N-tert-Prenylation of indole ring improves the cytotoxicity of a short antagonist G analogue against Small Cell Lung Cancer

Shaun Offerman, Manikandan Kadirvel, Osama Abusara, Jennifer Bryant, Brian Telfer, Gavin Brown, Sally Freeman, Anne White, Kaye Williams, Harmesh Aojula

Research output: Contribution to journalArticlepeer-review

Abstract

Natural prenylated indoles have been proposed as potential anticancer agents. To exploit this discovery for developing new peptide therapeutics we report the first studies whereby incorporation of prenylated indoles into primary sequences has been achieved. We developed a route to synthesise Nα-Fmoc protected tryptophan derivatives in which the prenyl groups is linked to the N-indole core, using Pd(II)-mediated C-H functionalisation of 2-methyl-2-butene. Based on the Substance P antagonist G (SPG), a well-known Small Cell Lung Cancer (SCLC) anticancer agent, we designed a new penta-peptide sequence to include a prenyl moiety on one of the tryptophan residues. The N-tert-Prenylated tryptophan analogue was assembled into the pentameric peptide using standard solid phase peptide synthesis or liquid phase synthesis using fragment coupling. In vitro screening showed that the N-tert-prenylation of the indole ring on the tryptophan residue located near the C-terminal of the penta-peptide enhanced the cytotoxicity against H69 (IC50 = 2.84 ± 0.14 μM) and DMS79 (IC50 = 4.37 ± 0.44 μM) SCLC cell lines when compared with the unmodified penta-peptide (H69, IC50 = 30.74 ± 0.30 μM and DMS79, IC50 = 23.00 ± 2.07 μM) or the parent SPG sequence (IC50 > 30 μM, both cell lines). SCLC almost invariably relapses with therapy-resistant disease. The DMS79 cell line was established from a patient following treatment with a number of chemotherapeutics (cytoxan, vincristine and methotrexate) and radiation therapy. Treating the DMS79 tumour bearing nude mice provided a human xenograft model of drug-resistance to test the efficacy of prenylated peptide. A low dose (1.5 mg/kg) of prenylated peptide was found to reduce tumour growth by ~30% (P < 0.05) at day 7, relative to the control group receiving vehicle only. We conclude that the availability of Fmoc-Trp(N-tert-prenyl)-OH amino acid facilitates the synthesis of prenylated-tryptophan containing peptides to explore their therapeutic potential.
Original languageEnglish
JournalMedChemComm
Early online date17 Feb 2017
DOIs
Publication statusPublished - 2017

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