c7897f6395783b2ff781bcab35eebca1 molecules_a2021v26n19p5770.pdf c08870c52bfc7b954eec1f79bcd6e4d7e05ac2bc molecules_a2021v26n19p5770.pdf 695ecc01d77580a4b4754597c55cb0da1c38d360cea6e2e446dfcbc546f4c4fc molecules_a2021v26n19p5770.pdf Title: Design, Synthesis, Biological Evaluation and In Silico Study of Benzyloxybenzaldehyde Derivatives as Selective ALDH1A3 Inhibitors Subject: Aldehyde dehydrogenase 1A3 (ALDH1A3) has recently gained attention from researchers in the cancer field. Several studies have reported ALDH1A3 overexpression in different cancer types, which has been found to correlate with poor treatment recovery. Therefore, finding selective inhibitors against ALDH1A3 could result in new treatment options for cancer treatment. In this study, ALDH1A3-selective candidates were designed based on the physiological substrate resemblance, synthesized and investigated for ALDH1A1, ALDH1A3 and ALDH3A1 selectivity and cytotoxicity using ALDH-positive A549 and ALDH-negative H1299 cells. Two compounds (ABMM-15 and ABMM-16), with a benzyloxybenzaldehyde scaffold, were found to be the most potent and selective inhibitors for ALDH1A3, with IC50 values of 0.23 and 1.29 M, respectively. The results also show no significant cytotoxicity for ABMM-15 and ABMM-16 on either cell line. However, a few other candidates (ABMM-6, ABMM-24, ABMM-32) showed considerable cytotoxicity on H1299 cells, when compared to A549 cells, with IC50 values of 14.0, 13.7 and 13.0 M, respectively. The computational study supported the experimental results and suggested a good binding for ABMM-15 and ABMM-16 to the ALDH1A3 isoform. From the obtained results, it can be concluded that benzyloxybenzaldehyde might be considered a promising scaffold for further drug discovery aimed at exploiting ALDH1A3 for therapeutic intervention. Keywords: aldehyde dehydrogenase; ALDH1A1; ALDH1A3; ALDH3A1; A549 cells; H1299 cells; non-small cell lung cancer; cytotoxicity; in silico Author: Ali I. M. Ibrahim, Balqis Ikhmais, Elisabet Batlle, Waed K. AbuHarb, Vibhu Jha, Khaled T. Jaradat, Rafael Jiménez, Raquel Pequerul, Xavier Parés, Jaume Farrés and Klaus Pors Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Sep 28 03:08:48 2021 CEST ModDate: Tue Sep 28 03:13:45 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 23 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 5681002 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- GEVXJZ+VnURWPalladioL Type 1 Custom yes yes no 10 0 ZAQYSV+EURM10 Type 1 Builtin yes yes no 15 0 BHBOIN+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 SCOOYC+URWPalladioL-Bold Type 1 Custom yes yes no 24 0 JOSTEY+URWPalladioL-Roma Type 1 Custom yes yes no 28 0 BTFGED+VnURWPalladioL-Bold Type 1 Custom yes yes no 32 0 PUSVWS+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 40 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 62 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 66 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 70 0 QMDDXF+CMSY10 Type 1 Builtin yes yes no 94 0 XIRVNA+EURB10 Type 1 Builtin yes yes no 105 0 FERHKG+CMR10 Type 1 Builtin yes yes no 185 0 UZKIAN+CMEX10 Type 1 Builtin yes yes no 189 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2022-02-10 02:29:56 CET RepresentationInformation: molecules_a2021v26n19p5770.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2022-02-04 12:46:57 CET Size: 5681002 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 409 FreeObjects: 5 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: Results and Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Children: Item: Title: Chemistry Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Inhibition Screening Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Determination of Half-Maximal Inhibitory Concentrations (IC50) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Cytotoxicity Experiments Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: In Silico Study Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Children: Item: Title: Chemistry Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Children: Item: Title: General Procedure for the Synthesis of Compounds ABMM-1 6, 17, 18, 27, 28, 32 34 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: General Procedure for the Synthesis of Compounds ABMM-15, 16, 24, 26 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: General Procedure for the Synthesis of Compounds ABMM-19, 23, 25, 35 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Purification of Recombinant Human ALDHs and Enzymatic Assays Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Inhibition Screening Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Determination of Half-Maximal Inhibitory Concentrations (IC50) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Biology Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Children: Item: Title: Cell Culture Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: Cytotoxicity Experiment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: In Silico Study Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Children: Item: Title: Protein and Ligand Preparation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: Molecular Docking Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: Visualization of the Docked Poses Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Info: Title: Design, Synthesis, Biological Evaluation and In Silico Study of Benzyloxybenzaldehyde Derivatives as Selective ALDH1A3 Inhibitors Author: Ali I. M. Ibrahim, Balqis Ikhmais, Elisabet Batlle, Waed K. AbuHarb, Vibhu Jha, Khaled T. Jaradat, Rafael Jiménez, Raquel Pequerul, Xavier Parés, Jaume Farrés and Klaus Pors Subject: Aldehyde dehydrogenase 1A3 (ALDH1A3) has recently gained attention from researchers in the cancer field. Several studies have reported ALDH1A3 overexpression in different cancer types, which has been found to correlate with poor treatment recovery. Therefore, finding selective inhibitors against ALDH1A3 could result in new treatment options for cancer treatment. In this study, ALDH1A3-selective candidates were designed based on the physiological substrate resemblance, synthesized and investigated for ALDH1A1, ALDH1A3 and ALDH3A1 selectivity and cytotoxicity using ALDH-positive A549 and ALDH-negative H1299 cells. Two compounds (ABMM-15 and ABMM-16), with a benzyloxybenzaldehyde scaffold, were found to be the most potent and selective inhibitors for ALDH1A3, with IC50 values of 0.23 and 1.29 M, respectively. The results also show no significant cytotoxicity for ABMM-15 and ABMM-16 on either cell line. However, a few other candidates (ABMM-6, ABMM-24, ABMM-32) showed considerable cytotoxicity on H1299 cells, when compared to A549 cells, with IC50 values of 14.0, 13.7 and 13.0 M, respectively. The computational study supported the experimental results and suggested a good binding for ABMM-15 and ABMM-16 to the ALDH1A3 isoform. From the obtained results, it can be concluded that benzyloxybenzaldehyde might be considered a promising scaffold for further drug discovery aimed at exploiting ALDH1A3 for therapeutic intervention. 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