal/mol greater than more benzenoid systems. Separation of charge in the carbon-oxygen π bond enhances aromaticity. Consequently, α-tropolones possess a strong molecular dipole (3.71 D), affinity for divalent metals, ambiphilic reactivity, and an acidic hydroxyl residue [pKa (where Ka is the acid dissociation constant) = 6.7, H2O]. α-Tropolones are found in many secondary metabolites, including a pseudodimeric metabolite known as (–)-gukulenin A that contains two substituted α-tropolone rings. (–)-Gukulenin A was isolated from the marine sponge Phorbas gukulensis and exhibited promise in a mouse model of ovarian cancer. However, the features of (–)-gukulenin A that drive its antitumor effects are unknown. RATIONALE: We envisioned that a convergent, stereoselective synthesis of (–)-gukulenin A could serve as a platform to determine which structural elements in the isolate are necessary for antiproliferative activity. Such structure-function relationships would aid in identification of gukulenin's biological target, as well as designing simplified derivatives for preclinical evaluation. We modeled our synthetic strategy around the hypothesis that nature prepares (–)-gukulenin A by dimerization of two identical α-tropolone intermediates. Experimentally, we envisioned that this could be achieved by coupling of two monomeric methyl tropolone ethers and a suitably oxidized two-carbon linker, followed by a biomimetic cyclization to form the tetracycle of (–)-gukulenin A. RESULTS: The cyclopentane rings of (–)-gukulenin A were derived from enantioenriched exo-(2R)-norbornylamine. After directed C–H arylation and further elaboration, a tandem Grob fragmentation–α-alkylation was implemented to reveal the cyclopentane rings of the target. We developed three methods to achieve the expansion of ortho-benzoquinone monoketals to α-tropolone methyl ethers, and the third method was ultimately used in the synthesis. The reagent (E)-1,2-di(tributylstannyl)-1-ethoxyethylene was designed, synthesized, and utilized in a twofold, site-selective cross-coupling reaction to access the carbon skeleton of (–)-gukulenin A. The cyclohexanol and hemiketal rings were introduced in one step by a thermal carbonyl-ene reaction. After deprotection, (–)-gukulenin A was obtained. We applied this chemistry to the synthesis of 15 derivatives, each of which was designed to probe a specific structure-function relationship. By this approach, we established that the dimeric, α-tropolone structure is necessary for potent cytotoxicity, that variation in the C2/C2′ substituents and two-carbon linker (C20, C21) is tolerated, and that the aldehyde residue enhances the cytotoxicity of dimeric (but not monomeric) derivatives. CONCLUSION: The synthetic strategy that we developed provides access to (–)-gukulenin A in 24 steps and 2.5% yield from commercial reagents. Our structure-function studies define the features of gukulenin that are critical for potent cytotoxic effects. Collectively, this work provides a foundation for target identification studies and the preclinical evaluation of simplified derivatives in single-agent and combinatorial chemotherapies. Properties of α-tropolones (left), our synthetic approach to (–)-gukulenin A (center), and key findings from structure-function studies (right).: [ABSTRACT FROM AUTHOR] |
| Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
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| Items | – Name: Title Label: Title Group: Ti Data: Three-component assembly and structure-function relationships of (–)-gukulenin A. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Gupta%2C+Vaani%22">Gupta, Vaani</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Wang%2C+Zechun%22">Wang, Zechun</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Combs%2C+Joshua+B%2E%22">Combs, Joshua B.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Wright%2C+Timothy%22">Wright, Timothy</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Chen%2C+Lei%22">Chen, Lei</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lin%2C+Boxu%22">Lin, Boxu</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Holmes%2C+Ryan%22">Holmes, Ryan</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Qin%2C+Bo%22">Qin, Bo</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Oh%2C+Joonseok%22">Oh, Joonseok</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Crawford%2C+Jason+M%2E%22">Crawford, Jason M.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Herzon%2C+Seth+B%2E%22">Herzon, Seth B.</searchLink> (AUTHOR) – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Science%22">Science</searchLink>. 12/11/2025, Vol. 390 Issue 6778, p1-9. 9p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Chemical+synthesis%22">Chemical synthesis</searchLink><br /><searchLink fieldCode="DE" term="%22Structure-activity+relationships%22">Structure-activity relationships</searchLink><br /><searchLink fieldCode="DE" term="%22Metabolites%22">Metabolites</searchLink><br /><searchLink fieldCode="DE" term="%22Alkaloids%22">Alkaloids</searchLink><br /><searchLink fieldCode="DE" term="%22Cytotoxins%22">Cytotoxins</searchLink><br /><searchLink fieldCode="DE" term="%22Marine+organisms%22">Marine organisms</searchLink><br /><searchLink fieldCode="DE" term="%22Antineoplastic+agents%22">Antineoplastic agents</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: α-Tropolones comprise an unsaturated seven-membered ring bearing a hydroxyl substituent adjacent to a polarized carbon-oxygen π bond. This polarization imparts a permanent molecular dipole and aromatic stabilization to the ring, resulting in distinct physical properties, including affinity for divalent metals and ambiphilic reactivity. Among secondary metabolites that contain α-tropolones, the pseudodimeric isolate (–)-gukulenin A (7) stands out for its complexity and has shown promise in treating mouse models of ovarian cancer. In this study, we describe an enantioselective