DABCO bond cleavage for the synthesis of piperazine derivatives

The applications of DABCO (1,4-diazabicyclo[2.2.2]octane) in the synthesis of piperazine derivatives including biologically active compounds via C–N bond cleavage are investigated in this review. Different reagents such as alkyl halides, aryl(heteroary) halides, carboxylic acids, diaryliodonium salts, tosyl halides, activated alkynes, benzynes etc. were applied for the preparation of the corresponding quaternary ammonium salts of DABCO, which are very good electrophiles for various nucleophiles such as phenols, thiophenols, thiols, alcohols, aliphatic and aromatic amines, sulfinates, phthalimide, indoles, NaN₃, triazole and terazoles, NaCN, enols and enolates, halides, carboxylic acid salts etc. Besides preactivated DABCO salts, the in situ activation of DABCO in multicomponent reactions is also an efficient tactic in synthetic organic chemistry for the diversity oriented synthesis of drug-like piperazine derivatives.

The applications of DABCO (1,4-diazabicyclo[2.2.2]octane) in the synthesis of piperazine derivatives including biologically active compounds via C–N bond cleavage are investigated in this review.     

Acquisition of Anatomic Parameters Concerning Molar Pulp Chamber Landmarks Using Cone-beam Computed Tomography

Introduction

Cone-beam computed tomographic (CBCT) imaging is a valuable tool for endodontic therapy. The aim of this study was to verify whether clinical use of CBCT imaging can accurately acquire parameters concerning molar pulp chamber landmarks, which are important data to help start a successful access cavity and avoid iatrogenic furcation perforations.

Methods

Seventy CBCT images were used to measure 118 maxillary and 104 mandibular molars. The following vertical distances were measured: from the cusp tip/central fossa to the pulp chamber floor, to the pulp chamber ceiling, and to furcation; from the pulp chamber ceiling to furcation; from the pulp chamber floor to furcation; and the pulp chamber height. Measurements were read to the nearest 0.05 mm.

Results

The measurements were as follows: the pulp chamber floor to furcation (maxillary molar: 1.97 ± 0.58 [mean ± standard deviation, mm], mandibular molar: 2.24 ± 0.47), the pulp chamber ceiling to furcation (maxillary molar: 4.09 ± 0.68, mandibular molar: 3.78 ± 0.70), the central fossa to furcation (maxillary molar: 8.78 ± 0.79, mandibular molar: 8.53 ± 0.65), the central fossa to the pulp chamber floor (maxillary molar: 6.81 ± 0.83, mandibular molar: 6.29 ± 0.65), the central fossa to the pulp chamber ceiling (maxillary molar: 4.69 ± 0.59, mandibular molar: 4.75 ± 0.56); and pulp chamber height (maxillary molar: 2.12 ± 0.81, mandibular molar: 1.53 ± 0.68). Measurements showing the least standard deviation were the central fossa to furcation and the central fossa to the pulp chamber floor.

Conclusions

CBCT imaging may be used for precise clinical acquisition of the pulp chamber landmark measurements for molars thereby facilitating successful access cavity.     

Evaluating Cardiovascular Safety of Novel Therapeutic Agents for the Treatment of Type 2 Diabetes Mellitus

Type 2 diabetes increases the risk of developing cardiovascular (CV) complications such as myocardial infarction, heart failure, stroke, peripheral vascular disease, and CV-associated mortality. Strict glycemic control in diabetics has shown improvement in microvascular complications related to diabetes but has been unable to demonstrate major effects on macrovascular complications including myocardial infarction and stroke. Conventional therapies for diabetes that include insulin, metformin, sulfonylureas (SU), and alpha-glucosidase inhibitors have limited and/or controversial data on CV safety based on observational studies not designed or powered to assess CV safety of these medications. In 2008, the US Food and Drug Administration (FDA) revised regulations for the approval of medications for type 2 diabetes by requiring that enough CV events are accrued prior to approval to rule out an upper 95 % confidence interval (95 % CI) for HR of 1.8 for CV events, followed by ruling out an upper 95 % CI for HR of 1.3 in the post-approval period. To date, novel diabetes therapies including peroxisome proliferator-activated receptor (PPAR) gamma agonists, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP 1) analogs, and sodium-glucose transporter-2 (SGL2) inhibitors have been evaluated in CV safety trials. Results from the first major CV outcome studies in type 2 diabetes, SAVOR-TIMI 53 and EXAMINE, have shown that neither saxagliptin nor alogliptin had increases in major CV events relative to placebo in high-risk patients. Ongoing and future trials will elucidate the CV safety for other DPP-4 inhibitors compared to SUs and the GLP-1 agonists versus placebo.     

