Synthesis and investigation of new cyclic molecules using the stilbene scaffold

A new approach to the synthesis of asymmetrical cyclic compounds using a stilbene scaffold has been developed. The use of boron trifluoride diethyl etherate as the catalyst, both with and without paraformaldehyde, allows us to obtain new substituted dioxanes, oxanes, cyclic compounds or dimer. The analysis of products was run using experimental and theoretical methods.

A new approach to the synthesis of asymmetrical cyclic compounds using a stilbene scaffold has been developed.

Various macrocycles have been widely investigated due to their interesting conformational characteristics and abundant host–guest properties. New macrocyclic receptors with high selectivity in molecular recognition are being looked for,¹ because they have many possible applications in the construction of diverse supramolecular systems.^2–15 In particular, various drug-delivery systems for tumours are being tested and looked at. Development of most solid tumours is strictly associated with the formation of their own functional vascular supply, the network of which is typically obtained in the process of angiogenesis from the host''s normal vascular system. The particular occurrence of tumour neo-vasculature is regarded as a well-fitting target for cancer cell annihilation. Two forms of vascular targeting agents (VTAs) can be distinguished. The first category concerns the substances that inhibit the angiogenesis process (they are referred to as the angiogenesis inhibitors, AIs). The second variant (referred to as the vascular disrupting agents, VDAs),¹⁶ are the compounds harmful to the already-established vessels. Combretastatins CA1P (OXi4503) and CA4P (a subtype of natural phenols) are new vascular disrupting and vascular targeting agents.¹⁶ They exhibit significant abilities of gastric tumour metastasis inhibition and of antitumor immune reactivity enhancement.¹⁷ These compounds additionally contain a notable characteristic of differentiated methoxy groups in the framework. Continuing our study concerning the synthesis and searching the biological activity of stilbenes¹⁸ and drug-delivery systems for tumours, we directed our attention to the new substituted dioxanes, oxanes, and cyclic compounds. We conducted studies on the reaction of substituted stilbenes and paraformaldehyde in the presence of a Lewis acid as the catalyst (BF₃·OEt₂) (​and2).2). The acid-catalyzed condensation of olefins with aldehydes, the Prins reaction, is generally used for the preparation of 1,3-dioxanes.¹⁹ The major products of the classical Prins reaction are normally 1,3-dioxanes, 1,3-glycols, or unsaturated alcohols depending on the reaction conditions¹⁹ (Fig. 1). The aza-Prins cyclization, which is the nitrogen version of the reaction, is of particular interest. The reaction permits rapid access to azaheterocycles and the wide applicability and usefulness of the aza-Prins reaction have been demonstrated by the synthesis of a variety of complex natural products.²⁰The compounds of (7–10) obtained from the reaction of suitable stilbene derivatives (1–4) with paraformaldehyde and BF₃·OEt₂ as the catalyst^a

High NaCl diet enhances arterial baroreceptor reflex in NaCl-sensitive spontaneously hypertensive rats

Previous studies from our laboratory have shown that arterial baroreceptor reflex control of lumbar sympathetic nerve activity is blunted in the NaCl-sensitive spontaneously hypertensive rat (SHR-S) compared with either the NaCl-resistant spontaneously hypertensive rat (SHR-R) or the normotensive Wistar-Kyoto (WKY) rat. In the current study, the effect of dietary NaCl supplementation on arterial baroreceptor reflex control of lumbar sympathetic nerve activity and heart rate was assessed in SHR-S and control SHR-R and WKY rats. Male SHR-S, SHR-R, and WKY rats were fed diets containing either 1% or 8% NaCl beginning at 7 weeks of age and were studied at age 9-10 weeks. Arterial baroreceptor reflex-mediated changes in lumbar sympathetic nerve activity and heart rate were recorded in conscious, unrestrained rats during phenylephrine-induced (15-40 micrograms/kg/min) and nitroprusside-induced (15-300 micrograms/kg/min) changes in mean arterial pressure. SHR-S maintained on a 1% NaCl diet had blunted baroreceptor reflex control of lumbar sympathetic nerve activity during acute increases in MAP compared with SHR-R and WKY rats (p less than 0.05). After ingestion of the 8% NaCl diet, this blunting was absent, indicating enhancement of baroreceptor reflex control of lumbar sympathetic nerve activity. SHR-S maintained on a 1% NaCl diet also had blunted arterial baroreceptor control of lumbar sympathetic nerve activity during nitroprusside-induced decreases in mean arterial pressure compared with WKY rats, but this was not significantly altered during ingestion of the 8% NaCl diet.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fabry disease: isolation of a cDNA clone encoding human alpha-galactosidase A.

