Photoresponsive antibiotics and cytotoxic agents:On the use of light for the advancement of medicine and the knowledge of living organisms

Cancer and the appearance of drug resistant bacteria are two of the major health problems of modern day society. The causes of cancer are numerous and not fully understood, making prevention difficult and treatments harsh as they cause many side effects. The rise in the drug resistances of bacteria is better understood, but as hard to combat as it is induced, in part, by the daily uncontrolled release of active antibiotics in nature by humans. Many ways are currently being investigated to better understand and combat these problems. A method which provides an answer to both of these is presented in this thesis. Herein, we present our work towards creating new types of drugs, which possesses either all the potency of modern anticancer drugs or of antibiotic drugs, but who additionally contain a light driven trigger that would allow us to control with the uttermost precision when and where this drug is active. This minute control, only made possible by the development of lasers, would allow us to only activate the drug where it is most needed, thereby lowering the side effect of cancer therapy or ensuring no active drug escapes into the environment, halting the uncontrolled growth of bacterial resistance. In addition, we take advantage of our knowledge of these new compounds to develop variations that could be used as probes to investigate the effect of oxidative stress on the human body, which has been shown to be potentially related to many diseases

Hydroxycinnamyl Derived BODIPY as a Lipophilic Fluorescence Probe for Peroxyl Radicals

Herein, we describe the synthesis of a fluorescent probe NB-2 and its use for the detection of peroxyl radicals. This probe is composed of two receptor segments (4-hydroxycinnamyl moieties) sensitive towards peroxyl radicals that are conjugated with a fluorescent reporter, dipyrrometheneboron difluoride (BODIPY), whose emission changes depend on the oxidation state of the receptors. The measurement of the rate of peroxidation of methyl linoleate in a micellar system in the presence of 1.0 µM NB-2 confirmed its ability to trap lipid peroxyl radicals with the rate constant kinh = 1000 M−1·s−1, which is ten-fold smaller than for pentamethylchromanol (an analog of α-tocopherol). The reaction of NB-2 with peroxyl radicals was further studied via fluorescence measurements in methanol, with α,α′-azobisisobutyronitrile (AIBN) used as a source of radicals generated by photolysis or thermolysis, and in the micellar system at pH 7.4, with 2,2′-azobis(2-amidinopropane) (ABAP) used as a thermal source of the radicals. The reaction of NB-2 receptors with peroxyl radicals manifests itself by the strong increase of a fluorescence with a maximum at 612–616 nm, with a 14-fold enhancement of emission in methanol and a 4-fold enhancement in the micelles, as compared to the unoxidized probe. Our preliminary results indicate that NB-2 behaves as a “switch on” fluorescent probe that is suitable for sensing peroxyl radicals in an organic lipid environment and in bi-phasic dispersed lipid systems

Green-Light-Sensitive BODIPY Photoprotecting Groups for Amines

We describe a series of easily accessible, visible-light-sensitive (λ > 500 nm) BODIPY (boron-dipyrromethene)-based photoprotecting groups (PPGs) for primary and secondary amines, based on a carbamate linker. The caged compounds are stable under aqueous conditions for 24 h and can be efficiently uncaged in vitro with visible light (λ = 530 nm). These properties allow efficient photodeprotection of amines, rendering these novel PPGs potentially suitable for various applications, including the delivery of caged drugs and their remote activation

Red-light-sensitive BODIPY photoprotecting groups for amines and their biological application in controlling heart rhythm

Control of biological function by the use of photoremovable protecting groups (PPGs) is a gateway towards many new medical developments. Herein, we report the synthesis and application of efficient and biocompatible BODIPY-based photoprotecting groups for amines, which are cleavable with red light in the phototherapeutic window region (λ > 650 nm). We use the most promising PPG for the protection of dopamine and apply it to control the beating frequency of human cardiomyocytes