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Pharmacophore - Directed Retrosynthesis Applied to Bioactive Natural Products Informing Mechanism of Action Studies

Award Number: R35GM134910
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: 01/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2029

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Pharmacophore - Directed Retrosynthesis Applied to Bioactive Natural Products Informing Mechanism of Action Studies - Project Summary/Abstract Our proposed studies of the chemistry and biology of natural products (NPs) that possess anticancer, immunosuppressive, anti-ischemic, and antibacterial effects are guided by the following inquiry: Can natural product total synthesis be more closely aligned with simultaneous biological studies by targeting designed, simplified derivatives, that each possess a proposed pharmacophore, during the retrosynthetic planning stages? This tactic, which begins with a hypothesis for a natural product’s ‘pharmacophore,’ enables collection of structure-activity relationship (SAR) data throughout a total synthesis effort enabling early discovery of simplified bioactive derivatives. Building on Wender’s call for function-oriented synthesis, this variation of retrosynthetic analysis, seeks to more closely align total synthesis efforts with concurrent biological studies and opens the potential to identify simplified versions of the natural product with similar potency or even new functions in the course of a total synthesis effort. We call this strategy ‘pharmacophore-directed retrosynthesis’ (PDR) to emphasize the importance of incorporating hypothesized pharmacophores into the retrosynthetic planning stages of a total synthesis effort. This approach has the potential to greatly accelerate harvesting the rich information content of NPs which historically has had immense impact on basic cell biology and medicine. Our strategy begins with a hypothesized pharmacophore, based on available SAR data, and this directs the retrosynthetic analysis. Stepwise, methodical introduction of structural complexity to this pharmacophore en route to the natural product enables concurrent collection of SAR data which informs probe synthesis useful for cellular target identification by our diverse group of ongoing collaborators employing biochemical, proteomic, and genetic approaches. We anticipate that our proposed research will continue to contribute to basic cell biology while also identifying new chemotypes for next generation small molecule therapeutics. Several NPs to be studied are proposed to engage protein targets covalently, thus this research will contribute to the re-emerging topic of covalent drugs. In the last grant period, a total synthesis of rameswaralide revealed the anticancer effects of a simple bicyclic b-ketoester. In addition, a synthetic intermediate, that was found to exhibit greater activity than the natural product, is showing potential as a new inhibitor chemotype for a poorly understood kinase. Several additional simplified derivatives of NPs, bearing a proposed pharmacophore, were synthesized and exhibited bioactivity. In the next grant period, we will fully develop a variant of PDR that targets alkynes as both synthetic intermediates and proteomic probes that may be more generally applicable. Inspired in some cases by our PDR approach, we are developing novel synthetic strategies including late-stage functionalizations of macrocycles reminiscent of biosynthetic tailoring enzymes, intramolecular directed CH oxidations and Diels- Alder reactions, tandem [2+2]/Grob-fragmentation reactions, and novel couplings with diborylated alkenes.


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: 2025 ( Subtotal = $446,414 )
2025	2025	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	002	6	12/31/2024	COMPETING CONTINUATION	$446,414
2025	2025	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	004	6	6/25/2025	COMPETING CONTINUATION	$194,541
2025	2024	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	003	5	6/25/2025	NON-COMPETING CONTINUATION	-$194,541
2025	2024	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	001	5	12/24/2024	NON-COMPETING CONTINUATION	$0
2025	2024	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	000	5	11/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $446,414

Issue Date FY: 2024 ( Subtotal = $360,100 )
2024	2024	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	000	5	1/1/2024	NON-COMPETING CONTINUATION	$324,090
2024	2024	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	001	5	5/20/2024	NON-COMPETING CONTINUATION	$36,010
														Subtotal = $360,100

Issue Date FY: 2023 ( Subtotal = $360,100 )
2023	2023	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	000	4	2/17/2023	NON-COMPETING CONTINUATION	$360,100
														Subtotal = $360,100

Issue Date FY: 2022 ( Subtotal = $390,100 )
2022	2022	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	000	3	1/4/2022	NON-COMPETING CONTINUATION	$351,090
2022	2022	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	001	3	6/24/2022	NON-COMPETING CONTINUATION	$39,010
														Subtotal = $390,100

Issue Date FY: 2021 ( Subtotal = $499,513 )
2021	2021	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	001	2	2/12/2021	NON-COMPETING CONTINUATION	$39,973
2021	2021	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	000	2	12/8/2020	NON-COMPETING CONTINUATION	$359,752
2021	2021	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	002	2	7/12/2021	SUPPLEMENT FOR EXPANSION	$99,788
														Subtotal = $499,513

Issue Date FY: 2020 ( Subtotal = $273,570 )
2020	2020	BAYLOR UNIVERSITY	700 S UNIVERSITY PARKS DR	WACO	TX	76706	MCLENNAN	USA	Biomedical Research and Research Training	000	1	1/1/2020	NEW	$273,570
														Subtotal = $273,570

Grand Total All Awards = $2,329,797

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Pharmacophore - Directed Retrosynthesis Applied to Bioactive Natural Products Informing Mechanism of Action Studies

Award Number: R35GM134910

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: 01/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2029

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