Radiation-Activated Cobalamin-Kinase Inhibitors for Treatment of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most dismal diagnoses that a patient can receive. PDAC is extremely difficult to treat, as drug delivery is challenging in part due to the lack of vascularization, high stromal content, and high collagen content of these tumors. We have previously demonstrated that attaching drugs to the cobalamin scaffold provides selectivity for tumors over benign cells due to a high vitamin demand in these rapidly growing cells and an overexpression of transcobalamin receptors in a variety of cancer types.

Tumor targeting vitamin B12 derivatives for X-ray induced treatment of pancreatic adenocarcinoma.

Background: X-Ray induced phototherapy is highly sought after as it provides a deep tissue, synergistic method of treating cancers via standard-of-care radiotherapy. When this is combined with releasable chemotherapy agents, it can provide high target selectivity, with reduced off-target organ effects that limit current systemic therapies. We have recently developed a unique light-activated drug delivery system whereby the drug is conjugated to an alkylcobalamin scaffold.

Visible Light-Induced Radical Mediated DNA Damage.

Light-responsive compounds have been used to manipulate biological systems with spatial and temporal control of the event of interest. Illumination of alkylcobalamins with green light (>500 nm) produces carbon-centered radicals, which have been demonstrated to effectively cause DNA damage. Molecules that cause DNA and RNA strand scission are useful for studying polynucleotide structure and the binding of small molecules and proteins to polynucleotides.

Fluorophore Assisted Photolysis of Thiolato-Cob(III)alamins.

Cobalamins are known to react with thiols to yield stable β-axial Co(III)-S bonded thiolato-cobalamin complexes. However, in stark contrast to the Co-C bond in alkylcobalamins, the photolability of the Co-S bond in thiolato-cobalamins remains undetermined. We have investigated the photolysis of N-acetylcysteinyl cob(III)alamin at several wavelengths within the ultraviolet and visible spectrum.

Vitamin B12: a tunable, long wavelength, light-responsive platform for launching therapeutic agents.

Light-responsive agents offer the promise of targeted therapy, whose benefits include (i) prolonged action at the target site, (ii) overall reduced systemic dosage, (iii) reduced adverse effects, and (iv) localized delivery of multiple agents. Although photoactivated prodrugs have been reported, these species generally require short wavelengths (<450 nm) for activation. However, maximal tissue penetrance by light occurs within the "optical window of tissue" (600-900 nm), well beyond the wavelength range of most existing photocleavable functional groups.

Tunable visible and near-IR photoactivation of light-responsive compounds by using fluorophores as light-capturing antennas.

Although the corrin ring of vitamin B12 is unable to efficiently absorb light beyond 550 nm, it is shown that commercially available fluorophores can be used as antennas to capture long-wavelength light to promote scission of the Co-C bond at wavelengths up to 800 nm. The ability to control the molecular properties of bioactive species with long visible and near-IR light has implications for drug delivery, nanotechnology, and the spatiotemporal control of cellular behavior.

Merging of confocal and caging technologies: selective three-color communication with profluorescent reporters.

Falling apart, on cue: Signaling pathways often display a profound spatiotemporal component that is best studied using light-activatable reagents. Three separate photolabile moieties that can be distinguished based upon their response to three distinct wavelengths (360, 440, and 560 nm) have been synthesized and evaluated. This tri-color system is also applied to imaging in microwells and HeLa cells (see picture).

Microwave-Assisted Synthesis of N-Phenylsuccinimide.

A microwave-assisted synthesis of N-phenylsuccinimide has been developed for the second-semester organic teaching laboratory. Utilizing this procedure, N-phenylsuccinimide can be synthesized by heating a mixture of aniline and succinic anhydride in a domestic microwave oven for four minutes in moderate yields (40-60%). This technique reduces the reaction time as compared to the traditional synthesis by several hours, which allows the preparation to be achieved in a single organic chemistry laboratory period.

A new trick (hydroxyl radical generation) for an old vitamin (B12).

Photolysis of hydroxocobalamin in the presence of plasmid DNA (pBR322) results in DNA cleavage. Temporal control of hydroxyl radical production and DNA strand scission by hydroxocobalamin was demonstrated using a 2-deoxyribose assay and a plasmid relaxation assay, respectively. The light-driven hydroxocobalamin-mediated catalytic formation of hydroxyl radicals was demonstrated using radical scavenging studies of DNA cleavage and via recycling of a hydroxocobalamin-resin conjugate several times without loss of efficacy.

Formal DNA hydrolysis by mono- and dinuclear iron complexes.

The complexes CpFe(CO)(2)Ph and [CpFe(CO)(2)](2) cleave DNA in the presence of H2O2 or organic peroxides to give products resulting from the formal hydrolysis of the phosphodiester groups.

The hydrogen peroxide induced enhancement of DNA cleavage in the ambient light photolysis of CpFe(CO)2Ph: a potential strategy for targeting cancer cells.

DNA strand scission is produced by the ambient light photolysis of CpFe(CO)(2)Ph and H(2)O(2), a result that shows potential as a means of targeting tumors, due to the high levels of hydrogen peroxide in cancer cells. This cleavage process is dependent on the concentration of both CpFe(CO)(2)Ph and H(2)O(2), and preliminary experiments implicate both carbon-centered radicals and reactive oxygen species.

Selective targeting of DNA for cleavage within DNA-histone assemblies by a spermine-[CpW(CO)3Ph]2 conjugate.

In contrast to the histone-modifying action of other complexes of the type CpML(n)R, the compound obtained by linking the phenyl rings of two CpW(CO)(3)Ph moieties to the DNA-binding agent spermine selectively cleaves DNA in DNA-histone assemblies.