Synthesis and Evaluation of Sulfobacin A and Analogues for Their Roles in Immunological Recognition

Chhabi Lal Chaudhary; Priscilla C. Lages; Angélica M. Peña; Amelia K. Pinto; Christopher D. Radka; Kevin J. Tidgewell

doi:10.1021/acsmedchemlett.5c00788

Synthesis and Evaluation of Sulfobacin A and Analogues for Their Roles in Immunological Recognition

Chhabi Lal Chaudhary
, Priscilla C. Lages
, Angélica M. Peña
, Amelia K. Pinto
, Christopher D. Radka
, Kevin J. Tidgewell

Producción científica: Letter › revisión exhaustiva

Resumen

We report the total synthesis of sulfobacin A (1) and its stereoisomeric analogue 1a via dynamic kinetic resolution of racemic precursors using catalytic asymmetric reactions to establish three stereogenic centers without chiral building blocks. Late-stage optimization of the amide coupling improved the overall yield of 1 to 7.8%. Preliminary biological evaluation reveals that sulfobacin A is recognized by multiple T-cell subsets (CD4, CD8, and NKT cells) when presented by multiple CD1 tetramers, indicating that this sulfonolipid can engage T cells that influence both innate (NKT) and adaptive (CD4 and CD8) immune responses. Moreover, our data suggest that modification of the lipid headgroup or alteration to a monoacyl lipid diminishes CD1-mediated T-cell recognition.

Idioma original	English
Páginas (desde-hasta)	1050-1056
Número de páginas	7
Publicación	ACS Medicinal Chemistry Letters
Volumen	17
N.º	5
DOI	https://doi.org/10.1021/acsmedchemlett.5c00788
Estado	Published - may 14 2026

Nota bibliográfica

Publisher Copyright:
© 2026 The Authors. Published by American Chemical Society

Financiación

The authors thank the NIH Tetramer Core Facility (NIH Contract 75N93020D00005 and RRID: SCR_026557) for providing OCH and fluorophore-conjugated unloaded human CD1a–d. This work was supported by the National Institutes of Health Grants P20-GM148326 (to A.K.P.), R00-AI166116 (to C.D.R.), and R35-GM159612 (to C.D.R.). Additional financial support from the Center for Pharmaceutical Research and Innovation (CPRI) as part of NIH Grant P20-GM130456 (to K.J.T.) supported synthesis. The authors thank the College of Pharmacy PharmNMR Center for analytical support. PharmNMR is supported in part by NIH Grants S10-OD28690 and P20-GM130456. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Financiadores	Número del financiador
National Institutes of Health (NIH)	R00-AI166116, P20-GM148326, 75N93020D00005, S10-OD28690, R35-GM159612, SCR_026557, P20-GM130456
Center for Pharmaceutical Research and Innovation, University of Kentucky	S10-OD28690, P20-GM130456

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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title = "Synthesis and Evaluation of Sulfobacin A and Analogues for Their Roles in Immunological Recognition",

abstract = "We report the total synthesis of sulfobacin A (1) and its stereoisomeric analogue 1a via dynamic kinetic resolution of racemic precursors using catalytic asymmetric reactions to establish three stereogenic centers without chiral building blocks. Late-stage optimization of the amide coupling improved the overall yield of 1 to 7.8\%. Preliminary biological evaluation reveals that sulfobacin A is recognized by multiple T-cell subsets (CD4, CD8, and NKT cells) when presented by multiple CD1 tetramers, indicating that this sulfonolipid can engage T cells that influence both innate (NKT) and adaptive (CD4 and CD8) immune responses. Moreover, our data suggest that modification of the lipid headgroup or alteration to a monoacyl lipid diminishes CD1-mediated T-cell recognition.",

keywords = "immune response, sulfobacin A, sulfonolipids, synthesis",

author = "Chaudhary, \{Chhabi Lal\} and Lages, \{Priscilla C.\} and Pe{\~n}a, \{Ang{\'e}lica M.\} and Pinto, \{Amelia K.\} and Radka, \{Christopher D.\} and Tidgewell, \{Kevin J.\}",

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doi = "10.1021/acsmedchemlett.5c00788",

language = "English",

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T1 - Synthesis and Evaluation of Sulfobacin A and Analogues for Their Roles in Immunological Recognition

AU - Chaudhary, Chhabi Lal

AU - Lages, Priscilla C.

AU - Peña, Angélica M.

AU - Pinto, Amelia K.

AU - Radka, Christopher D.

AU - Tidgewell, Kevin J.

PY - 2026/5/14

Y1 - 2026/5/14

N2 - We report the total synthesis of sulfobacin A (1) and its stereoisomeric analogue 1a via dynamic kinetic resolution of racemic precursors using catalytic asymmetric reactions to establish three stereogenic centers without chiral building blocks. Late-stage optimization of the amide coupling improved the overall yield of 1 to 7.8%. Preliminary biological evaluation reveals that sulfobacin A is recognized by multiple T-cell subsets (CD4, CD8, and NKT cells) when presented by multiple CD1 tetramers, indicating that this sulfonolipid can engage T cells that influence both innate (NKT) and adaptive (CD4 and CD8) immune responses. Moreover, our data suggest that modification of the lipid headgroup or alteration to a monoacyl lipid diminishes CD1-mediated T-cell recognition.

AB - We report the total synthesis of sulfobacin A (1) and its stereoisomeric analogue 1a via dynamic kinetic resolution of racemic precursors using catalytic asymmetric reactions to establish three stereogenic centers without chiral building blocks. Late-stage optimization of the amide coupling improved the overall yield of 1 to 7.8%. Preliminary biological evaluation reveals that sulfobacin A is recognized by multiple T-cell subsets (CD4, CD8, and NKT cells) when presented by multiple CD1 tetramers, indicating that this sulfonolipid can engage T cells that influence both innate (NKT) and adaptive (CD4 and CD8) immune responses. Moreover, our data suggest that modification of the lipid headgroup or alteration to a monoacyl lipid diminishes CD1-mediated T-cell recognition.

KW - immune response

KW - sulfobacin A

KW - sulfonolipids

KW - synthesis

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U2 - 10.1021/acsmedchemlett.5c00788

DO - 10.1021/acsmedchemlett.5c00788

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AN - SCOPUS:105038635548

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EP - 1056

JO - ACS Medicinal Chemistry Letters

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Synthesis and Evaluation of Sulfobacin A and Analogues for Their Roles in Immunological Recognition

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

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