Guanidinium Hypoiodite-Catalyzed Intramolecular Oxidative Coupling Reaction of Oxindoles with ß-Dicarbonyls.

Spiro[indoline-3,4'-piperidine] is a fundamental motif present in various biologically active compounds. Here, we report an intramolecular oxidative coupling reaction of oxindoles with ß-dicarbonyls in the presence of a guanidinium hypoiodite catalyst, providing spiro-coupling products in moderate to excellent yields. Furthermore, a chiral hypoiodite catalyst derived from the chiral guanidinium organocatalyst is effective for the challenging asymmetric carbon-carbon bond-forming reaction, affording optically active spiro[indoline-3,4'-piperidines].

Synthetic Chemical Probes That Dissect Vitamin D Activities.

Vitamin D3 metabolites are capable of controlling gene expression in mammalian cells through two independent pathways: vitamin D receptor (VDR) and sterol regulatory element-binding protein (SREBP) pathways. In the present study, we dissect the complex biological activity of vitamin D by designing synthetic vitamin D3 analogs specific for VDR or SREBP pathway, i.e., a VDR activator that lacks SREBP inhibitory activity, or an SREBP inhibitor devoid of VDR activity. These synthetic vitamin D probes permitted identification of one of the vitamin D-responsive genes, Soat1, as an SREBP-suppressed gene. The chemical probes developed in the present study may prove useful in dissecting the intricate interplay of vitamin D actions, thereby providing insights into how vitamin D target genes are regulated.

A-Ring Synthons of 19-Nor Type Vitamin D Derivatives.

Various 19-nor vitamin D analogs, which lack the methylene group at C19, exhibit significant vitamin D (VD)-related biological activities, but generally show a reduced calcemic side-effect compared with VD itself. Among them, paricalcitol is already used clinically for treatment and prevention of secondary hyperparathyroidism associated with chronic renal failure. Therefore, considerable synthetic efforts have been directed towards 19-nor VD analogs, focusing especially on A-ring synthons suitable for use in convergent synthetic strategies based on coupling of CD-ring synthons and A-ring synthons. For example, we have recently developed a new synthetic route to A-ring synthons from linear dienes based upon a ring-closing olefin metathesis strategy. Here, we review recent synthetic approaches to A-ring synthons for 19-nor VD derivatives.

Synthesis of Diastereomers of 1,3-cis-25-Dihydroxy-19-norvitamin D3.

1ß,3ß,25-Dihydroxy-19-norvitamin D3 (4a) and 1α,3α,25-dihydroxy-19-norvitamin D3 (4b) were synthesized by employing a new A-ring synthon, (1R,3S)-3-((tert-butyldimethylsilyl)oxy)-5-oxocyclohexyl benzoate (19), which was derived from D-(-)-quinic acid in 12 steps. The A-ring was coupled with the circular dichroism (CD) ring by means of Julia-Kocienski olefination to construct the diene unit. The structures of the products were confirmed by (1)H-NMR and nuclear Overhauser effect (NOE) experiments.

Synthesis of 24,24-Difluoro-1,3-cis-25-dihydroxy-19-norvitamin D3 Derivatives and Evaluation of Their Vitamin D Receptor-Binding Affinity.

Two vitamin D3 derivatives, namely 24,24-difluoro-1ß,3ß,25-dihydroxy-19-norvitamin D3 (6a) and 24,24-difluoro-1α,3α,25-dihydroxy-19-norvitamin D3 (6b), were synthesized via a convergent route employing Julia-Kocienski olefination as a key step. Compounds 6a and b bound to vitamin D receptor (VDR) with IC50 values of 64.8 and 57.6 nM, respectively, exhibiting about 400- and 30-fold greater binding affinity than the corresponding non-fluorinated derivatives 5a and b.

Guanidinium iodide-catalyzed oxidative α-nitroalkylation of ß-ketoamides.

Oxidative nitroalkylation of ß-ketoamides and nitroalkanes, mediated by hypoiodide generated from tert-butyl hydrogen peroxide and a catalytic amount of guanidinium iodide, afforded the corresponding α-nitroalkyl-ß-ketoamides in up to 97% yield.

Efficacy of ethyl nitrite in reversing surgical vasospasm.

Vasospasm leading to thrombosis is a major cause of free flap failure. Flap blood flow may improve by application of vasodilating agents to the pedicle. The purpose of this study is to evaluate the effect of a novel S-nitrosylating agent, O-ethyl nitrite, on flap blood flow and pedicle vessels diameter in a rat model, after induction of vasospasm. Two hours after surgery, the arterial diameter was significantly (P < .05) dilated by treatment with O-ethyl nitrite, lidocaine, or lidocaine + O-ethyl nitrite. None of these treatments had a statistically significant effect on blood flow or venous diameter. Twenty-four hours following surgery, both O-ethyl nitrite- and lidocaine-treated groups had larger arteries than the control group (P < .05). The O-ethyl nitrite-treated animals also had significantly (P < .05) elevated blood flow compared with control animals, but lidocaine-treated animals did not demonstrate any improved flow at 24 hours. O-Ethyl nitrite may become clinically useful in microvascular surgery procedures.

