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Cascade Reactions for Biologically Active Natural Products

Award Number: R01GM140183
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: 09/20/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Cascade Reactions for Biologically Active Natural Products - Project Summary / Abstract Homoharringtonine (HHT) is a clinically used protein translation inhibitor that is used to treat chronic myeloid leukemia. In addition to its FDA-approved role as a leukemia drug, HHT shows exciting promise for the treatment of other hematologic malignancies and tumors. Finally, it is a perfect molecule to use as a probe to investigate protein translation inhibition. HHT is currently prepared through semi-synthesis from naturally derived cephalotaxine. Cephalotaxine is obtained from Asian plum yew trees grown in China. The cost of HHT in particular, along with other leukemia treatments, has been described as “astronomical” and “harmful to patients” by a group of 100 leading cancer specialists. This cost results in part from a supply bottleneck reflecting its tree-based sourcing. This project will eliminate this supply problem, and provide cephalotaxine and HHT for our studies and those by other research groups. Natural products have been the source of the majority of drugs throughout history, and still are today. The field of chemical synthesis directly contributes to the application of natural products as medicines. Aromatic and heteroaromatic rings are indispensible motifs in biologically active compounds. Thus, chemical reactions that allow for the construction of molecular architectures containing substituted aromatic rings are particularly valuable to human health. Polycyclic nitrogenous molecules, exemplified by the Cephalotaxus alkaloids in this proposal, are also critically important as biologically active molecules and pharmaceuticals. However, polycyclic nitrogenous molecules, such as alkaloids, are notoriously difficult to prepare, often requiring arduous chemical syntheses for preparation. We will develop two new cascade reactions that efficiently prepare: 1. Substituted arenes, and 2. Complex polycyclic alkaloids. The innovativeness of this research is the strategic use of cascade reactions to assemble structures that previously required multiple steps to prepare. Specifically, we will prepare substituted: phenols, indoles, furans, and related structures. A distinguishing feature of this strategy is its inherent efficiency. Additionally, we will showcase these pericyclic cascades in syntheses of natural products and natural product analogs. More widely, this strategy will find immediate application in the preparation of biologically active molecules, such as HHT; chemical probes for biological systems, and related alkaloid natural products.


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 = $24,822 )
2025	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Biomedical Research and Research Training	005	5	5/13/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$431,436
2025	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Biomedical Research and Research Training	001	5	4/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$253,019
2025	2023	OREGON STATE UNIVERSITY	1500 SW JEFFERSON AVE	CORVALLIS	OR	97331	BENTON	USA	Biomedical Research and Research Training	004	4	5/13/2025	NON-COMPETING CONTINUATION	-$17,015
2025	2023	OREGON STATE UNIVERSITY	1500 SW JEFFERSON AVE	CORVALLIS	OR	97331	BENTON	USA	Biomedical Research and Research Training	000	4	4/24/2025	NON-COMPETING CONTINUATION	-$228,197
2025	2022	OREGON STATE UNIVERSITY	1500 SW JEFFERSON AVE	CORVALLIS	OR	97331	BENTON	USA	Biomedical Research and Research Training	003	3	5/13/2025	NON-COMPETING CONTINUATION	-$245,212
2025	2021	OREGON STATE UNIVERSITY	1500 SW JEFFERSON AVE	CORVALLIS	OR	97331	BENTON	USA	Biomedical Research and Research Training	002	2	5/13/2025	NON-COMPETING CONTINUATION	-$169,209
														Subtotal = $24,822

Issue Date FY: 2023 ( Subtotal = $245,212 )
2023	2023	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Biomedical Research and Research Training	000	4	8/8/2023	NON-COMPETING CONTINUATION	$245,212
														Subtotal = $245,212

Issue Date FY: 2022 ( Subtotal = $245,212 )
2022	2022	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Biomedical Research and Research Training	000	3	8/8/2022	NON-COMPETING CONTINUATION	$245,212
														Subtotal = $245,212

Issue Date FY: 2021 ( Subtotal = $245,212 )
2021	2021	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Biomedical Research and Research Training	000	2	8/25/2021	NON-COMPETING CONTINUATION	$245,212
														Subtotal = $245,212

Issue Date FY: 2020 ( Subtotal = $245,212 )
2020	2020	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Biomedical Research and Research Training	000	1	9/9/2020	NEW	$245,212
														Subtotal = $245,212

Grand Total All Awards = $1,005,670

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Cascade Reactions for Biologically Active Natural Products

Award Number: R01GM140183

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: 09/20/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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