03769a21ed7517c3bbb7db17904208e2 pmc_33801507.pdf 89ebb33fe51586ad79dae3f4cffe09dc87fa3a64 pmc_33801507.pdf 0f8e18f8dbf46d9d1a929e0ec5aae5df29821c19e3c9ca0adf632a84df9101c4 pmc_33801507.pdf Title: Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma Subject: Gastric cancer is one of the deadliest cancers in modern societies, so there is a high level of interest in discovering new drugs for this malignancy. Previously, we demonstrated the ability of tryptophanol-derived polycyclic compounds to activate the tumor suppressor protein p53, a relevant therapeutic target in cancer. In this work, we developed a novel series of enantiomerically pure tryptophanol-derived small molecules to target human gastric adenocarcinoma (AGS) cells. From an initial screening of fourteen compounds in AGS cell line, a hit compound was selected for optimization, leading to two derivatives selective for AGS gastric cells over other types of cancer cells (MDA-MB-231, A-549, DU-145, and MG-63). More importantly, the compounds were non-toxic in normal cells (HEK 293T). Additionally, we show that the growth inhibition of AGS cells induced by these compounds is mediated by apoptosis. Stability studies in human plasma and human liver microsomes indicate that the compounds are stable, and that the major metabolic transformations of these molecules are mono- and di-hydroxylation of the indole ring. Keywords: anticancer agents; cytotoxicity; enantioselective synthesis; gastric adenocarcinoma; tryptophanol Author: Margarida Espadinha, Valentina Barcherini, Lídia M. Gonçalves, Elies Molins, Alexandra M. M. Antunes and Maria M. M. Santos Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Fri Mar 19 11:19:01 2021 CET ModDate: Fri Mar 19 11:24:02 2021 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 20 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3472760 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ZDQHGB+VnURWPalladioL Type 1 Custom yes yes no 10 0 BIJHIA+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 KRVNIR+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 KVXEVJ+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 WLENKM+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 VWRBXB+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 36 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 58 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 62 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 66 0 HHBSSZ+CMSY10 Type 1 Builtin yes yes no 87 0 DOFHAZ+EURM10 Type 1 Builtin yes yes no 100 0 XIRVNA+EURB10 Type 1 Builtin yes yes no 113 0 IOLAWT+PazoMath-Italic Type 1 Builtin yes yes no 144 0 JHYTSG+CMR10 Type 1 Builtin yes yes no 176 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2021-09-11 03:34:25 CEST RepresentationInformation: pmc_33801507.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2021-04-12 03:39:47 CEST Size: 3472760 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 343 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Results and Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Children: Item: Title: Chemistry Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Effect of Tryptophanol-Derived Oxazolopyrrolidone Lactams on Cell Viability and on Apoptosis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Stability Studies in PBS, Human Plasma, and Human Liver Microsomes and Identification of Metabolites Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Children: Item: Title: Chemistry Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Biological Assays Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Children: Item: Title: Cytotoxicity Assays Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Caspase 3/7 Activity Assay Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: In Vitro Stability Assays Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Children: Item: Title: Buffer and Human Plasma Stabilities for Compound 7s Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Metabolic Stability for Compound 7s Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Half-Life t1/2 Determination Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: Metabolite Identification Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Info: Title: Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma Author: Margarida Espadinha, Valentina Barcherini, Lídia M. Gonçalves, Elies Molins, Alexandra M. M. Antunes and Maria M. M. Santos Subject: Gastric cancer is one of the deadliest cancers in modern societies, so there is a high level of interest in discovering new drugs for this malignancy. Previously, we demonstrated the ability of tryptophanol-derived polycyclic compounds to activate the tumor suppressor protein p53, a relevant therapeutic target in cancer. In this work, we developed a novel series of enantiomerically pure tryptophanol-derived small molecules to target human gastric adenocarcinoma (AGS) cells. From an initial screening of fourteen compounds in AGS cell line, a hit compound was selected for optimization, leading to two derivatives selective for AGS gastric cells over other types of cancer cells (MDA-MB-231, A-549, DU-145, and MG-63). More importantly, the compounds were non-toxic in normal cells (HEK 293T). Additionally, we show that the growth inhibition of AGS cells induced by these compounds is mediated by apoptosis. Stability studies in human plasma and human liver microsomes indicate that the compounds are stable, and that the major metabolic transformations of these molecules are mono- and di-hydroxylation of the indole ring. 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