Regio- and stereoselective microwave-assisted synthesis of 5-alkyl-4-alkenyl-4-phenyl-1,3-oxazolidin-2-ones

Chiral symmetrical alk-2-yne-1,4-diols have been stereoselectively transformed into 5-alkyl-4-alkenyl-4-phenyl-1,3-oxazolidin- 2-ones, which are precursors of quaternary α-amino β-hydroxy acids. The key step was the cyclization of the bis(tosylcarbamates) of 2- phenylalk-2-yne-1,4-diols, easily obtained from the starting chiral diols. These cyclizations were accomplished with complete regioselectivity and up to 92:8 dr in the presence of catalytic amounts of Ni(0) or Pd (II) derivatives under microwave heating.

Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma.

BACKGROUND: Immune checkpoint inhibitors targeting programmed cell death 1 (PD1) or its ligand (PD-L1) showed activity in several cancer types. METHODS: We performed immunohistochemistry for CD3, CD8, CD20, HLA-DR, phosphatase and tensin homolog (PTEN), PD-1, and PD-L1 and pyrosequencing for assessment of the O6-methylguanine-methyltransferase (MGMT) promoter methylation status in 135 glioblastoma specimens (117 initial resection, 18 first local recurrence). PD-L1 gene expression was analyzed in 446 cases from The Cancer Genome Atlas. RESULTS: Diffuse/fibrillary PD-L1 expression of variable extent, with or without interspersed epithelioid tumor cells with membranous PD-L1 expression, was observed in 103 of 117 (88.0%) newly diagnosed and 13 of 18 (72.2%) recurrent glioblastoma specimens. Sparse-to-moderate density of tumor-infiltrating lymphocytes (TILs) was found in 85 of 117 (72.6%) specimens (CD3+ 78/117, 66.7%; CD8+ 52/117, 44.4%; CD20+ 27/117, 23.1%; PD1+ 34/117, 29.1%). PD1+ TIL density correlated positively with CD3+ (P < .001), CD8+ (P < .001), CD20+ TIL density (P < .001), and PTEN expression (P = .035). Enrichment of specimens with low PD-L1 gene expression levels was observed in the proneural and G-CIMP glioblastoma subtypes and in specimens with high PD-L1 gene expression in the mesenchymal subtype (P = 5.966e-10). No significant differences in PD-L1 expression or TIL density between initial and recurrent glioblastoma specimens or correlation of PD-L1 expression or TIL density with patient age or outcome were evident. CONCLUSION: TILs and PD-L1 expression are detectable in the majority of glioblastoma samples but are not related to outcome. Because the target is present, a clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastoma.

Fetal laser therapy: applications in the management of fetal pathologies.

Fetoscopic coagulation of placental anastomoses is the treatment of choice for severe twin-to-twin transfusion syndrome. In the present day, fetal laser therapy is also used to treat amniotic bands, chorioangiomas, sacrococcygeal teratomas, lower urinary tract obstructions and chest masses, all of which will be reviewed in this article. Amniotic band syndrome can cause limb amputation by impairing downstream blood flow. Large chorioangiomas (>4 cm), sacrococcygeal teratomas or fetal hyperechoic lung lesions can lead to fetal compromise and hydrops by vascular steal phenomenon or compression. Renal damage, bladder dysfunction and lastly death because of pulmonary hypolasia may be the result of megacystis caused by a posterior urethral valve. The prognosis of these pathologies can be dismal, and therapy options are limited, which has brought fetal laser therapy to the forefront. Management options discussed here are laser release of amniotic bands, laser coagulation of the placental or fetal tumor feeding vessels and laser therapy by fetal cystoscopy. This review, largely based on case reports, does not intend to provide a level of evidence supporting laser therapy over other treatment options. Centralized evaluation by specialists using strict selection criteria and long-term follow-up of these rare cases are now needed to prove the value of endoscopic or ultrasound-guided laser therapy.

Occurrence of the "applause sign" in patients with amyotrophic lateral sclerosis.

