Alkyne-Bridged α-Conotoxin Vc1.1 Potently Reverses Mechanical Allodynia in Neuropathic Pain Models.

Several Conus-derived venom peptides are promising lead compounds for the management of neuropathic pain, with α-conotoxins being of particular interest. Modification of the interlocked disulfide framework of α-conotoxin Vc1.1 has been achieved using on-resin alkyne metathesis. Although introduction of a metabolically stable alkyne motif significantly disrupts backbone topography, the structural modification generates a potent and selective GABAB receptor agonist that inhibits Cav2.2 channels and exhibits dose-dependent reversal of mechanical allodynia in a behavioral rat model of neuropathic pain. The findings herein support the hypothesis that analgesia can be achieved via activation of GABABRs expressed in dorsal root ganglion (DRG) sensory neurons.

A Formal Synthesis of (-)-Perhydrohistrionicotoxin Using a Cross Metathesis-Hydrogenation Approach.

The development of an efficient, high yielding six-step convergent synthesis of the semisynthetic alkaloid (-)-perhydrohistrionicotoxin is described. The key transformations include the cross metathesis of a Brønsted-acid masked primary homoallylic amine with a vinyl cyclohexenone and a regioselective palladium catalyzed hydrogenation. This sequence generated the advanced Winterfeldt spirocyclic precursor in 47% overall yield, with a longest linear sequence of five steps.

Cross-Metathesis Approach to the Tricyclic Marine Alkaloids (-)-Fasicularin and (-)-Lepadiformine A.

A cross-metathesis protocol has been developed to provide facile access to highly hindered trisubstituted α-branched olefins, which when coupled with a cationic azaspirocyclization reaction, generates the marine alkaloids (-)-fasicularin 2 and a pro-forma synthesis of (-)-lepadiformine A 1.

One-Pot Selective Homodimerization/Hydrogenation Strategy for Sequential Dicarba Bridge Formation.

The installation of interlocked dicarba bridges into peptide sequences requires the development of a regioselective and chemoselective methodology. This manuscript describes a one-pot, chemoselective synthesis of three 2,7-diaminosuberic acid derivatives from an alkyne, a cobalt-carbonyl protected alkyne, and an alkene using metathesis and homogeneous hydrogenation catalysis.

Optimal source distribution for focal boosts using high dose rate (HDR) brachytherapy alone in prostate cancer.

PURPOSE: To investigate the optimal distribution of sources using high dose rate brachytherapy to deliver a focal boost to a dominant lesion within the whole prostate gland based on multi-parametric magnetic resonance imaging (mpMRI). METHODS: Sixteen patients with prostate cancer underwent mpMRI each of which demonstrated a dominant lesion. There were single lesions in 6 patients, two lesions in 4 and 3 lesions in 6 patients. Two dosimetric models and parameters were compared in each case. The first model used 10mm intervals between needles, and the second model used additional needles at 5 mm intervals between each needle in the boost area. RESULTS: Three of thirty-two plans did not achieve the plan objectives. These three plans were in the first model. A higher median urethral volume was seen in the 'unsuccessful' group (2.7 cc, and 1.9 cc, respectively, p-value=0.12). Conformity indices of the second model were also better than the first model (COIN index; 0.716 and 0.643, respectively). CONCLUSIONS: Focal monotherapy based on mpMRI achieves optimal dosimetry by individualizing the needle positions using 5mm spacing rather than 10mm spacing within the boost volume. A larger urethral volume may have an adverse effect on this distribution. Formal clinical evaluation of this approach is currently underway.

A catalytic and tert-butoxide ion-mediated amidation of aldehydes with para-nitro azides.

We report here a new catalytic reaction in which, para-nitro azides are acylated by aldehydes to produce amides and molecular nitrogen in a single step. The transformation is believed to proceed via an electron transfer process mediated by the tert-butoxide ion, and catalysed by a thiazolium salt derived species.

A synthetic approach to kingianin A based on biosynthetic speculation.

A synthetic approach towards the structurally complex dimer, kingianin A is reported. The strategy involved a cascade of complexity generating reactions, inspired through biosynthetic speculation. A concise protecting group free synthesis of the proposed monomeric precursor pre-kingianin A has been achieved using a tandem Stille cross-coupling reaction and electrocyclisation process. However, preliminary studies of the key dimerisation reaction have been conducted, which indicate that the process is not spontaneous, raising questions as to the origin of this complex natural product.