title: Identification of an anti-inflammatory derivative with anti-cancer potential: The impact of each of its structural components on inflammatory responses in macrophages and bladder cancer cells.
abstract: Inflammation plays a crucial role in many types of cancer and is known to be involved in their initiation and promotion. As such, it is presently recognized as an important risk factor for several types of cancers such as bladder, prostate and breast cancers. The discovery of novel anti-inflammatory compounds can have a huge implication not only for the treatment of cancer but also as preventive and protective treatment modalities. We have recently identified a new compound (1) that presents interesting anti-inflammatory activity. In order to better understand its biological action, we have divided the molecule in its basic components and verified their respective contribution towards the anti-inflammatory response of the whole molecule. We have discovered that only the combination of the maleimide function together with the tert-butyloxycarbonylhydrazinamide function lead to important anti-inflammatory properties. The main derivative 1 can decrease the activating effects of INFγ or IL6 on human (hMϕs) macrophages by 38% or by 64% at a concentration of 10 μM as indicated by a decrease of STAT1 or STAT3 activation. The expression of pro-inflammatory markers CD40 and MHCII in INFγ stimulated hMϕs were reduced by 87% and 49%, respectively with a 3 h pretreatment of 1 at 10 μM. The cell motility assay revealed that 1 at 10 μM can reduce relative cell motility induced by IL6 by 92% in comparison with the untreated control hMϕ monolayers. Compound 1 reduced by 91% the inflammatory response induced by the cytokines (INFγ + TNFα) in the macrophage-like J774A.1 cells at a concentration of 25 μM, as measured by the detection of NO production with the Griess reagent. Furthermore, upon removal of the tert-butyloxycarbonyl protective group the unprotected derivative as a hydrochloride salt (1A) retains interesting anti-inflammatory activity and was found to be less toxic than the parent compound (1).
authors.affiliation: Département de Biologie Médicale et, Canada. Electronic address: jovane.hamelin@outlook.com.
authors.forename: Jovane
authors.initials: J
authors.lastname: Hamelin-Morrissette
authors.affiliation: Département de Chimie, Biochimie et Physique, Université du Québec à Trois-Rivières, C.P. 500, Trois-Rivières, Québec G9A 5H7, Canada. Electronic address: Suzie.Cloutier@uqtr.ca.
authors.forename: Suzie
authors.initials: S
authors.lastname: Cloutier
authors.affiliation: Département de Biologie Médicale et, Canada. Electronic address: Julie.Girouard@uqtr.ca.
authors.forename: Julie
authors.initials: J
authors.lastname: Girouard
authors.affiliation: Instituto de Oncologia "Ángel H. Roffo" Área Investigación, Ciudad de Buenos Aires, C1417DTB, Argentina. Electronic address: d_belgo@hotmail.com.
authors.forename: Denise
authors.initials: D
authors.lastname: Belgorosky
authors.affiliation: Instituto de Oncologia "Ángel H. Roffo" Área Investigación, Ciudad de Buenos Aires, C1417DTB, Argentina. Electronic address: anamariaeijan@fibertel.com.ar.
authors.forename: Ana María
authors.initials: AM
authors.lastname: Eiján
authors.affiliation: Département des Sciences Fondamentales, Université du Québec à Chicoutimi, 555 boulevard de l'Université, Chicoutimi, Québec G7H 2B1, Canada. Electronic address: jean.legault@uqac.ca.
authors.forename: Jean
authors.initials: J
authors.lastname: Legault
authors.affiliation: Département de Biologie Médicale et, Canada. Electronic address: Carlos.Reyes-Moreno@uqtr.ca.
authors.forename: Carlos
authors.initials: C
authors.lastname: Reyes-Moreno
authors.affiliation: Département de Chimie, Biochimie et Physique, Université du Québec à Trois-Rivières, C.P. 500, Trois-Rivières, Québec G9A 5H7, Canada. Electronic address: Gervais.Berube@uqtr.ca.
authors.forename: Gervais
authors.initials: G
authors.lastname: Bérubé
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects*; D008301:Maleimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009569:Nitric Oxide / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D006834:Hydrazines; D008301:Maleimides; C043592:maleimide; C029424:hydrazine; D009569:Nitric Oxide
keywords: Bladder cancer; Inflammation; Interferon gamma; Interleukine 6; Nitric oxide; STAT pathway