Morpholine As a Scaffold in Medicinal Chemistry: An Update on Synthetic Strategies.

Morpholine is a frequently used heterocycle in medicinal chemistry and a privileged structural component of bioactive molecules. This is mainly due to its contribution to a plethora of biological activities as well as to an improved pharmacokinetic profile of such bioactive molecules. The synthesis of morpholines is a subject of much study due to their biological and pharmacological importance, with the last such review being published in 2013. Here, an overview of the main approaches toward morpholine synthesis or functionalization is presented, emphasizing on novel work which has not been reviewed so far. This review is an update on synthetic strategies leading to easily accessible libraries of bioactives which are of interest for drug discovery projects.

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules.

Morpholine is a heterocycle featured in numerous approved and experimental drugs as well as bioactive molecules. It is often employed in the field of medicinal chemistry for its advantageous physicochemical, biological, and metabolic properties, as well as its facile synthetic routes. The morpholine ring is a versatile and readily accessible synthetic building block, it is easily introduced as an amine reagent or can be built according to a variety of available synthetic methodologies. This versatile scaffold, appropriately substituted, possesses a wide range of biological activities. There are many examples of molecular targets of morpholine bioactive in which the significant contribution of the morpholine moiety has been demonstrated; it is an integral component of the pharmacophore for certain enzyme active-site inhibitors whereas it bestows selective affinity for a wide range of receptors. A large body of in vivo studies has demonstrated morpholine's potential to not only increase potency but also provide compounds with desirable drug-like properties and improved pharamacokinetics. In this review we describe the medicinal chemistry/pharmacological activity of morpholine derivatives on various therapeutically related molecular targets, attempting to highlight the importance of the morpholine ring in drug design and development as well as to justify its classification as a privileged structure.

Molecular tools that block maturation of the nuclear lamin A and decelerate cancer cell migration.

Lamin A contributes to the structure of nuclei in all mammalian cells and plays an important role in cell division and migration. Mature lamin A is derived from a farnesylated precursor protein, known as prelamin A, which undergoes post-translational cleavage catalyzed by the zinc metalloprotease STE24 (ZPMSTE24). Accumulation of farnesylated prelamin A in the nuclear envelope compromises cell division, impairs mitosis and induces an increased expression of inflammatory gene products. ZMPSTE24 has been proposed as a potential therapeutic target in oncology. A library of peptidomimetic compounds were synthesized and screened for their ability to induce accumulation of prelamin A in cancer cells and block cell migration in pancreatic ductal adenocarcinoma cells. The results of this study suggest that inhibitors of lamin A maturation may interfere with cell migration, the biological process required for cancer metastasis.

Chylous Ascites Following Open Abdominal Aortic Aneurysm Repair: An Unusual Complication.

Chylous ascites is a rare complication after abdominal aortic aneurysm repair. Accumulation of chyle within the close space of the peritoneal cavity may cause severe discomfort to the patient, complicating the postoperative course. Prompt diagnosis is needed to adopt measures for reducing lymph leakage and contributing to lymphatic fistula closure. Fortunately, conservative treatment is successful in the majority of cases. In the rare cases that do not respond to conservative treatment, surgery becomes mandatory. Accurate preoperative localization of lymph leakage is a prerequisite for a successful outcome. Postoperative chyloperitoneum has a benign course and an excellent prognosis.

Discovery of HIV Type†1 Aspartic Protease Hit Compounds through Combined Computational Approaches.

A combination of computational techniques and inhibition assay experiments was employed to identify hit compounds from commercial libraries with enhanced inhibitory potency against HIV type 1 aspartic protease (HIV PR). Extensive virtual screening with the aid of reliable pharmacophore models yielded five candidate protease inhibitors. Subsequent molecular dynamics and molecular mechanics Poisson-Boltzmann surface area free-energy calculations for the five ligand-HIV PR complexes suggested a high stability of the systems through hydrogen-bond interactions between the ligands and the protease's flaps (Ile50/50'), as well as interactions with residues of the active site (Asp25/25'/29/29'/30/30'). Binding-energy calculations for the three most promising compounds yielded values between -5 and -10 kcal mol(-1) and suggested that van der Waals interactions contribute most favorably to the total energy. The predicted binding-energy values were verified by in vitro inhibition assays, which showed promising results in the high nanomolar range. These results provide structural considerations that may guide further hit-to-lead optimization toward improved anti-HIV drugs.

Endovascular repair of blunt axillo-subclavian arterial injuries as the first line treatment.

AIM: To report and analyse our results regarding the endovascular management of blunt axillo-subclavian arterial injuries as the first line treatment. METHODS: During an eight-year period, seven patients (mean age 56.4±14.1 years, all males) with blunt traumatic axillo-subclavian arterial injuries were presented to the emergency department. All patients suffered also from concomitant other injuries and had a supraclavicular haematoma along with diminished or absent upper limb peripheral pulses, while computed tomography angiography set the diagnosis. RESULTS: The endovascular procedure was technically successful in all patients. No procedure-related complication was encountered during the in-hospital stay, while none of the patients died. The median hospital stay was 22 days (range 12-46). During a follow-up period spanning an average of 27 months (range 6-44 months) there was one stent-graft thrombosis at 12 months in an otherwise asymptomatic patient that required no further intervention. CONCLUSION: Endovascular technique seems to constitute a reliable approach for treating blunt axillo-subclavian arterial injuries in the emergent setting. Despite uncertainties in patient selection and optimal management algorithms, it seems that endovascular approach could be the first line treatment for such injuries. Accumulation of data on larger number of patients with longer follow-up is warranted to further define the value of this therapeutic modality in the trauma setting.

