Structure-Activity Relationship of the Thiacalix[4]arenes Family with Sulfobetaine Fragments: Self-Assembly and Cytotoxic Effect against Cancer Cell Lines.

Luidmila Yakimova,Aisylu Kunafina,Aigul Nugmanova,Alexandra Voloshina,Konstantin Petrov,Ivan Stoikov,Pavel Padnya

doi:10.3390/molecules27041364

Abstract

Regulating the structure of macrocyclic host molecules and supramolecular assemblies is crucial because the structure–activity relationship often plays a role in governing the properties of these systems. Herein, we propose and develop an approach to the synthesis of the family of sulfobetaine functionalized thiacalix[4]arenes with regulation of the self-assembly and cytotoxic effect against cancer cell lines. The dynamic light scattering method showed that the synthesized macrocycles in cone, partial cone and 1,3-alternate conformations form submicron-sized particles with Ag+ in water, but the particle size and polydispersity of the systems studied depend on the macrocycle conformation. Based on the results obtained by 1H and 1H-1H NOESY NMR spectroscopy and transmission electron microscopy for the macrocycles and their aggregates with Ag+, a coordination scheme for the Ag+ and different conformations of p-tert-butylthiacalix[4]arene functionalized with sulfobetaine fragments was proposed. The type of coordination determines the different shapes of the associates. Cytotoxic properties are shown to be controlled by the shape of associates, with the highest activity demonstrated by thiacalix[4]arenes in partial cone conformation. This complex partial cone/Ag+ is two times higher than the reference drug imatinib mesylate. High selectivity against cervical carcinoma cell line indicates the prospect of their using as components of new anticancer system.

Highlights

Multiple drug resistance (MDR) is a growing public health concern worldwide [1,2,3,4,5].The main challenge faced by many researchers is the resistance to cancer and various bacterial and viral infections
The arrangement of substituents at phenolic oxygen in space is different for all stereoisomers, which makes it possible to organize an orientation of the binding sites that is individual for each conformer, and this will undoubtedly lead to selectivity of interaction with the substrate
In order to evaluate the effect of the conformation of the macrocyclic platform on self-assembly with Ag (I) cations, we synthesized three conformers of thiacalix[4]arene containing four sulfobetaine fragments (3–5) (Scheme 1)

Summary

Introduction

Multiple drug resistance (MDR) is a growing public health concern worldwide [1,2,3,4,5]. The main challenge faced by many researchers is the resistance to cancer and various bacterial and viral infections. It leads to the ineffectiveness of therapy. It is well established that inappropriate use of antimicrobial, antiviral, anticancer agents or use of ineffective dosage forms [6], as well as premature termination of treatment can lead to the development of drug resistances [7]. Cancer cells are drug resistant too [8,9]. Existing research recognizes that any drug effects both on cancer and on healthy cells [11]

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Conclusion