Ugi Adducts as Novel Anti-austerity Agents against PANC-1 Human Pancreatic Cancer Cell Line: A Rapid Synthetic Approach

Pancreatic cancer cells have an inherent tolerance to withstand nutrition starvation, allowing them to survive in hypovascular tumor microenvironments that lack of sufficient nutrients and oxygen. Developing anti-cancer agents that target this tolerance to nutritional starvation is a promising anti-...

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Published in:	Biological & pharmaceutical bulletin Vol. 46; no. 10; pp. 1412 - 1420
Main Authors:	Tomohara, Keisuke, Maneenet, Juthamart, Ohashi, Nao, Nose, Takeru, Fujii, Rintaro, Kim, Min Jo, Sun, Sijia, Awale, Suresh
Format:	Journal Article
Language:	English
Published:	Japan The Pharmaceutical Society of Japan 01-10-2023 Japan Science and Technology Agency
Subjects:	1-Phosphatidylinositol 3-kinase Absolute configuration Adducts AKT protein anti-austerity agent Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Antineoplastic Agents, Phytogenic - pharmacology Antitumor agents Cell death Cell Line, Tumor Cytology Cytotoxicity Drug development Drug Screening Assays, Antitumor Humans Kinases natural product hybrid Natural products Pancreatic cancer Pancreatic Neoplasms Pancreatic Neoplasms - drug therapy Phosphatidylinositol 3-Kinases preferential cytotoxicity Rapamycin Signal transduction TOR protein Tumor Microenvironment Ugi reaction preferential cytotoxicity pancreatic cancer natural product hybrid Ugi reaction anti-austerity agent
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Abstract	Pancreatic cancer cells have an inherent tolerance to withstand nutrition starvation, allowing them to survive in hypovascular tumor microenvironments that lack of sufficient nutrients and oxygen. Developing anti-cancer agents that target this tolerance to nutritional starvation is a promising anti-austerity strategy for eradicating pancreatic cancer cells in their microenvironment. In this study, we employed a chemical biology approach using the Ugi reaction to rapidly synthesize new anti-austerity agents and evaluate their structure–activity relationships. Out of seventeen Ugi adducts tested, Ugi adduct 11 exhibited the strongest anti-austerity activity, showing preferential cytotoxicity against PANC-1 pancreatic cancer cells with a PC50 value of 0.5 µM. Further biological investigation of Ugi adduct 11 revealed a dramatic alteration of cellular morphology, leading to PANC-1 cell death within 24 h under nutrient-deprived conditions. Furthermore, the R absolute configuration of 11 was found to significantly contribute to the preferential anti-austerity ability toward PANC-1, with a PC50 value of 0.2 µM. Mechanistically, Ugi adduct (R)-11 was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway preferentially under nutrition starvation conditions. Consequently, Ugi-adduct (R)-11 could be a promising candidate for drug development targeting pancreatic cancer based on the anti-austerity strategy. Our study also demonstrated that the Ugi reaction-based chemical engineering of natural product extracts can be used as a rapid method for discovering novel anti-austerity agents for combating pancreatic cancer.
