Neuropeptide Antagonists for Cancer Treatment

UoM administered thesis: Phd

  • Authors:
  • Osama Abusara

Abstract

Small Cell Lung Cancer (SCLC) is an aggressive form of cancer accounting for 25% of lung cancer deaths worldwide. Treatment relies on combination chemotherapy (etoposide and cisplatin or carboplatin) with or without radiation therapy. However, disease relapse and resistance occurs quickly, prompting unmet need for alternative treatment options. One such option is the use of broad-spectrum antagonists, known as Substance P (SP) analogues. Historically, these analogues have not succeeded clinically due to low potency and bioavailability. In this project, novel SP analogues were developed to address these shortfalls. A chemical strategy was designed to synthesise novel short peptides including DMePhe-DTrp-Phe-DTrp-Leu-NH2 (25) as the new lead. Fmoc and Boc D-Trp derivatives with indole nitrogen having substituents (methyl, ethyl, propyl, butyl, pentyl, propargyl, benzyl and tert-prenyl) were made and characterised by 1H and 13C NMR spectroscopy and mass spectrometry (MS). These building blocks were incorporated into the first series of peptides, substituting the D-Trp residue located near the C-terminal of 25, via solid and/or liquid phase procedures. Final products were purified by RP-HPLC to >90% purity and structures verified by MS and/or 1H NMR. Cell viability assays were conducted to evaluate cytotoxicity against two SCLC cell lines: H69 (chemo-naive) and DMS79 (from a patient after treatment). The IC50 values for the D-Trp residue modified peptides were

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Original languageEnglish
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Award date1 Aug 2018