Morbidity and outcomes of foreign travelers in Zakynthos island, Greece: a retrospective study.

BACKGROUND: Although there is satisfactory recording of diseases affecting travelers visiting developing countries, little is known regarding morbidity of travelers when visiting developed countries. We sought to evaluate the morbidity of foreign travelers in Zakynthos, a popular Greek island attracting large number of foreign tourists every summer. METHODS: Data from foreign travelers that accommodated in Zakynthos and sought medical services from the private offices of Zante Medical Care from May 1 to October 30 2012 were retrospectively analyzed. RESULTS: Two thousand six hundred and eighty-eight patients were included in the study. The mean age (± SD) of the patients whom the age was recorded was 29.6 (± 18.3) and 51.5% of them were from 18 to 40 years old. Disorders of the respiratory tract (32.7%), dermatologic conditions (21.1%), musculoskeletal injuries (16.4%), and gastrointestinal disorders (16.3%) were the four most prevalent clinical categories among patients. Ear disorder was the most common syndromic description (14.5%) among which 81.2% were ear infections; otitis externa and otitis media were diagnosed in 8.5% and 3.3% patients in total. The most common specific diagnosis was gastroenteritis (14.3%). Insect bite and sunburn were the most common diagnosis (6.5% and 3.8%, respectively) among patients with a dermatologic condition. Ear infection was the most common diagnosis in pediatric patients. CONCLUSION: Disorders mainly of the upper respiratory tract were the predominant causes of illness among foreign travelers in Zakynthos. Traveler's diarrhea was the most common specific diagnosis but the prevalence within the total population was not very high.

Endovascular treatment of isolated iliac artery aneurysms with anaconda stent graft limb.

Isolated aneurysms of the iliac arteries are relatively rare conditions that traditionally have been treated by surgical reconstruction. We report our experience with endovascular treatment of iliac artery aneurysms (IAAs) with Anaconda stent graft limb. Two male patients were found to have 4.5 and 3.6 cm isolated common IAAs, respectively. The endograft was successfully advanced and deployed precisely to the intended position in both cases. In one case the internal iliac artery was embolized. No type I or II endoleak was observed immediately after the procedure. In one patient postimplantation fever (>38°C) and gluteal claudication occurred. After 2 years followup both iliac endovascular stent grafts are patent and without endoleak. Endovascular treatment with Anaconda limb stent graft seems to be a safe and feasible alternative to open surgery.

Endovascular management of an arteriovenous malformation using an occluder stent graft.

A 58-year-old woman presented with gangrene of the left upper arm stump caused by an arteriovenous malformation originating from the subclavian artery. She had been treated unsuccessfully in the past with repeated attempts of coil embolization and débridement, but finally she underwent arm amputation. A 14 mm diameter occlusion self-expandable stent was placed in the left subclavian artery via ipsilateral brachial artery access, with immediate and complete interruption of arterial supply to the vascular malformation. This minimally invasive treatment provides an alternative method of management of arteriovenous malformations in the subclavian region.

Hybrid management of a false aneurysm complicating an arteriovenous graft in a patient with critical limb ischemia.

End-stage renal diabetic patients undergoing dialysis through an arteriovenous graft (AVG) often present with multiple graft complications which demand a combined therapeutic approach. We report a case of a male suffering from a pseudoaneurysm and venous outflow stenosis of his thigh AVG, as well as from critical limb ischemia caused by multiple significant stenoses of the femoropopliteal arterial segment. The patient was managed in a single session with a combination of classic open surgical and endovascular techniques in order to treat his aneurysm, salvage the AVG and to revascularize his leg. This case illustrates the prospect of combining classic open surgical and endovascular techniques for the optimal management of complicated AVGs. Using the hybrid approach in these cases one can succeed in optimizing the result, while simultaneously minimizing the overall risk for the patient.

Endovascular repair for thoracic aortic disease: tertiary single-center experience in northwestern Greece.

The purpose of this article is to report the initial experience with endovascular repair of thoracic aortic disease in a single tertiary vascular unit in northwestern Greece. Between 2003 and 2005, 16 patients were treated with endovascular techniques for various pathologies of the descending thoracic aorta. Twelve patients were treated electively and four emergently. Operative and follow-up data for a mean time of 18.4 months were retrospectively collected and analyzed. Primary technical success was obtained in 14 (87.5%) cases. No early or late deaths occurred, and there was no major operation-related complication. No paraplegia was observed in our patients. Stent graft-related complications occurred in 18.75% (one type 2 and two type 3 endoleaks), but they all had a favorable outcome. No further problems have been reported in any of our patients. Endovascular stent graft repair for diseases of the thoracic aorta seems to be a promising alternative to open surgery, especially for high-risk patients. Long-term results are needed to confirm the early benefit of this treatment option with regard to morbidity and mortality rates. The potential of this technique to be applicable even in relatively small, tertiary vascular centers might be of great benefit to patients.