Synthesis and in vitro cytotoxic activity of dye-linker-macrocycle conjugates with variable linker length and components

Mateusz D Tomczyk; Karolina Matczak; Magdalena Skonieczna; Pavel Chulkin; Marta Denel-Bobrowska; Daria Różycka; Sebastian Rykowski; Agnieszka B Olejniczak; Krzysztof Walczak

doi:10.1016/j.bioorg.2023.106782

Synthesis and in vitro cytotoxic activity of dye-linker-macrocycle conjugates with variable linker length and components

Bioorg Chem. 2023 Nov:140:106782. doi: 10.1016/j.bioorg.2023.106782. Epub 2023 Aug 21.

Authors

Mateusz D Tomczyk¹, Karolina Matczak², Magdalena Skonieczna³, Pavel Chulkin⁴, Marta Denel-Bobrowska⁵, Daria Różycka⁵, Sebastian Rykowski⁵, Agnieszka B Olejniczak⁵, Krzysztof Walczak⁶

Affiliations

¹ Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Krzywoustego 4, Gliwice 44-100, Poland. Electronic address: mateusz.d.tomczyk@polsl.pl.
² Department of Medical Biophysics, University of Łódź, Pomorska 141/143, Łódź 90-236, Poland.
³ Department of Systems Biology and Engineering, Silesian University of Technology, Akademicka 16, Gliwice 44-100, Poland.
⁴ Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, Strzody 9, Gliwice 44-100, Poland.
⁵ Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, Łódź 93-232, Poland.
⁶ Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Krzywoustego 4, Gliwice 44-100, Poland.

PMID: 37659149
DOI: 10.1016/j.bioorg.2023.106782

Abstract

The study investigated the structure-activity relationship of newly synthesized dye-linker-macrocycle (DLM) conjugates and the effect of each component on various biological properties, including cytotoxicity, cellular uptake, intracellular localization, interaction with DNA and photodynamic effects. The conjugates were synthesized by combining 1,8-naphthalimide and thioxanthone dyes with 1,4,7,10-tetraazacyclododecane (cyclen) and 1-aza-12-crown-4 (1A12C4) using alkyl linkers of different lengths. The results revealed significant differences in biological activity among the various series of conjugates. Particularly, 1A12C4 conjugates exhibited notably higher cytotoxicity compared to cyclen conjugates. Conjugation with 1A12C4 proved to be an effective strategy for increasing cellular uptake and cytotoxicity of small-molecule conjugates. In addition, the results highlighted the critical role of linker length in modulating the biological activity of DLM conjugates. It became clear that the choice of each component (dye, macrocycle and linker) could significantly alter the biological activity of the conjugates.

Keywords: 1,8-Naphthalimide; Crown ethers; Cyclic polyamines; Cytotoxic activity; Thioxanthone.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / pharmacology
Biological Transport
Coloring Agents
Cyclams*

Substances

cyclen
Cyclams
Antineoplastic Agents
Coloring Agents