Discovery and SAR of 2-arylbenzotriazoles and 2-arylindazoles as potential treatments for Duchenne muscular dystrophy.

Families of 2-arylbenzotriazoles and 2-arylindazoles that show positive effects in screens predictive of endogenous utrophin upregulation have been identified. Synthesis and structure-activity relationships are described leading to compounds with attractive in vitro profiles.

Discovery of 2-arylbenzoxazoles as upregulators of utrophin production for the treatment of Duchenne muscular dystrophy.

A series of novel 2-arylbenzoxazoles that upregulate the production of utrophin in murine H2K cells, as assessed using a luciferase reporter linked assay, have been identified. This compound class appears to hold considerable promise as a potential treatment for Duchenne muscular dystrophy. Following the delineation of structure-activity relationships in the series, a number of potent upregulators were identified, and preliminary ADME evaluation is described. These studies have resulted in the identification of 1, a compound that has been progressed to clinical trials.

Terahertz pulsed spectroscopy of human Basal cell carcinoma.

Good contrast is seen between normal tissue and regions of tumor in terahertz pulsed imaging of basal cell carcinoma (BCC). To date, the source of contrast at terahertz frequencies is not well understood. In this paper we present results of a spectroscopy study comparing the terahertz properties (absorption coefficient and refractive index) of excised normal human skin and BCC. Both the absorption coefficient and refractive index were higher for skin that contained BCC. The difference was statistically significant over the range 0.2 to 2.0 THz (6.6 cm(-1) to 66.6 cm(-1)) for absorption coefficient and 0.25 to 0.90 THz (8.3 cm(-1) to 30 cm(-1)) for refractive index. The maximum difference for absorption was at 0.5 THz(16.7 cm(-1)). These changes are consistent with higher water content. These results account for the contrast seen in terahertz images of BCC and explain why parameters relating to the reflected terahertz pulse provide information about the lateral spread of the tumor. Knowing the properties of the tissue over the terahertz frequency range will enable the use of mathematical models to improve understanding of the terahertz response of normal and diseased tissue.

Terahertz pulsed imaging of human breast tumors.

The feasibility of using terahertz pulsed imaging to map margins of exposed breast tumors was investigated by imaging 22 excised human breast tissue specimens with carcinoma excised from 22 women (mean age, 59 years; range, 39-80 years). The study was approved by the local ethics research committee, and informed consent was obtained from all patients. The size and shape of tumor regions on terahertz images were compared with those identified at histopathologic examination of the imaged section. Two image parameters were investigated: the minimum of the terahertz impulse function and the ratio of the minimum to the maximum of the terahertz impulse function. The correlation coefficient for the tumor area on images compared with that on a photomicrograph of all 22 samples was greater than 0.82 for both parameters. The shape of the tumor regions on terahertz images also correlated well with that on a photomicrograph (median Spearman rank correlation coefficient, 0.69). Findings of this study demonstrate the potential of terahertz pulsed imaging to depict both invasive breast carcinoma and ductal carcinoma in situ under controlled conditions and encourage further studies to determine the sensitivity and specificity of the technique.

Concise and enantioselective synthesis of the aminocyclitol core of hygromycin A.

[reaction: see text] Stereoselective aminohydroxylation and dihydroxylation using osmium(VIII) oxidants enabled the short and efficient synthesis of the aminocyclitol core of hygromycin A. In addition to allowing the selective introduction of the heteroatoms N and O, the use of osmium (via an osmate ester) as a protecting group for a 1,2-glycol is also reported. This tactic allowed efficient differentiation of otherwise equivalent hydroxyl groups and allowed us to complete the synthesis in short order (14 steps) and excellent overall yield (12%).

Simulating the response of terahertz radiation to basal cell carcinoma using ex vivo spectroscopy measurements.

Studies of basal cell carcinoma using terahertz pulsed imaging have revealed a significant difference between regions of tumor and healthy tissue. These differences are manifested in the reflected pulse due to what is thought to be changes in refractive index and absorption. We present measurements of the refractive index and absorption coefficient of excised normal tissue and basal cell carcinoma using terahertz (THz) transmission spectroscopy. We extract Debye parameters from these data and enter them into a finite difference time domain simulation to predict the shape of the waveforms reflected off the normal tissue and basal cell carcinoma and compare them with published in vivo data. Simulating the interaction of terahertz radiation with normal and cancerous tissue is a key step toward understanding the origin of contrast in terahertz images of skin cancer.

