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Click and Modify: Design of Editable SuFEx Linchpins for the Expedient Construction of Drug-like Compounds and Polymers

Award Number: R35GM138079
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/05/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Click and Modify: Design of Editable SuFEx Linchpins for the Expedient Construction of Drug-like Compounds and Polymers - Project Summary/Abstract Click chemistry has revolutionized modern synthesis, enabling diverse applications such as biomolecule labeling and polymer functionalization. The hallmark features of click reactions—modularity, broad applicability, exceptional chemoselectivity, and high yields with minimal purification—offer unparalleled opportunities for molecular design. However, conventional click linkers (e.g., triazoles) typically function as inert covalent bridges between molecules, such as a drug and a target-recognition warhead, without providing additional functionality or improving key properties, such as binding affinity. Their inherent stability makes these linkers unsuitable for selective chemical modification under mild conditions. Consequently, click reactions are not typically part of the medicinal chemist's toolkit for diversifying bioactive scaffolds through systematic functional-group variations, including ‘single-atom’ logic. We propose to shift this paradigm through the development of editable click linchpins that can be selectively converted into prevalent C–C or C–X bonds (X = heteroatom). Our strategy seeks to leverage the efficiency, practicality, and robustness of click chemistry to construct the bonds found in all pharmaceutical agents. The overarching theme of our ‘click and modify’ approach is to transform primary amines into 1,2- dialkyldiazenes and subsequently harness their unique photochemistry into a variety of catalytic deaminative processes. Primary amines represent one of the most abundant family of commercially available building blocks for synthesis and are ubiquitous across a diverse array of structurally complex biomolecules, including amino acids and peptides, biogenic neurotransmitters and signaling molecules, lipids, amino sugars, as well as alkaloid secondary metabolites. To streamline the access to 1,2-dialkyldiazenes from the large pool of primary amines, we developed an efficient and practical one-pot process Sulfur(VI)-Fluoride-Exchange (SuFEx) click chemistry coupled with the aza-Ramberg-Bäcklund reaction. The propensity of 1,2-dialkyldiazenes to undergo clean homolytic fragmentation under photocatalytic ambient conditions will be leveraged as a branching point for selective functionalizations via the controlled generation of alkyl radicals. We will first focus on strategies for forging C(sp3)–C(sp2) bonds through the deamination of a broad range of primary amines. A thorough understanding of the mechanism underpinning the proposed catalysis will enable the use of a variety of coupling partners and the optimization of enantioselective variants. Concurrently, strategies for C(sp3)–C(sp3) and C(sp3)– X couplings will be explored from the same alkyl radicals. Finally, the synthetic potential of this diverse transformation manifold will be demonstrated through the synthesis of macrocyclic or stapled peptides and construction of polymers for healthcare applications.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $359,796 )
2026	2026	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	001	6	5/12/2026	COMPETING CONTINUATION	$361,218
2026	2024	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	5	4/9/2026	NON-COMPETING CONTINUATION	-$1,422
														Subtotal = $359,796

Issue Date FY: 2024 ( Subtotal = $363,288 )
2024	2024	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	5	7/16/2024	NON-COMPETING CONTINUATION	$363,288
														Subtotal = $363,288

Issue Date FY: 2023 ( Subtotal = $363,288 )
2023	2023	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	4	8/14/2023	NON-COMPETING CONTINUATION	$363,288
														Subtotal = $363,288

Issue Date FY: 2022 ( Subtotal = $363,288 )
2022	2022	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	3	7/12/2022	NON-COMPETING CONTINUATION	$363,288
														Subtotal = $363,288

Issue Date FY: 2021 ( Subtotal = $363,288 )
2021	2021	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	2	7/20/2021	NON-COMPETING CONTINUATION	$363,288
														Subtotal = $363,288

Issue Date FY: 2020 ( Subtotal = $363,288 )
2020	2020	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	1	9/2/2020	NEW	$363,288
														Subtotal = $363,288

Grand Total All Awards = $2,176,236

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Click and Modify: Design of Editable SuFEx Linchpins for the Expedient Construction of Drug-like Compounds and Polymers

Award Number: R35GM138079

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/05/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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