AbstractList	Pancreatic cancer cells have an inherent tolerance to withstand nutrition starvation, allowing them to survive in hypovascular tumor microenvironments that lack of sufficient nutrients and oxygen. Developing anti-cancer agents that target this tolerance to nutritional starvation is a promising anti-austerity strategy for eradicating pancreatic cancer cells in their microenvironment. In this study, we employed a chemical biology approach using the Ugi reaction to rapidly synthesize new anti-austerity agents and evaluate their structure-activity relationships. Out of seventeen Ugi adducts tested, Ugi adduct 11 exhibited the strongest anti-austerity activity, showing preferential cytotoxicity against PANC-1 pancreatic cancer cells with a PC value of 0.5 µM. Further biological investigation of Ugi adduct 11 revealed a dramatic alteration of cellular morphology, leading to PANC-1 cell death within 24 h under nutrient-deprived conditions. Furthermore, the R absolute configuration of 11 was found to significantly contribute to the preferential anti-austerity ability toward PANC-1, with a PC value of 0.2 µM. Mechanistically, Ugi adduct (R)-11 was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway preferentially under nutrition starvation conditions. Consequently, Ugi-adduct (R)-11 could be a promising candidate for drug development targeting pancreatic cancer based on the anti-austerity strategy. Our study also demonstrated that the Ugi reaction-based chemical engineering of natural product extracts can be used as a rapid method for discovering novel anti-austerity agents for combating pancreatic cancer. Pancreatic cancer cells have an inherent tolerance to withstand nutrition starvation, allowing them to survive in hypovascular tumor microenvironments that lack of sufficient nutrients and oxygen. Developing anti-cancer agents that target this tolerance to nutritional starvation is a promising anti-austerity strategy for eradicating pancreatic cancer cells in their microenvironment. In this study, we employed a chemical biology approach using the Ugi reaction to rapidly synthesize new anti-austerity agents and evaluate their structure-activity relationships. Out of seventeen Ugi adducts tested, Ugi adduct 11 exhibited the strongest anti-austerity activity, showing preferential cytotoxicity against PANC-1 pancreatic cancer cells with a PC50 value of 0.5 µM. Further biological investigation of Ugi adduct 11 revealed a dramatic alteration of cellular morphology, leading to PANC-1 cell death within 24 h under nutrient-deprived conditions. Furthermore, the R absolute configuration of 11 was found to significantly contribute to the preferential anti-austerity ability toward PANC-1, with a PC50 value of 0.2 µM. Mechanistically, Ugi adduct (R)-11 was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway preferentially under nutrition starvation conditions. Consequently, Ugi-adduct (R)-11 could be a promising candidate for drug development targeting pancreatic cancer based on the anti-austerity strategy. Our study also demonstrated that the Ugi reaction-based chemical engineering of natural product extracts can be used as a rapid method for discovering novel anti-austerity agents for combating pancreatic cancer.
ArticleNumber	b23-00224
Author	Maneenet, Juthamart Ohashi, Nao Nose, Takeru Tomohara, Keisuke Fujii, Rintaro Kim, Min Jo Sun, Sijia Awale, Suresh
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Cites_doi	10.1016/j.phytochem.2020.112646 10.1002/anie.196200081 10.1038/s41598-022-19579-6 10.1038/s41429-020-0340-3 10.3390/plants10020229 10.1016/j.bmc.2022.116963 10.1080/10409238.2021.1934811 10.1248/cpb.c17-00684 10.1016/j.phyplu.2021.100101 10.1248/cpb.c12-00834 10.1021/acs.jnatprod.0c00330 10.1002/cmdc.201900549 10.1371/journal.pone.0192464 10.1007/s11033-021-06607-3 10.1016/j.fitote.2021.104901 10.3390/ijms231710132 10.1016/j.bmc.2020.115950 10.1002/cbdv.202000495 10.1016/j.ejmech.2019.03.013 10.1016/j.bmcl.2020.126964 10.1186/s13045-020-01030-w 10.1021/acs.jnatprod.1c00150 10.1016/j.tet.2022.132931 10.1016/j.tetlet.2022.153881 10.1021/acs.jnatprod.9b01109 10.1016/j.bmcl.2020.127352 10.3390/plants11192466 10.1016/j.bmc.2021.116563 10.1038/s43018-022-00393-y 10.1002/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO;2-U 10.1158/0008-5472.CAN-05-3143 10.1016/j.bmcl.2021.127967 10.3390/md20110661
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SubjectTerms	1-Phosphatidylinositol 3-kinase Absolute configuration Adducts AKT protein anti-austerity agent Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Antineoplastic Agents, Phytogenic - pharmacology Antitumor agents Cell death Cell Line, Tumor Cytology Cytotoxicity Drug development Drug Screening Assays, Antitumor Humans Kinases natural product hybrid Natural products Pancreatic cancer Pancreatic Neoplasms Pancreatic Neoplasms - drug therapy Phosphatidylinositol 3-Kinases preferential cytotoxicity Rapamycin Signal transduction TOR protein Tumor Microenvironment Ugi reaction
Title	Ugi Adducts as Novel Anti-austerity Agents against PANC-1 Human Pancreatic Cancer Cell Line: A Rapid Synthetic Approach
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ispartofPNX	Biological and Pharmaceutical Bulletin, 2023/10/01, Vol.46(10), pp.1412-1420
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