Synthesis and biological evaluation of a fluorescent analog of phenytoin as a potential inhibitor of neuropathic pain and imaging agent.

Here we report on a novel fluorescent analog of phenytoin as a potential inhibitor of neuropathic pain with potential use as an imaging agent. Compound 2 incorporated a heptyl side chain and dansyl moiety onto the parent compound phenytoin and produced greater displacement of BTX from sodium channels and greater functional blockade with greatly reduced toxicity. Compound 2 reduced mechano-allodynia in a rat model of neuropathic pain and was visualized ex vivo in sensory neuron axons with two-photon microscopy. These results suggest a promising strategy for developing novel sodium channel inhibitors with imaging capabilities.

Fluorescent cyclin-dependent kinase inhibitors block the proliferation of human breast cancer cells.

Inhibitors of cyclin-dependent kinases (CDKs) are an emerging class of drugs for the treatment of cancers. CDK inhibitors are currently under evaluation in clinical trials as single agents and as sensitizers in combination with radiation therapy and chemotherapies. Drugs that target CDKs could have important inhibitory effects on cancer cell cycle progression, an extremely important mechanism in the control of cancer cell growth. Using rational drug design, we designed and synthesized fluorescent CDK inhibitors (VMY-1-101 and VMY-1-103) based on a purvalanol B scaffold. The new agents demonstrated more potent CDK inhibitory activity, enhanced induction of G2/M arrest and modest apoptosis as compared to purvalanol B. Intracellular imaging of the CDK inhibitor distribution was performed to reveal drug retention in the cytoplasm of treated breast cancer cells. In human breast cancer tissue, the compounds demonstrated increased binding as compared to the fluorophore. The new fluorescent CDK inhibitors showed undiminished activity in multidrug resistance (MDR) positive breast cancer cells, indicating that they are not a substrate for p-glycoprotein. Fluorescent CDK inhibitors offer potential as novel theranostic agents, combining therapeutic and diagnostic properties in the same molecule.

Fluorescent epigenetic small molecule induces expression of the tumor suppressor ras-association domain family 1A and inhibits human prostate xenograft.

Epigenetic silencing of Ras-association domain family 1A (RASSF1A) protein in cancer cells results in a disruption of cell cycle control, genetic instability, enhanced cell motility, and apoptotic resistance. Ectopic expression of RASSF1A reverses this tumorigenic phenotype. Thus, small molecules with the ability to restore RASSF1A expression may represent a new class of therapeutic agents. Recently, we designed and synthesized a fluorescent carbazole analogue of mahanine (alkaloid from Murraya koenigii) that restored RASSF1A mRNA expression. Our fluorescent lead compound up-regulated RASSF1A in vitro, potently inhibited human prostate cancer cell proliferation, and fluoresced at a visible wavelength, allowing for the observation of intracellular distribution. The small molecule lead was not acutely toxic up to 550 mg/kg, and dosing at 10 mg/kg reduced human xenograft tumor volume by about 40%.

Meso-substituted [34]octaphyrin(1.1.1.0.1.1.1.0) and corrole formation in reactions of a dipyrromethanedicarbinol with 2,2'-bipyrrole.

The reaction of a dipyrromethanedicarbinol with 2,2'-bipyrrole leading to meso-substituted [34]octaphyrin(1.1.1.0.1.1.1.0) and/or corrole was investigated to determine the effect of key reaction parameters on the distribution of the two macrocycles. Solvent, acid catalyst, acid quantity, oxidant, oxidant quantity, and reaction time were surveyed for a model reaction affording 5,10,19,24,29,38-hexaphenyl[34]octaphyrin(1.1.1.0.1.1.1.0) (HPO) and/or meso-triphenylcorrole (TPC). HPO was found to be a fairly ubiquitous product, produced in yields as high as 23% (UV-vis), while TPC was observed infrequently, in yields up to 10% (UV-vis). A preparative-scale reaction provided HPO in an isolated yield of 25%. The methodology was extended to the synthesis of an octaphyrin bearing two different substituents in defined locations and to an octaphyrin possessing electron-withdrawing pentafluorophenyl substituents. Preferential formation of octaphyrin instead of corrole suggests that the anti conformation of 2,2'-bipyrrole is the relevant form under the reaction conditions surveyed. The spectral properties of the novel meso-substituted [34]octaphyrin(1.1.1.0.1.1.1.0) species are similar to those of the known beta-substituted analogue, including spectra consistent with the absence of macrocycle aromaticity despite a main conjugation path of 34 pi-electrons. Key to the overall study was the development of a refined synthesis of 2,2'-bipyrrole.