The applause sign was originally described as a quick bedside test to discriminate progressive supranuclear palsy (PSP) (positive applause sign, PAS) from Parkinson's disease (PD) and frontotemporal dementia (FTD) (negative applause sign). However, recent research demonstrated that the test is positive not only in a subset of patients with PD and FTD, but also in other neurodegenerative diseases. We tested 22 patients with amyotrophic lateral sclerosis (ALS) together with 22 healthy sex- and age-matched controls for the occurrence of PAS. Furthermore, we performed neuropsychological testing with the EXIT-25 battery to correlate PAS with neuropsychological deficits, especially frontal lobe dysfunction. Five ALS patients (23%) and none of the controls displayed PAS (p≤0.05). The occurrence of PAS in ALS patients was not correlated with pathologic EXIT-25 scores or subtests for aberrant motor behaviour. We describe for the first time the occurrence of the applause sign in ALS and provide additional evidence that PAS is not specific for Parkinsonian disorders. Although its occurrence has been related to aberrant motor behaviour due to frontal involvement, in our study PAS did not correlate with executive dysfunction as tested by the EXIT-25 test battery, or with subtests of aberrant motor behaviour.

Análisis de la Fisioterapia Domiciliaria Versus la Fisioterapia Ambulatoria en las zonas básicas de salud de Burgete, Salazar e Isaba de Navarra.

Introducción: La población de Navarra tiene una tendencia hacia una población más anciana y con un aumento de patologías crónicas. Esto hace que aumente el número de discapacitados y como consecuencia incremente la demanda asistencial tanto de cuidadores como de profesionales y aumente el gasto sanitario. Por estos motivos el servicio de fisioterapia a domicilio puede ser una buena alternativa de trabajo, ya que con este servicio ayudaremos a disminuir la carga asistencial de los cuidadores, ayudándoles a manejar la situación, disminuiremos la carga asistencial de los profesionales y los gastos sanitario evitando reingresos. A su vez el realizar el tratamiento de Fisioterapia en el domicilio del paciente, es decir en su entorno, mejorara la adherencia al tratamiento y, por lo tanto, su implicación en alcanzar los objetivos terapéuticos planteados. Hipótesis: la fisioterapia domiciliaria (FD) mejora los resultados del tratamiento, la calidad de vida de los pacientes y cuidadores y estos resultados son similares o mejores en comparación con la rehabilitación ambulatoria y hospitalaria en los pacientes con accidente cerebrovascular (ICTUS), prótesis de cadera (PD) y prótesis de rodilla (PR) y con enfermedad pulmonar obstructiva crónica (EPOC). Los objetivos planteados son los siguientes: Objetivo principal: valorar si es factible introducir la rehabilitación domiciliaria en Navarra. Objetivos secundarios: a) Valorar si la FD mejora más la calidad de vida de los pacientes comparando con la rehabilitación en el Hospital Virgen del Camino (HVC) y de la Clínica Ubarmin de Navarra (CU). b) Comprobar si se reducirían costes sanitarios con el Programa Piloto de Fisioterapia Domiciliaria. c) Evaluar la carga del cuidador. d) Comprobar el número de reingresos hospitalarios realizando la Fisioterapia Domiciliaria. e) Valorar la autonomía en la capacidad de realizar las actividades básicas de la vida diaria (AVBD) con la FD en comparación con la rehabilitación en el HVC y la CU. f) Valorar si los pacientes con ICTUS consiguen mejores resultados cognitivos realizando la FD en vez de la rehabilitación en el HVC y la CU. g) Estimar si los pacientes con ICTUS y con PD o PR consiguen un mejor equilibrio y autonomía para realizar la marcha, cambiando el lugar de tratamiento del HVC y la CU a su domicilio. h) Valorar si el realizar la FD hace que los pacientes con EPOC disminuyan en el índice de BODE en comparación con los que realizan la rehabilitación en el HVC y la CU. i) Comparar la media de sesiones al alta del Proceso de Atención en Fisioterapia. Metodología: el estudio de investigación implica la confección de dos grupos donde el grupo control llevará a cabo un tratamiento de fisioterapia ambulatoria u hospitalaria, mientras que el grupo experimental hará tratamiento en ámbito domiciliario. La evaluación se llevará a cabo mediante diferentes escalas validadas, (Barthel, Tinetti, Minni mental test, índice de BODE, Escala de Sobrecarga del Cuidador de Zarit y SF-36) al inicio del estudio, a los 15 días, al mes, a los 3 meses y a los 6 meses. El lugar de estudio serán las zonas básicas de salud de Burguete, Salazar e Isaba. Criterios de inclusión: pacientes con ICTUS, PD y PR o con EPOC, mayores de 65 años, independientemente del sexo. Limitación para desplazarse a un centro de salud y un buen soporte socio-familiar. Criterios de exclusión: afectación cognitiva, enfermedades o complicaciones que impida la realización de la FD. Pacientes con EPOC, fumadores y con peligro de broncoespasmo. Falta de colaboración por parte del paciente. Análisis estadístico: Para el análisis estadístico se utilizara el programa estadístico SPSS (versión 20). Para obtener las conclusiones se realizaran las relaciones oportunas entre las diferentes variables explicadas anteriormente. En el caso de la relación entre variables cuantitativas se utilizará el coeficiente de correlación lineal de Pearson. En la relación entre variables cualitativas el Test chi-cuadrado de Pearson. Por último en la relación entre diferentes modalidades de variables se hará la comparación de medias, Z t-test o t- test.

