Letter to the editor

Orally effective iron chelators for the treatment of iron overload disease: The case for a further look at pyridoxal isonicotinoyl hydrazone and its analogs

The current available therapeutics face several challenges such as the development of ideal drug delivery systems towards the goal of personalized treatments for patients benefit. The application of light as an exogenous activation mechanism has shown promising outcomes, owning to the spatiotemporal confinement of the treatment in the vicinity of the diseased tissue, which offers many intriguing possibilities. Engineering therapeutics with light responsive moieties have been explored to enhance the bioavailability, and drug efficacy either in vitro or in vivo. The tailor-made character turns the so-called photocaged compounds highly desirable to reduce the side effects of drugs and, therefore, have received wide research attention. Herein, we seek to highlight the potential of photocaged compounds to obtain a clear understanding of the mechanisms behind its use in therapeutic delivery. A deep overview on the progress achieved in the design, fabrication as well as current and possible future applications in therapeutics of photocaged compounds is provided, so that novel formulations for biomedical field can be designed.

Three hesperetin Schiff bases N-[2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-ylidene]thiosemicarbazide (HTSC), N-[2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-ylidene]isonicotinohydrazide (HIN) and N-[2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxy-phenyl)chromen-4-ylidene] benzhydrazide (HHSB) were synthesized and evaluated for their electronic and physicochemical properties using experimental and theoretical methods. In order to determine antioxidant activity of the above mentioned compounds a detailed kinetic study of hesperetin analogues has been performed and comprehensive results have been reported with DPPH assay using UV–Vis and ¹H NMR spectroscopy. Using DPPH assay, the order of the antioxidant activity increase was established as HTSC > HIN > HHSB > hesperetin. Based on the theoretical DFT(B3LYP) calculations it was concluded that in polar solvents (methanol and DMSO) the first step of free radical scavenging mechanism of hesperetin derivatives is deprotonation of the 7-OH groups leading to the formation of anionic forms. These anionic species are considered to be the entering species to the two coexisting or competing mechanisms: SPLET and SPL-HAT.

The development of new therapeutic alternatives for cancers is a major public health priority. Among the more promising approaches, the iron depletion strategy based on metal chelation in the tumoral environment has been particularly studied in recent decades. After a short description of the importance of iron for cancer cell proliferation, we will review the different iron chelators developed as potential chemotherapeutics. Finally, the recent efforts to vectorize the chelating agents specifically in the microtumoral environment will be discussed in detail.

UVA radiation can damage cells and tissues by direct photodamage of biomolecules as well as by initiating metal-catalyzed oxidative stress. In order to alleviate both concerns simultaneously, we synthesized a multifunctional prochelator PC-HAPI (2-((E)-1-(2-isonicotinoylhydrazono)ethyl)phenyl (trans)-3-(2,4-dihydroxyphenyl)acrylate) that contains a trans-(o-hydroxy)cinnamate ester photocleavable protecting group that is cleaved upon UVA exposure to release a coumarin, umbelliferone, and an aroylhydrazone metal chelator, HAPI (N′-[1-(2-hydroxyphenyl)ethyliden]isonicotinoylhydrazide). While the prochelator PC-HAPI exhibits negligible affinity for iron, it responds rapidly to UVA irradiation and converts to an iron-binding chelator that inhibits iron-catalyzed formation of reactive oxygen species and protects cells from UVA damage.

Iron is an essential element and a critical component of molecules involved in energy production, cell cycle and intermediate metabolism. However, the same characteristic chemistry that makes it so biologically versatile may lead to iron-associated toxicity as a consequence of increased oxidative stress. The fact that free iron accumulates with age and generates ROS led to the hypothesis that it could be involved in the etiogenesis of several chronic diseases. Iron has been consistently linked to carcinogenesis, either through persistent failure in the redox balance or due to its critical role in cellular proliferation. Several reports have given evidence that alterations in the import, export and storage of cellular iron may contribute to breast cancer development, behavior and recurrence. In this review, we summarize the basic mechanisms of systemic and cellular iron regulation and highlight the findings that link their deregulation with breast cancer. To conclude, progresses in iron chelation therapy in breast cancer, as a tool to fight chemotherapy resistance, are also reviewed.

Iron chelators inhibit the growth of the malaria parasite, Plasmodium falciparum, in culture and in animal and human studies. We previously reported the anti-plasmodial activity of the chelators, 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), 2-hydroxy-1-naphthylaldehyde 4-methyl-3-thiosemicarbazone (N4mT), and 2-hydroxy-1-naphthylaldehyde 4-phenyl-3-thiosemicarbazone (N4pT). In fact, these ligands showed greater growth inhibition of chloroquine-sensitive (3D7) and chloroquine-resistant (7G8) strains of P. falciparum in culture compared to desferrioxamine (DFO). The present study examined the effects of 311, N4mT and N4pT on erythrocyte membrane integrity and asexual parasite development. While the characteristic biconcave disk shape of the erythrocytes was unaffected, the chelators caused very slight hemolysis at IC₅₀ values that inhibited parasite growth. The chelators 311, N4mT and N4pT affected all stages of the intra-erythrocytic development cycle (IDC) of P. falciparum in culture. However, while these ligands primarily affected the ring-stage, DFO inhibited primarily trophozoite and schizont-stages. Ring, trophozoite and schizont-stages of the IDC were inhibited by significantly lower concentrations of 311, N4mT, and N4pT (IC₅₀ = 4.45 ± 1.70, 10.30 ± 4.40, and 3.64 ± 2.00 μM, respectively) than DFO (IC₅₀ = 23.43 ± 3.40 μM). Complexation of 311, N4mT and N4pT with iron reduced their anti-plasmodial activity. Estimation of the intracellular labile iron pool (LIP) in erythrocytes showed that the chelation efficacy of 311, N4mT and N4pT corresponded to their anti-plasmodial activities, suggesting that the LIP may be a potential source of non-heme iron for parasite metabolism within the erythrocyte. This study has implications for malaria chemotherapy that specifically disrupts parasite iron utilization.