title: Design, synthesis and biological evaluation of 2H-benzo[b][1,4] oxazine derivatives as hypoxia targeted compounds for cancer therapeutics.
abstract: A small library of 2H-benzo[b][1,4] oxazine derivative was synthesized and their biological activity was tested on HepG2 cells under normoxic and hypoxic conditions. From preliminary screening, we found compound 10 and 11 specifically inhibit hypoxic cancer cell growth IC(50) 87+/-1.8microM and IC(50) 10+/-3.7microM while sparing 'normoxic' cells IC(50) >600M and >1mM (not applicable), respectively. We tested the effect of 10 on MTT, clonogenic and hypoxia induced genes. The MTT correlates with clonogenic assays and most importantly compound 10 down regulates hypoxia induces genes (HIF-1alpha, P21 and VEGF) appropriately. We are in the process to explore the molecular mechanism of action of oxazine derivative compounds on hypoxia tumor cells.
authors.affiliation: Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA. bdas@aecom.yu.edu
authors.forename: Bhaskar C
authors.initials: BC
authors.lastname: Das
authors.forename: Ankanahlli V
authors.initials: AV
authors.lastname: Madhukumar
authors.forename: Jaime
authors.initials: J
authors.lastname: Anguiano
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D049268:Positron-Emission Tomography / Q000379:methods; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D048588:Benzoxazines; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010078:Oxazines; D013778:Tetrazolium Salts; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; C022616:thiazolyl blue