synthesis of (–)-gukulenin A (7). Key steps include a directed C–H arylation, a tandem Grob fragmentation–alkylation, an innovative synthesis of methyl tropolone ethers, a multicomponent cross-coupling, and a thermal carbonyl-ene reaction. Structure-function studies establish the dimeric tropolone and aldehyde substructures as drivers of cytotoxicity. Editor's summary: Gukulenin A, an organic compound isolated from a marine sponge, has attracted fundamental interest on account of the pair of seven-carbon tropolone ring motifs in its framework. Preliminary studies have also highlighted the compound's anticancer activity in mouse models. Gupta et al. report the synthesis of this compound in 24 steps, hinging in particular on the use of a tin reagent that was custom developed to couple the two tropolone fragments in a manner that differentiates their subtly distinct substituents. The route also enabled the preparation of 15 analogs to study the structural factors underlying the previously reported cytotoxicity. —Jake S. Yeston INTRODUCTION: α-Tropolones are aromatic seven-membered rings that contain hydroxyl and carbonyl substituents in a 1,2-relationship. Their aromatic resonance stabilization energy has been estimated as ~47 kcal/mol, ~10 kcal/mol greater than more benzenoid systems. Separation of charge in the carbon-oxygen π bond enhances aromaticity. Consequently, α-tropolones possess a strong molecular dipole (3.71 D), affinity for divalent metals, ambiphilic reactivity, and an acidic hydroxyl residue [pKa (where Ka is the acid dissociation constant) = 6.7, H2O]. α-Tropolones are found in many secondary metabolites, including a pseudodimeric metabolite known as (–)-gukulenin A that contains two substituted α-tropolone rings. (–)-Gukulenin A was isolated from the marine sponge Phorbas gukulensis and exhibited promise in a mouse model of ovarian cancer. However, the features of (–)-gukulenin A that drive its antitumor effects are unknown. RATIONALE: We envisioned that a convergent, stereoselective synthesis of (–)-gukulenin A could serve as a platform to determine which structural elements in the isolate are necessary for antiproliferative activity. Such structure-function relationships would aid in identification of gukulenin's biological target, as well as designing simplified derivatives for preclinical evaluation. We modeled our synthetic strategy around the hypothesis that nature prepares (–)-gukulenin A by dimerization of two identical α-tropolone intermediates. Experimentally, we envisioned that this could be achieved by coupling of two monomeric methyl tropolone ethers and a suitably oxidized two-carbon linker, followed by a biomimetic cyclization to form the tetracycle of (–)-gukulenin A. RESULTS: The cyclopentane rings of (–)-gukulenin A were derived from enantioenriched exo-(2R)-norbornylamine. After directed C–H arylation and further elaboration, a tandem Grob fragmentation–α-alkylation was implemented to reveal the cyclopentane rings of the target. We developed three methods to achieve the expansion of ortho-benzoquinone monoketals to α-tropolone methyl ethers, and the third method was ultimately used in the synthesis. The reagent (E)-1,2-di(tributylstannyl)-1-ethoxyethylene was designed, synthesized, and utilized in a twofold, site-selective cross-coupling reaction to access the carbon skeleton of (–)-gukulenin A. The cyclohexanol and hemiketal rings were introduced in one step by a thermal carbonyl-ene reaction. After deprotection, (–)-gukulenin A was obtained. We applied this chemistry to the synthesis of 15 derivatives, each of which was designed to probe a specific structure-function relationship. By this approach, we established that the dimeric, α-tropolone structure is necessary for potent cytotoxicity, that variation in the C2/C2′ substituents and two-carbon linker (C20, C21) is tolerated, and that the aldehyde residue enhances the cytotoxicity of dimeric (but not monomeric) derivatives. CONCLUSION: The synthetic strategy that we developed provides access to (–)-gukulenin A in 24 steps and 2.5% yield from commercial reagents. Our structure-function studies define the features of gukulenin that are critical for potent cytotoxic effects. Collectively, this work provides a foundation for target identification studies and the preclinical evaluation of simplified derivatives in single-agent and combinatorial chemotherapies. Properties of α-tropolones (left), our synthetic approach to (–)-gukulenin A (center), and key findings from structure-function studies (right).: [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1126/science.aea9310 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 9 StartPage: 1 Subjects: – SubjectFull: Chemical synthesis Type: general – SubjectFull: Structure-activity relationships Type: general – SubjectFull: Metabolites Type: general – SubjectFull: Alkaloids Type: general – SubjectFull: Cytotoxins Type: general – SubjectFull: Marine organisms Type: general – SubjectFull: Antineoplastic agents Type: general Titles: – TitleFull: Three-component assembly and structure-function relationships of (–)-gukulenin A. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Gupta, Vaani – PersonEntity: Name: NameFull: Wang, Zechun – PersonEntity: Name: NameFull: Combs, Joshua B. – PersonEntity: Name: NameFull: Wright, Timothy – PersonEntity: Name: NameFull: Chen, Lei – PersonEntity: Name: NameFull: Lin, Boxu – PersonEntity: Name: NameFull: Holmes, Ryan – PersonEntity: Name: NameFull: Qin, Bo – PersonEntity: Name: NameFull: Oh, Joonseok – PersonEntity: Name: NameFull: Crawford, Jason M. – PersonEntity: Name: NameFull: Herzon, Seth B. IsPartOfRelationships: – BibEntity: Dates: – D: 11 M: 12 Text: 12/11/2025 Type: published Y: 2025 Identifiers: – Type: issn-print Value: 00368075 Numbering: – Type: volume Value: 390 – Type: issue Value: 6778 Titles: – TitleFull: Science Type: main |
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