Substituted tetrahydroisoquinolines: synthesis, characterization, antitumor activity and other biological properties

• Published in: European journal of medicinal chemistry Vol. 145; pp. 51 - 63
• Main Authors: Capilla, A. Sergi, Soucek, Richard, Grau, Laura, Romero, Manel, Rubio-Martínez, Jaime, Caignard, Daniel H., Pujol, Maria Dolors
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 10.02.2018; Elsevier
• Subjects: Allosteric sites; Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Dioxigenated compounds; Dose-Response Relationship, Drug; Drug design; Drug Screening Assays, Antitumor; Isoquinolines; KRas; Life Sciences & Biomedicine; Mice; Models, Molecular; Molecular dynamics; Molecular Structure; Osteoporosis - drug therapy; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Proto-Oncogene Proteins p21(ras) - metabolism; Science & Technology; Structure-Activity Relationship; Tetrahydroisoquinolines - chemical synthesis; Tetrahydroisoquinolines - chemistry; Tetrahydroisoquinolines - pharmacology; Allosteric sites; Isoquinolines; HMRS; Molecular dynamics; TLC; Dioxigenated compounds; PDA; TFA; DCM; BINAP; NMR; TFAA; Antitumor; IC50; KRas; Drug design; ESI; DMF; MOLECULAR-DYNAMICS; DESIGN; RAS; PARAMETERS; PATHWAY; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.12.098

This work deals with the molecular design, synthesis and biological activity of a series of tetrahydro[1,4]dioxanisoquinolines and dimethoxyisoquinoline analogues. This study describes the synthesis strategy of these potential antitumor compounds, their multi-step synthesis and their optimization. A series of tetrahydroisoquinolines was synthesized and their cytotoxicity evaluated. Some of these tetrahydroisoquinolines showed promising KRas inhibition, antiangiogenesis activity and antiosteoporosis properties. Molecular modeling studies showed that compound 12 bind in the p1 pocket of the KRas protein making interactions with the hydrophobic residues Leu56, Tyr64, Tyr71 and Thr74 and hydrogen bonds with residues Glu37 and Asp38. [Display omitted] •18 Dioxigenated tetradydroisoquinoline compounds were synthesized from the corresponding aldehyde.•Compounds 12, 13, 14, 15, 16, 18, 20 and 21 exhibited significant cytotoxic activity.•Isoquinoline 14 presents the best KRas activity profile on RKO KRasSL.•Molecular modeling studies showed that the tetrahydroisoquinoline 12 binds directly to the p1 pocket of the KRas protein.