Fabry disease is an X-linked inborn error of metabolism resulting from the deficient activity of the lysosomal hydrolase, alpha-galactosidase A (alpha-Gal A; alpha-D-galactoside galactohydrolase, EC 3.2.1.22). To investigate the structure, organization, and expression of alpha-Gal A, as well as the nature of mutations in Fabry disease, a clone encoding human alpha-Gal A was isolated from a lambda gt11 human liver cDNA expression library. To facilitate screening, an improved affinity purification procedure was used to obtain sufficient homogeneous enzyme for production of monospecific antibodies and for amino-terminal and peptide microsequencing. On the basis of an amino-terminal sequence of 24 residues, two sets of oligonucleotide mixtures were synthesized corresponding to adjacent, but not overlapping, amino acid sequences. In addition, an oligonucleotide mixture was synthesized based on a sequence derived from an alpha-Gal A internal tryptic peptide isolated by reversed-phase HPLC. Four positive clones were initially identified by antibody screening of 1.4 X 10(7) plaques. Of these, only one clone (designated lambda AG18) demonstrated both antibody binding specificity by competition studies using homogeneous enzyme and specific hybridization to synthetic oligonucleotide mixtures corresponding to amino-terminal and internal amino acid sequences. Nucleotide sequencing of the 5' end of the 1250-base-pair EcoRI insert of clone lambda AG18 revealed an exact correspondence between the predicted and known amino-terminal amino acid sequence. The insert of clone lambda AG18 appears to contain the full-length coding region of the processed, enzymatically active alpha-Gal A, as well as sequences coding for five amino acids of the amino-terminal propeptide, which is posttranslationally cleaved during enzyme maturation.     

Validity of plasma aldosterone-to-renin activity ratio in African American and white subjects with resistant hypertension

BACKGROUND: Recent reports suggesting that primary aldosteronism (PA) is more common than historically thought have often relied on use of the plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio (ARR) to identify patients with PA. Prior determinations of the validity of the ARR had been generally limited to subjects that could be withdrawn from antihypertensive therapy and to non-African American subjects. METHODS AND RESULTS: The current study was designed to evaluate prospectively the diagnostic value of the ARR in treated African American and white subjects with resistant hypertension. Consecutive subjects referred to a university hypertension clinic for resistant hypertension were evaluated with an early morning ARR and a 24-h urinary aldosterone and sodium. The presence of PA was defined as a suppressed PRA (<1.0 ng/mL/h) and elevated urinary aldosterone excretion (>12 microg/24 h) during high dietary sodium ingestion (>200 mEq/24 h). In 58 subjects, PA was confirmed. The ARR was elevated (>20) in 45 of 58 subjects with PA and in 35 of the 207 patients without PA, resulting in a sensitivity of 78% and specificity of 83% with a corresponding positive predictive value of 56% and a negative predictive value of 93%. Among African American subjects, the ARR was less sensitive than in white subjects (75% v 80%), but it still had a high negative predictive value (92% v 94%). CONCLUSIONS: These data indicate that the ARR is valid as a screening test for PA in African American and white patients on stable antihypertensive treatments, but a high percentage of false-positive results precludes using it for accurate diagnosis of PA.     

Barriers to Primary Care Physicians Prescribing Buprenorphine

PURPOSE

Despite the efficacy of buprenorphine-naloxone for the treatment of opioid use disorders, few physicians in Washington State use this clinical tool. To address the acute need for this service, a Rural Opioid Addiction Management Project trained 120 Washington physicians in 2010–2011 to use buprenorphine. We conducted this study to determine what proportion of those trained physicians began prescribing this treatment and identify barriers to incorporating this approach into outpatient practice.

METHODS

We interviewed 92 of 120 physicians (77%), obtaining demographic information, current prescribing status, clinic characteristics, and barriers to prescribing buprenorphine. Residents and 7 physicians who were prescribing buprenorphine at the time of the course were excluded from the study. We analyzed the responses of the 78 remaining respondents.

RESULTS

Almost all respondents reported positive attitudes toward buprenorphine, but only 22 (28%) reported prescribing buprenorphine. Most (95%, n = 21) new prescribers were family physicians. Physicians who prescribed buprenorphine were more likely to have partners who had received a waiver to prescribe buprenorphine. A lack of institutional support was associated with not prescribing the medication (P = .04). A lack of mental health and psychosocial support was the most frequently cited barrier by both those who prescribe and who do not prescribe buprenorphine.

CONCLUSION

Interventions before and after training are needed to increase the number of physicians who offer buprenorphine for treatment of addiction. Targeting physicians in clinics that agree in advance to institute services, coupled with technical assistance after they have completed their training, their clinical teams, and their administrations is likely to help more physicians become active providers of this highly effective outpatient treatment.