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.
Subject(s)
Antineoplastic Agents/pharmacology , Indolequinones/chemical synthesis , Naphthalimides/chemistry , Naphthols/chemistry , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Fluorescence Resonance Energy Transfer , Humans , Indolequinones/chemistry , Indolequinones/pharmacology , MCF-7 Cells , Molecular Structure , Photochemical Processes , Quantum TheoryABSTRACT
The photophysical properties and photochemical reactivities of a series of bis-naphthols 4a-4e and bis-anthrols 5a and 5e were investigated by preparative irradiation in CH3OH, fluorescence spectroscopy and laser flash photolysis (LFP). Methanolysis taking place via photodehydration (bis-naphthols: ΦR = 0.04-0.05) is in competition with symmetry breaking charge separation (SB-CS). The SB-CS gave rise to radical ions that were detected for 4a and 4e by LFP. Photodehydration gave quinone methides (QMs) that were also detected by LFP (λmax = 350 nm, τ ≈ 1-2 ms). In the aqueous solvent, excited state proton transfer (ESPT) competes with the abovementioned processes, giving rise to naphtholates, but the process is inefficient and can only be observed in the buffered aqueous solution at pH > 7. Since the dehydration of bis-naphthols delivers QMs, their potential antiproliferative activity was investigated by an MTT test on three human cancer cell lines (NCI-H1299, lung carcinoma; MCF-7, breast adenocarcinoma; and SUM159, pleomorphic breast carcinoma). Cells were treated with 4 or 5 with or without irradiation (350 nm). An enhancement of the activity (up to 10-fold) was observed upon irradiation, which may be associated with QM formation. However, these QMs do not cross-link DNA. The activity is most likely associated with the alkylation of proteins present in the cell cytoplasm, as evidenced by photoinduced alkylation of bovine and human serum albumins by 4a.