Anxiety, depression, and attachment before and after the first-trimester screening for Down syndrome: comparing couples who undergo ART with those who conceive spontaneously.

OBJECTIVES: This study's aim was to describe the emotional status of parents to be before and after the first-trimester combined prenatal screening test. METHODS: One hundred three couples participated, of which 52 had undergone an in vitro fertilization/intracytoplasmic sperm injection treatment [assisted reproductive technology (ART)] and 51 had conceived spontaneously. Participants completed the state scale of the State-trait Anxiety Inventory, the Edinburgh Depression Scale, and the Maternal and Paternal Antenatal Attachment Questionnaire before the first-trimester combined prenatal screening test at around 12 weeks of gestational age (T1) and just after receiving the results at approximately 14 weeks of gestational age (T2). RESULTS: We observed a significant decrease in anxiety and depression symptoms and a significant increase in attachment from T1 to T2. Results showed no differences between groups at either time point, which suggests that ART parents are more similar to than different from parents conceiving spontaneously. Furthermore, given the importance of anxiety during pregnancy, a subsample of women with clinical anxiety was identified. They had significantly higher rates of clinical depression and lower attachment. CONCLUSIONS: These results indicate that, regardless of whether conception was through ART or spontaneous, clinical anxiety in women over the prenatal testing period is associated with more vulnerability during pregnancy (i.e. clinical depression and less attachment to fetus). © 2015 John Wiley & Sons, Ltd.

Future perspectives in melanoma research: meeting report from the "Melanoma Bridge": Napoli, December 3rd-6th 2014.

The fourth "Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma.

Effect of Antecolic versus Retrocolic Gastroenteric Reconstruction after Pancreaticoduodenectomy on Delayed Gastric Emptying: A Meta-Analysis of Six Randomized Controlled Trials.

BACKGROUND: One of the most frequent complications of pancreaticoduodenectomy (PD) is delayed gastric emptying (DGE). The study aim was to evaluate the impact of the type of gastro/duodenojejunal reconstruction (antecolic vs. retrocolic) after PD on DGE incidence. METHODS: A systematic review was made according to the PRISMA guidelines. Randomized controlled trials (RCTs) comparing antecolic vs. retrocolic reconstruction were included irrespective of the PD techniques. A meta-analysis was then performed. RESULTS: Six RCTs were included for a total of 588 patients. The overall quality was good. General risk of bias was low. DGE was not statistically significantly different between the antecolic and retrocolic group (OR 0.6, 95% CI 0.31-1.16, p = 0.13). The other main surgery-related complications (pancreatic fistula, hemorrhage, intra-abdominal abscess, bile leak and wound infection) were not dependent on the reconstruction route (OR 0.84, 95% CI 0.41-1.70, p = 0.63). No statistically significant difference in terms of length of hospital stay was found between the 2 groups. There was also no difference of DGE incidence if only pylorus-preserving PD was considered and between the DGE grades A, B or C. CONCLUSION: This meta-analysis shows that antecolic reconstruction after PD is not superior to retrocolic reconstruction in terms of DGE.

