Analogs of penfluridol as chemotherapeutic agents with reduced central nervous system activity. Issue 23 (15th December 2018)

• Record Type: Journal Article
• Authors: Ashraf-Uz-Zaman, Md; Sajib, Md Sanaullah; Cucullo, Luca; Mikelis, Constantinos M.; German, Nadezhda A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 23/24(2018)
• Page Start: 3652
• Page End: 3657
• Publication Date: 2018-12-15
• Subjects: ALP alkaline phosphatase creatine kinase -- ALT alanine aminotransferase -- AST aspartate aminotransferase -- BBB blood brain barrier -- BOC tert-butoxycarbonyl -- BUN blood urea nitrogen test -- CK creatine kinase -- CNS central nervous system -- D1-5 dopamine receptor subtypes -- DAT dopamine transporter -- DCM dichloromethane -- DOR delta opioid receptor -- DPPH 1, 1′-bis(diphenylphosphino)ferrocene -- ESI electrospray ionization -- EtOH ethanol -- FDA Food and Drug Administration -- GI gastrointestinal -- GLDH glutamine dehydrogenase -- H1-2 histamine receptor subtypes -- 5HT serotonin receptors -- IC50 half-maximum inhibitory concentration -- i.p intraperitoneal injection -- Ki inhibition constant -- KOR kappa opioid receptor -- LC liquid chromatography -- LC-MS liquid chromatography-mass spectrometry -- LLC luc mouse-derived luciferin expressing Lewis lung carcinoma cell line -- MDA MB231 human triple-negative breast cancer cell line -- MOR mu opioid receptor -- MTT 3-[4, 5-dimethylthiazol-2-yl]-2, 5-dimethyltetrazolium bromide -- NET norepinephrine transporter -- NMR nuclear magnetic resonance -- r.t room temperature -- SERT serotonin transporter -- THF tetrahydrofuran -- TLC thin-layer chromatography; Penfluridol -- Anticancer agent -- Central nervous system -- Repurposing -- Toxicity -- Optimization; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.10.036
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Anticancer doses of penfluridol inhibit a majority of G-protein coupled receptors. Analysis of antipsychotic pharmacophore allowed to design less toxic analogs. Confirmed in vitro cytotoxicity of analogs, in vivo permeability of the BBB. Clinical chemistry analysis confirmed optimized toxicity profile. Abstract: Several recent reports have highlighted the feasibility of the use of penfluridol, a well-known antipsychotic agent, as a chemotherapeutic agent. In vivo experiments have confirmed the cytotoxic activity of penfluridol in triple-negative breast cancer model, lung cancer model, and further studies have been proposed to assess its anticancer activity and viability for the treatment of glioblastomas. However, penfluridol anticancer activity was observed at a dosage significantly higher than that administered in antipsychotic therapy, thus raising the concern for the potential onset of CNS side effects in patients undergoing intensive pharmacological treatment. In this study, we evaluate the potential CNS toxicity of penfluridol side by side with a set of analogs.