Photochemical Reactivity of Naphthol-Naphthalimide Conjugates and Their Biological Activity.

Matija Sambol,Antonija Erben,Ivo Piantanida,Nikola Basarić,Branka Mihaljević,Patricia Benčić,Marijeta Kralj,Marija Matković

doi:10.3390/molecules26113355

Abstract

Quinone methide precursors 1a–e, with different alkyl linkers between the naphthol and the naphthalimide chromophore, were synthesized. Their photophysical properties and photochemical reactivity were investigated and connected with biological activity. Upon excitation of the naphthol, Förster resonance energy transfer (FRET) to the naphthalimide takes place and the quantum yields of fluorescence are low (ΦF ≈ 10−2). Due to FRET, photodehydration of naphthols to QMs takes place inefficiently (ΦR ≈ 10−5). However, the formation of QMs can also be initiated upon excitation of naphthalimide, the lower energy chromophore, in a process that involves photoinduced electron transfer (PET) from the naphthol to the naphthalimide. Fluorescence titrations revealed that 1a and 1e form complexes with ct-DNA with moderate association constants Ka ≈ 105–106 M−1, as well as with bovine serum albumin (BSA) Ka ≈ 105 M−1 (1:1 complex). The irradiation of the complex 1e@BSA resulted in the alkylation of the protein, probably via QM. The antiproliferative activity of 1a–e against two human cancer cell lines (H460 and MCF 7) was investigated with the cells kept in the dark or irradiated at 350 nm, whereupon cytotoxicity increased, particularly for 1e (>100 times). Although the enhancement of this activity upon UV irradiation has no imminent therapeutic application, the results presented have importance in the rational design of new generations of anticancer phototherapeutics that absorb visible light.

Highlights

Reagents that can alkylate and cross-link DNA molecules are among the most cytotoxic molecules, often employed in anticancer treatment [1]
The synthesis synthesisof ofnaphthol-naphthalimide naphthol-naphthalimideconjugates conjugates based a Grignard reacis is based onon a Grignard reaction tion askey thestep key in step in connecting two molecular fragments
Since naphthalimide derivatives are known to bind to polynucleotides [50,51], we investigated the non-covalent binding of 1 with naturally occurring calf thymus DNA, characterized by the typical B-helical secondary structure and the almost equimolar ratio of AT- and GC-basepairs

Summary

Introduction

Reagents that can alkylate and cross-link DNA molecules are among the most cytotoxic molecules, often employed in anticancer treatment [1]. Among the molecules that have been intensively studied as DNA cross-linking agents are quinone methides (QMs), reactive intermediates in phenol chemistry and photochemistry [2]. The biological activity of QMs [3,4] has been connected to their reactivity with proteins [5,6,7], nucleobases [8], DNA [9,10,11,12] and G-quadruplexes [13,14,15,16]. The antiproliferative action of the anticancer antibiotic mitomycin [17,18,19] is rationalized by the intracellular formation of QMs, followed by reversible DNA cross-linking [20,21,22]. QMs react efficiently with H2 O molecules [25,26,27], which competes with the reactivity with biological targets such as DNA.

Methods

Discussion

Conclusion