Randomised, multicentre, phase III, open-label study of alectinib vs crizotinib in treatment-naïve anaplastic lymphoma kinase (ALK)-positive advanced NSCLC (ALEX study).

Background: In ∼5% of advanced NSCLC tumours, ALK tyrosine kinase is constitutively activated after translocation of ALK. ALK+ NSCLC was shown to be highly sensitive to the first approved ALK inhibitor, crizotinib. However, all pts eventually relapse on crizotinib mainly due to secondary ALK mutations/amplification or CNS metastases. Alectinib is a highly selective, potent, oral next-generation ALK inhibitor. Clinical phase II alectinib data in 46 crizotinib-naïve pts with ALK+ NSCLC reported an objective response rate (ORR) of 93.5% and a 1-year progression-free rate of 83% (95% CI: 68-92) (Inoue et al. J Thorac Oncol 2013). CNS activity was seen: of 14 pts with baseline brain metastasis, 11 had prior CNS radiation, 9 of these experienced CNS and systemic PFS of >12 months; of the 3 pts without prior CNS radiation, 2 were >15 months progression free. Trial design: Randomised, multicentre, phase III, open-label study in pts with treatment-naïve ALK+ advanced, recurrent, or metastatic NSCLC. All pts must provide pretreatment tumour tissue to confirm ALK rearrangement (by IHC). Pts (∼286 from ∼180 centres, ∼30 countries worldwide) will be randomised to alectinib (600mg oral bid, with food) or crizotinib (250mg oral bid, with/without food) until disease progression (PD), unacceptable toxicity, withdrawal of consent, or death. Stratification factors are: ECOG PS (0/1 vs 2), race (Asian vs non-Asian), baseline CNS metastases (yes vs no). Primary endpoint: PFS by investigators (RECIST v1.1). Secondary endpoints: PFS by Independent Review Committee (IRC); ORR; duration of response; OS; safety; pharmacokinetics; quality of life. Additionally, time to CNS progression will be evaluated (MRI) for the first time in a prospective randomised NSCLC trial as a secondary endpoint. Pts with isolated asymptomatic CNS progression will be allowed to continue treatment beyond documented progression until systemic PD and/or symptomatic CNS progression, according to investigator opinion. Time to CNS progression will be retrospectively assessed by the IRC using two separate criteria, RECIST and RANO. Further details: ClinicalTrials.gov (NCT02075840). Disclosure: T.S.K. Mok: Advisory boards: AZ, Roche, Eli Lilly, Merck Serono, Eisai, BMS, AVEO, Pfizer, Taiho, Boehringer Ingelheim, Novartis, GSK Biologicals, Clovis Oncology, Amgen, Janssen, BioMarin; board of directors: IASLC; corporate sponsored research: AZ; M. Perol: Advisory boards: Roche; S.I. Ou: Consulting: Pfizer, Chugai, Genentech Speaker Bureau: Pfizer, Genentech, Boehringer Ingelheim; I. Bara: Employee: F. Hoffmann-La Roche Ltd; V. Henschel: Employee and stock: F. Hoffmann-La Roche Ltd.; D.R. Camidge: Honoraria: Roche/Genentech. All other authors have declared no conflicts of interest.

Prospective evaluation of circulating VEGF in patients with advanced non-small cell lung cancer treated with bevacizumab, pemetrexed and cisplatin in the trial SAKK19/09.

