Presenter: Md. Imdadul H. Khanhttps://egrove.olemiss.edu/pharm_annual_posters_2021/1014/thumbnail.jp

Akins, Nicholas S.

Claudio, Pier Paolo

Hossein, Md. Imran

Khan, Md. Imdadul H.

Kim, Seong Jong

Le, Hoang V.

Mahdi, Fakhri

Paris, Jason J.

Penfornis, Patrice

Slusher, Barbara S.

English

eGrove (Univ. of Mississippi)

University of Mississippi eGrove Annual Poster Session 2021 Annual Poster Session 10-19-2021 Development of L-γ-Methyleneglutamine-based compounds for cancer Md. Imran Hossein University of Mississippi Fakhri Mahdi University of Mississippi Md. Imdadul H. Khan University of Mississippi Nicholas S. Akins University of Mississippi Patrice Penfornis University of Mississippi See next page for additional authors Follow this and additional works at: https://egrove.olemiss.edu/pharm_annual_posters_2021 Recommended Citation Hossein, Md. Imran; Mahdi, Fakhri; Khan, Md. Imdadul H.; Akins, Nicholas S.; Penfornis, Patrice; Kim, Seong Jong; Slusher, Barbara S.; Paris, Jason J.; Le, Hoang V.; and Claudio, Pier Paolo, "Development of L-γ-Methyleneglutamine-based compounds for cancer" (2021). Annual Poster Session 2021. 15. https://egrove.olemiss.edu/pharm_annual_posters_2021/15 This Book is brought to you for free and open access by the Annual Poster Session at eGrove. It has been accepted for inclusion in Annual Poster Session 2021 by an authorized administrator of eGrove. For more information, please contact egrove@olemiss.edu. Authors Md. Imran Hossein, Fakhri Mahdi, Md. Imdadul H. Khan, Nicholas S. Akins, Patrice Penfornis, Seong Jong Kim, Barbara S. Slusher, Jason J. Paris, Hoang V. Le, and Pier Paolo Claudio This book is available at eGrove: https://egrove.olemiss.edu/pharm_annual_posters_2021/15 Development of L-γ-Methyleneglutamine-based Compounds for CancerMd Imran Hossain, Fakhri Mahdi,1 Md Imdadul H. Khan,1, Nicholas S. Akins,1, Seong Jong Kim,2 Jason J. Paris,1,* Hoang V. Le1,*,1Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA2Natural Products Utilization Research Unit, United States Department of Agriculture, Agricultural Research Service, University, Mississippi 38677, U.S.ACancer metabolismL-γ-methyleneglutamateGlutamine analoguesL-γ-methyleneglutamate analoguesResultsGeneral Synthetic schemeResultsConclusion & Future Plan▪ Compound 5 and 6, compare to other analougues showed most potent indifferent cancer cell lines whereas, every analogues is non toxic to MCF-10.▪ We will do further study in zebra fish animal model to investigate bindingtarget.• We will also assay these two compounds in different mitochondrial targets.References: Hensley et al, J. Clin. Invest. 2013, 123(9),3678-3684; Shapiro et al, J. Biol. Chem. 1979,254(8),2835-2838; Wailes et al, Nature, 1954,174(4420),130-131; Done et al, BioChem. J. 1952,51(4),451-458; Hossain et al, RSC Adv.,2021,11,7115.DiscussionCurrent workDiscussion051015202530 min 1h 2hconcentration (uM)TimeBrain concentration versus time profile051015202530 min 1h 2hconcentration (uM)TimeSpinal Cord concentration versus time profile051015202530 min 1h 2hconcentration (uM)TimeLiver concentration versus time profile02468101214161830 min 1h 2hconcentration (uM)TimePlasma concentration versus time profile▪ Amides with primary amine or aromatic amine are more potent in inhibiting the cancer cells growth  than with secondary amine or branched alkyl amine.▪ Within each subset, the amines with a stronger electron withdrawing group exhibit better potency. ▪ N-benzyl amides with an electron withdrawing group at the para position were the only compounds to inhibit the growth of triple-negative MDA-MB-231 cells commensurate to olaparib.▪ We will assay the anticancer activity of protected L-γ-Methyleneglutamineanalogues against MCF-7, SK-BR-3, MDA-MB-231 cell lines. ▪ For most potent compound 5, we will do the PK/PD study.▪ We will also investigate the anticancer activity of both metabolite and protected metabolites of L-γ-Methyleneglutamine analogues.▪ For selected compounds from 1-10, we will study anticancer activity against brain, and head and neck cancer.Protected L-γ-methyleneglutamate analogues & metabolitesInhibition of cell growth Necrosis StudyPK study of compound 5Inhibition of cell growthStudy on brain cancer Study on head and neck cancer▪ Compare to compound 5 and 6, protected L-γ-methyleneglutamateanalogues, compound 11-30 did not show promising activity in MCF-7, SK-BR-3, MDA-MB-231 cell lines.▪ Both metabolites and protected metabolites, compound 31-35 also did notshow promising activity. However, compound 33 showed better activity inMDA-MB-231 than others.▪ PK study showed the good distribution of compound 5 in brain after 30minutes.▪ Study of compound 1,4-9 in brain, and head and neck cancer cell linesshowed the concentration dependent inhibition of cell growth of thesecancer cells.▪ There are a number of naturally occurring glutamine analogues, such as azaserine, acivicin, and 6-diazo-5-oxo-L-norleucine (DON).▪ These inhibit different glutamine- dependent enzymes including glutaminase, NAD synthase, CTP synthetase, FGAR aminotransferase.▪ Therefore, they demonstrated variable degrees of gastrointestinal toxicity, myelosuppression, and neurotoxicity, due to their non-selectivity.▪ L-γ-Methyleneglutamine (1) were first isolated from groundnut seedling (Arachis hypogaea) in 1952.▪ It plays a major role in nitrogen transport in Arachis and Amorpha plants.▪ The syntheses of racemic mixture of 1 were reported in 1955. However, no efficient synthetic route was reported before our work. ▪ In cancer cells, glutaminolysis is the primary source of biosynthetic precursors, fueling the TCA cycle with glutamine-derived α-ketoglutarate.▪ α-ketoglutarate provides carbons for the citric acid cycle to produce glutathione, fatty acids, and nucleotides. ▪ It also contributes nitrogen to produce hexosamines, nucleotides, and many nonessential amino acids.▪ Efforts to inhibit glutamine metabolism in cancer using amino acid analogs have been extensive.

Development of L-γ-Methyleneglutamine-based compounds for cancer

https://egrove.olemiss.edu/cgi/viewcontent.cgi?article=1014&context=pharm_annual_posters_2021

Development of L-γ-Methyleneglutamine-based compounds for cancer

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