Efficient acyclic stereocontrol using the tethered aminohydroxylation reaction.

[reaction: see text] The tethered aminohydroxylation (TA) of acyclic allylic carbamates has been achieved in a stereospecific and stereoselective manner. Unusually high levels of stereocontrol were observed in the oxidation of 1,1-disubstituted substrates.

Terahertz pulsed imaging and spectroscopy for biomedical and pharmaceutical applications.

Terahertz (THz) radiation lies between the infrared and microwave regions of the electromagnetic spectrum. Advances in THz technology have opened up many opportunities in this scientifically and technologically important spectroscopic region. The THz frequency range excites large amplitude vibrational modes of molecules as well as probing the weak interactions between them. Here we describe two techniques that utilize THz radiation, terahertz pulsed imaging (TPI) and terahertz pulsed spectroscopy (TPS). Both have a variety of possible applications in biomedical imaging and pharmaceutical science. TPI, a non-invasive imaging technique, has been used to image epithelial cancer ex vivo and recently in vivo. The diseased tissue showed a change in absorption compared to normal tissue, which was confirmed by histology. To understand the origins of the differences seen between diseased and normal tissue we have developed a TPS system. TPS has also been used to study solids of interest in the pharmaceutical industry. One particularly interesting example is ranitidine hydrochloride, which is used in treatment of stomach ulcers. Crystalline ranitidine has two polymorphic forms known as form 1 and form 2. These polymorphs have the same chemical formula but different crystalline structure that give rise to different physiochemical properties of the material. Using TPS it is possible to rapidly distinguish between the two polymorphic forms.

The tethered aminohydroxylation (TA) reaction.

Since Sharpless' discovery of the asymmetric aminohydroxylation (AA) reaction, a major challenge for chemists has been to find ways of controlling the regio- and stereochemical outcome of this important reaction. Detailed herein is a review of our novel approach towards gaining reliable and predictable regio- and stereocontrol through the use of a tethered carbamate to promote an intramolecular AA reaction, along with a description of the mechanism proposed for this new methodology.

Terahertz pulse imaging of ex vivo basal cell carcinoma.

Terahertz pulse imaging has been used for the first time to study basal cell carcinoma ex vivo, the most common form of skin cancer. This noninvasive technique uses part of the electromagnetic spectrum in the frequency range 0.1-2.7 THz. A total of 21 samples were imaged; the study was performed blind and results were compared to histology. Each image consisted of possible diseased tissue and normal tissue from the same patient. The diseased tissue showed an increase in absorption compared to normal tissue, which is attributed to either an increase in the interstitial water within the diseased tissue or a change in the vibrational modes of water molecules with other functional groups. Seventeen of the images showed a significant difference between the normal and the diseased tissue. These were confirmed by histology to be basal cell carcinomas. Of the remaining four cases, three showed no contrast and were confirmed as blind controls of normal tissue; the fourth case was a suspected basal cell carcinoma but showed no contrast, and histology showed no tumor. Cross-sections of the terahertz images, showing the terahertz absorption, were compared to histology. Regions of increased terahertz absorption agreed well with the location of the tumor sites. Resolutions at 1 THz of 350 microm laterally and 40 microm axially in skin were attainable with our system. These results demonstrate the ability of terahertz pulse imaging to distinguish basal cell carcinoma from normal tissue, and this macroscopic technique may, in the future, help plan surgery.

Terahertz pulse imaging in reflection geometry of human skin cancer and skin tissue.

We demonstrate the application of terahertz pulse imaging (TPI) in reflection geometry for the study of skin tissue and related cancers both in vitro and in vivo. The sensitivity of terahertz radiation to polar molecules, such as water, makes TPI suitable for studying the hydration levels in the skin and the determination of the lateral spread of skin cancer pre-operatively. By studying the terahertz pulse shape in the time domain we have been able to differentiate between diseased and normal tissue for the study of basal cell carcinoma (BCC). Basal cell carcinoma has shown a positive terahertz contrast, and inflammation and scar tissue a negative terahertz contrast compared to normal tissue. In vivo measurements on the stratum corneum have enabled visualization of the stratum corneum-epidermis interface and the study of skin hydration levels. These results demonstrate the potential of terahertz pulse imaging for the study of skin tissue and its related disorders, both in vitro and in vivo.