Side-to-side sutureless vascular anastomosis with magnets.

OBJECTIVE: Abbe and Payr introduced vascular techniques and devices to facilitate vessel anastomosis over a century ago. Obora published the idea of a sutureless vascular anastomosis with use of magnetic rings in 1978. The purpose of this study was to assess the performance of a new magnetic device to perform a side-to-side arteriovenous anastomosis in a dog model. MATERIAL AND METHODS: Male fox hounds (25 kg) were treated preoperatively and daily postoperatively with clopidogrel bisulfate (Plavix) and aspirin. The femoral artery and vein were exposed unilaterally in 3 dogs and bilaterally in 4 dogs (n = 11 anastomoses). A 4-mm arteriotomy was performed, and 1 oval magnet 0.5 mm thick was inserted into the lumen of the artery and a second magnet was applied external to the artery, compressing and stabilizing the arterial wall to create a magnetic port. An identical venous magnetic port was created with another pair of oval magnets. When the 2 ports were allowed to approach each other, they self-aligned and magnetically coupled to complete the arteriovenous anastomosis. Patency was assessed for the first hour with direct observation, again after 9 weeks with duplex ultrasound scanning, and at 10 weeks under direct open observation. The anastomoses were explanted after 10 weeks. Hydrodynamic resistance was measured ex vivo on the final 8 anastomoses by measuring the pressure drop across an anastomosis with a known flow rate. RESULTS: After implantation, very high flow created visible turbulence and palpable vibration. All 11 anastomoses were patent under direct observation and palpation. Ten of 11 anastomoses were clearly patent on duplex scans, and patency of 1 anastomosis was questionable. Hydrodynamic resistance averaged 0.73 +/- 0.33 mm Hg min/mL (mean +/- SEM). CONCLUSIONS: Vascular anastomoses performed with magnets demonstrated feasibility; exhibited 100% patency after 10 weeks in a dog arteriovenous shunt model; lacked apparent aneurysm or other potentially catastrophic failure; demonstrated remodeling of the vessel wall after several weeks to incorporate the magnets, making the magnetic force unnecessary; and warrants further study in vessels with different sizes, flow rates, and locations. CLINICAL RELEVANCE: We present a magnet-based device used to perform side-to-side peripheral vascular anastomoses. Its advantages include the ability to anastomose vessels without requiring circumferential surgical exposure. Vascular anastomosis performed with these magnets demonstrated 100% patency in the dog, lacked apparent aneurysm or other potentially catastrophic failure, and demonstrated remodeling of the vessel wall after several weeks, to incorporate the magnets, making indefinite retention of field strength unnecessary. This technique could enable minimally invasive procedures, such as complex reconstructive and revascularizing surgery, and warrants further study in vessels with different sizes, flow rates, and locations.

Novel circular-beam equalizing techniques that use graded-index fiber optics for a high-power laser diode.

We demonstrate a novel method of equalizing a laser diode (LD) beam into a circular beam. This method uses the twist effect of graded index (GI) fiber optics. An asymmetric LD beam with beam qualities of M2 = 500 in the slow axis and M2 = 4 in the fast axis is converted successfully into a symmetric circular beam with a beam quality of M2 = 175. The circular-output beam with 92% coupling efficiency from the fiber input to the fiber output is obtained with a 5-m-long GI1200 (1200 means a core diameter of 1200 microm) fiber for a 2-W LD array. We extend the experiments to a higher-power source with higher asymmetric beam qualities of M2 = 3000 and M2 = 4. By slightly bending the GI10000 (10000 means a core diameter of 10,000 microm) fiber, we have succeeded in generating a symmetric beam with a improved beam quality of M2 = 2000. The average beam quality is preserved when the asymmetric ratio is not high, and the beam quality degradation ratio is investigated up to asymmetric ratios of 750.

Microsurgical free flap transfer to amputation sites: indications and results.

A series of microsurgical free flap reconstructions to amputation stumps of the upper as well as the lower extremities was reviewed in 7 male and 2 female patients. Indications included preservation of length after trauma in 6 patients and cure of local infection in 2 patients. In 1 patient an extensive defect after resection of a recurrent shoulder sarcoma required use of a complete arm fillet free flap for tumor reconstruction. Microvascular free flaps used included four scapular flaps, two fillet flaps from the amputated extremity, one anterolateral thigh flap, and one lateral arm flap. Seven of 9 patients were fitted with a prosthesis and underwent occupational therapy resulting in ambulatory and improved functional status. Microvascular reconstruction is indicated in emergency settings as well as for elective reconstruction of amputation sites. Using uninjured "spare parts" of the amputated extremity should be considered. Elective reconstruction is performed preferably with free flaps based on the subscapular vascular system.

Automatic output-beam-collimating configuration for high-average-power multirod resonator-amplifier systems.

A novel configuration for a multirod solid-state laser system is proposed. We stabilize the thermal-lens-dependent variation in the output-beam parameters by extracting the laser beam from the collimating point of periodic beam propagation. The performance is confirmed with a 100-W class diode-pumped Nd:YAG laser-amplifier system to demonstrate tenfold stabilization of the output-beam diameter.