Cryptococcosis masquerading as a tuboovarian abscess.

This report describes a 25-year-old human immunodeficiency virus- seropositive patient who initially presented with clinical features of a tuboovarian abscess. After a poor response to antibiotic therapy, laparotomy and excision of a right-sided, unilocular, pseudocystic ovarian mass measuring 140 x 80 x 60 mm were undertaken. Mucoid gelatinous material, with a glistening appearance and slimy consistency, coated the inner surface of the thick wall. The cyst contained clear, viscid fluid with a similar slimy consistency. Although the macroscopic diagnosis was that of an ovarian mucinous cystadenocarcinoma, histopathologic assessment confirmed a well-circumscribed pseudocystic cryptococcoma with a wall of granulation and fibrous tissue and compressed ovarian stroma. The inner surface was covered by large, paucireactive, extracellular "yeast lakes" of carminophilous Cryptococcus neoformans yeasts of varying shape and size. To the best of our knowledge, this is the first documentation of ovarian cryptococcosis in the English language literature. Despite their rarity in the female genital tract, fungal infections must be considered in the differential diagnosis of patients presenting with pelvic pain of obscure origin and a pelvic mass that is refractory to antibiotic therapy.     

Magnetic resonance cerebral metabolic rate of oxygen utilization in hyperacute stroke patients

The purpose of this study was to explore the feasibility of obtaining magnetic resonance-measured cerebral metabolic rate of oxygen utilization (MR-CMRO(2)) in acute ischemic stroke patients. Seven stroke patients were serially imaged: 4.5 +/- 0.9 hours (tp1), 3 to 5 days (tp2), and 1 to 3 months (tp3) after symptom onset. Diffusion-weighted, perfusion-weighted, and multiecho gradient-echo/spin-echo images were acquired; cerebral blood flow and oxygen extraction fraction maps were obtained from which CMRO(2) was calculated as the product of cerebral blood flow and oxygen extraction fraction. The final infarct lesions obtained from tp3 T2-weighted images and the "penumbra" obtained from the tp1 perfusion-weighted image-defined lesion were coregistered onto tp1 CMRO(2) maps. CMRO(2) values in the region of brain that eventually infarcted were reduced to 0.40 +/- 0.24 of the respective region on the contralateral hemisphere. The "salvaged penumbra" defined by the area of mismatch between the final infarct and the tp1 perfusion-weighted lesion demonstrated an average CMRO(2) value of 0.55 +/- 0.11 of the contralateral hemisphere. Although our results are preliminary and require further evaluation, the ability to obtain in vivo measurements of MR-CMRO(2) noninvasively potentially can provide information for determining brain tissue viability in acute ischemic stroke patients.     

Isotopic effect study of propofol deuteration on the metabolism,activity, and toxicity of the anesthetic

The use of isotopic substitution to delay the oxidative metabolism of the anesthetic propofol 1 was studied. The aromatic hydrogens of propofol 1 were replaced by deuterium to produce the mono- and trideuterated derivatives 4 and 5. In vitro metabolic studies on human hepatic microsomes showed no isotopic effect in the para hydroxylation of propofol, and 1, 4, and 5 display similar hypnotic activity and toxicity in mice.     

Fibroblast migration on fibronectin requires three distinct functional domains

Mesenchymal cell movement is normally constrained; however, fibronectin can provide a pathway for stromal cell migration during embryogenesis, morphogenesis, and wound healing. Cells can adhere to fibronectin via integrin and nonintegrin receptors, which bind multiple unique peptide sequences. Synthetic peptides and recombinant proteins were used to delineate the functional domains needed for human fibroblast migration over fibronectin. The 9th and 10th fibronectin type III repeats, which contain RGD and PHSRN synergy cell attachment sequences, support almost maximal fibroblast attachment, but not migration of primary dermal fibroblasts. Specific sequences within the heparin domain and the IIICS region are also required for migration. These findings predict and additional data confirm the necessity for the cooperation of multiple integrin and nonintegrin receptors for fibroblast migration on fibronectin. Such stringency of migration most likely imposes an immense constraint on normal mesenchymal cell mobility in unperturbed tissue. Loss of such restraint may be critical for the migration cancer cells through the extracellular matrix.