Effects of 6-Aminonicotinic Acid Esters on the Reprogrammed Epigenetic State of Distant Metastatic Pancreatic Carcinoma

Run Duo Gao; Masahiro Maeda; Carolyn Tallon; Andrew P. Feinberg; Barbara S. Slusher; Takashi Tsukamoto

doi:10.1021/acsmedchemlett.2c00404

Effects of 6-Aminonicotinic Acid Esters on the Reprogrammed Epigenetic State of Distant Metastatic Pancreatic Carcinoma

Run Duo Gao, Masahiro Maeda, Carolyn Tallon, Andrew P. Feinberg, Barbara S. Slusher, Takashi Tsukamoto

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

In the search for alternatives to 6-aminonicotinamide (6AN), a series of 6-aminonicotinic acid esters were designed and synthesized as precursors of 6-amino-NADP⁺, a potent inhibitor of 6-phosphogluconate dehydrogenase (6PGD). Like 6AN, some of these esters were found to reverse the loss of histone 3 lysine 9 trimethylation (H3K9me3) in patient-derived pancreatic ductal adenocarcinoma (PDAC) distant metastasis (A38-5). Among them, 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 6-aminonicotinate (5i) showed more potent antiproliferative activity than 6AN. Metabolite analysis revealed that compound 5i produced a marked increase in metabolites upstream of 6PGD, indicating intracellular inhibition of 6PGD by 6-amino-NADP⁺derived from compound 5i through 6-aminonicotinic acid (6ANA) via the Preiss-Handler pathway. Despite the more potent pharmacological effects shown by compound 5i in A38-5, compound 5i was found to be substantially less toxic to primary hippocampal rat neurons compared to 6AN, indicating its therapeutic potential in targeting distant metastatic cells.

Original language	English (US)
Pages (from-to)	1892-1897
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	13
Issue number	12
DOIs	https://doi.org/10.1021/acsmedchemlett.2c00404
State	Published - Dec 8 2022

Keywords

6-Aminonicotinamide
6-aminonicotinic acid esters
6-phosphogluconate dehydrogenase
epigenetics
metabolomics
pancreatic cancer

ASJC Scopus subject areas

Drug Discovery
Biochemistry
Organic Chemistry

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10.1021/acsmedchemlett.2c00404

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title = "Effects of 6-Aminonicotinic Acid Esters on the Reprogrammed Epigenetic State of Distant Metastatic Pancreatic Carcinoma",

abstract = "In the search for alternatives to 6-aminonicotinamide (6AN), a series of 6-aminonicotinic acid esters were designed and synthesized as precursors of 6-amino-NADP+, a potent inhibitor of 6-phosphogluconate dehydrogenase (6PGD). Like 6AN, some of these esters were found to reverse the loss of histone 3 lysine 9 trimethylation (H3K9me3) in patient-derived pancreatic ductal adenocarcinoma (PDAC) distant metastasis (A38-5). Among them, 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 6-aminonicotinate (5i) showed more potent antiproliferative activity than 6AN. Metabolite analysis revealed that compound 5i produced a marked increase in metabolites upstream of 6PGD, indicating intracellular inhibition of 6PGD by 6-amino-NADP+derived from compound 5i through 6-aminonicotinic acid (6ANA) via the Preiss-Handler pathway. Despite the more potent pharmacological effects shown by compound 5i in A38-5, compound 5i was found to be substantially less toxic to primary hippocampal rat neurons compared to 6AN, indicating its therapeutic potential in targeting distant metastatic cells.",

keywords = "6-Aminonicotinamide, 6-aminonicotinic acid esters, 6-phosphogluconate dehydrogenase, epigenetics, metabolomics, pancreatic cancer",

author = "Gao, {Run Duo} and Masahiro Maeda and Carolyn Tallon and Feinberg, {Andrew P.} and Slusher, {Barbara S.} and Takashi Tsukamoto",

note = "Funding Information: This work was supported by the Lustgarten Foundation and the National Institute of Mental Health (P30MH075673). Publisher Copyright: {\textcopyright} 2022 American Chemical Society. All rights reserved.",

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T1 - Effects of 6-Aminonicotinic Acid Esters on the Reprogrammed Epigenetic State of Distant Metastatic Pancreatic Carcinoma

AU - Gao, Run Duo

AU - Maeda, Masahiro

AU - Tallon, Carolyn

AU - Feinberg, Andrew P.

AU - Slusher, Barbara S.

AU - Tsukamoto, Takashi

N1 - Funding Information: This work was supported by the Lustgarten Foundation and the National Institute of Mental Health (P30MH075673). Publisher Copyright: © 2022 American Chemical Society. All rights reserved.

PY - 2022/12/8

Y1 - 2022/12/8

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AB - In the search for alternatives to 6-aminonicotinamide (6AN), a series of 6-aminonicotinic acid esters were designed and synthesized as precursors of 6-amino-NADP+, a potent inhibitor of 6-phosphogluconate dehydrogenase (6PGD). Like 6AN, some of these esters were found to reverse the loss of histone 3 lysine 9 trimethylation (H3K9me3) in patient-derived pancreatic ductal adenocarcinoma (PDAC) distant metastasis (A38-5). Among them, 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 6-aminonicotinate (5i) showed more potent antiproliferative activity than 6AN. Metabolite analysis revealed that compound 5i produced a marked increase in metabolites upstream of 6PGD, indicating intracellular inhibition of 6PGD by 6-amino-NADP+derived from compound 5i through 6-aminonicotinic acid (6ANA) via the Preiss-Handler pathway. Despite the more potent pharmacological effects shown by compound 5i in A38-5, compound 5i was found to be substantially less toxic to primary hippocampal rat neurons compared to 6AN, indicating its therapeutic potential in targeting distant metastatic cells.

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Effects of 6-Aminonicotinic Acid Esters on the Reprogrammed Epigenetic State of Distant Metastatic Pancreatic Carcinoma

Abstract

Keywords

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