New Analogs of Polyamine Toxins from Spiders and Wasps: Liquid Phase Fragment Synthesis and Evaluation of Antiproliferative Activity.

Christos Vassileiou,Stefania Kalantzi,Dionissios Papaioannou,Theodora Stivarou,Nikos Karamanos,Eleanna Vachlioti,Zoi Piperigkou,Christos Koutsakis,Constantinos M Athanassopoulos,Peggy Lymberi,Konstantinos Avgoustakis

doi:10.3390/molecules27020447

Abstract

Polyamine toxins (PATs) are conjugates of polyamines (PAs) with lipophilic carboxylic acids, which have been recently shown to present antiproliferative activity. Ten analogs of the spider PATs Agel 416, HO-416b, and JSTX-3 and the wasp PAT PhTX-433 were synthesized with changes in the lipophilic head group and/or the PA chain, and their antiproliferative activity was evaluated on MCF-7 and MDA-MB-231 breast cancer cells, using Agel 416 and HO-416b as reference compounds. All five analogs of PhTX-433 were of very low activity on both cell lines, whereas the two analogs of JSTX-3 were highly active only on the MCF-7 cell line with IC50 values of 2.63–2.81 μΜ. Of the remaining three Agel 416 or HO-416b analogs, only the one with the spermidine chain was highly active on both cells with IC50 values of 3.15–12.6 μM. The two most potent compounds in this series, Agel 416 and HO-416b, with IC50 values of 0.09–3.98 μΜ for both cell lines, were found to have a very weak cytotoxic effect on the MCF-12A normal breast cells. The present study points out that the structure of both the head group and the PA chain determine the strength of the antiproliferative activity of PATs and their selectivity towards different cells.

Highlights

IntroductionPolyamine toxins (PATs) are conjugates of polyamines (PAs) with lipophilic acids isolated from spider or wasp venoms (Figure 1)
A general approach for the liquid-phase fragment synthesis of orthogonally protected PAs and their application to the synthesis of the Polyamine toxins (PATs) Agel 416 and HO-416b has been reported [13]. This particular methodology, with minor modifications, was applied for the synthesis of the PAT analogs 1–10 described in the present work, which involved the assembly of the required PA skeleta orthogonally protected at their amino functions so that selective deprotection of the desired terminal amino functionality would allow the attachment of the appropriate lipophilic head group on that particular position of the PA chain
The antiproliferative activity of the -synthesized conjugates was evaluated in MCF-7 and the MDA-MB-231 breast cancer cell lines, using the PATs Agel 416 and HO-416b as reference compounds

Summary

Introduction

Polyamine toxins (PATs) are conjugates of polyamines (PAs) with lipophilic acids isolated from spider or wasp venoms (Figure 1). PATs are primarily investigated for their ability to block ionotropic glutamate receptors (iGluR) and constitute interesting drug targets for neurological and psychiatric disorders [1,2,3,4]. Recent studies showed that the PATs are endowed with interesting antiproliferative activity, which seems to depend on the structure of the lipophilic head group (PATs PA366 and PA389 from spider venom), with. PA366 being significantly more active than PA389 in MCF-7 breast cancer cells. Both PATs incorporate the spermine (Spm, a 3-4-3 PA) chain and either a 4-hydroxyphenyl (PA366 ) or

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