Aim: Bevacizumab is a monoclonal antibody directed against the vascular endothelial growth factor (VEGF). The previous phase II trial ABIGAIL (Reck, 2010) suggested circulating VEGF as a prognostic, but not predictive, biomarker for patients (pts) with non-small cell lung cancer (NSCLC) treated with bevacizumab. We prospectively measured VEGF in the multicenter phase II trial SAKK19/09 (NCT01116219). Methods: SAKK19/09 enrolled 77 evaluable patients (pts) with previously untreated, advanced nonsquamous NSCLC and EGFR wild type. Pts received 4 cycles of cisplatin 75mg/m2 (or carboplatin AUC5), pemetrexed 500mg/m2 and bevacizumab 7.5mg/kg, followed by maintenance therapy with pemetrexed and bevacizumab until progression by RECIST1.1. Follow-up CT scans were performed every 6 weeks until week 54 and every 12 weeks thereafter. Baseline EDTA blood samples were sent by same-day courier to the central laboratory for centrifugation, aliquoting, and freezing. Upon completion of enrollment, aliquots were thawed, and VEGF quantification was performed centrally using Luminex® Performance Assay Human Base Kit A (R&D Systems, Abingdon, UK). The mean value was used to stratify pts into two groups (low versus high VEGF). Best response rate assessed by RECIST1.1 (CR + PR versus SD + PD). Results: Clinical results of the SAKK19/09 trial were reported previously (Gautschi, 2013). Baseline plasma VEGF was detectable in 71 of 77 (92%) evaluable patients treated with chemotherapy and bevacizumab. The mean value was 74.9 pg/ml, the median 47.5 pg/ml, and the range 3.55 to 310 pg/ml. Using the mean as a predefined cutoff value, 50 patients had low VEGF levels and 21 patients had high VEGF levels. High VEGF was significantly associated with shorter PFS (4.1 vs 8.3 months, HR = 2.56; 95%CI: 1.43- 4.57; p = 0.0015) and OS (8.7 vs 17.5 months, HR = 2.67; 95% CI: 1.37-5.20; p = 0.0041), but not with best response rate ( p = 0.2256). Conclusions: Consistent with the ABIGAIL trial, circulating VEGF was prognostic, but not predictive for response, in the current trial. Further work is ongoing to identify potentially predictive biomarkers for bevacizumab, using comprehensive proteomic analyses. Disclosure: S.I. Rothschild: I received honoraria for the participation in advisory boards from Eli Lilly and Roche and for presentations at scientific symposiums sponsored by Roche; O. Gautschi: Honoraria for advisory boards of Eli Lilly and Roche; R. Cathomas: Advisory board member: Eli Lilly. All other authors have declared no conflicts of interest.

Long-term controlled GDNF over-expression reduces dopamine transporter activity without affecting tyrosine hydroxylase expression in the rat mesostriatal system.

The dopamine (DA) transporter (DAT) is a plasma membrane glycoprotein expressed in dopaminergic (DA-) cells that takes back DA into presynaptic neurons after its release. DAT dysfunction has been involved in different neuro-psychiatric disorders including Parkinson's disease (PD). On the other hand, numerous studies support that the glial cell line-derived neurotrophic factor (GDNF) has a protective effect on DA-cells. However, studies in rodents show that prolonged GDNF over-expression may cause a tyrosine hydroxylase (TH, the limiting enzyme in DA synthesis) decline. The evidence of TH down-regulation suggests that another player in DA handling, DAT, may also be regulated by prolonged GDNF over-expression, and the possibility that this effect is induced at GDNF expression levels lower than those inducing TH down-regulation. This issue was investigated here using intrastriatal injections of a tetracycline-inducible adeno-associated viral vector expressing human GDNF cDNA (AAV-tetON-GDNF) in rats, and doxycycline (DOX; 0.01, 0.03, 0.5 and 3mg/ml) in the drinking water during 5weeks. We found that 3mg/ml DOX promotes an increase in striatal GDNF expression of 12× basal GDNF levels and both DA uptake decrease and TH down-regulation in its native and Ser40 phosphorylated forms. However, 0.5mg/ml DOX promotes a GDNF expression increase of 3× basal GDNF levels with DA uptake decrease but not TH down-regulation. The use of western-blot under non-reducing conditions, co-immunoprecipitation and in situ proximity ligation assay revealed that the DA uptake decrease is associated with the formation of DAT dimers and an increase in DAT-α-synuclein interactions, without changes in total DAT levels or its compartmental distribution. In conclusion, at appropriate GDNF transduction levels, DA uptake is regulated through DAT protein-protein interactions without interfering with DA synthesis.

Síntese e caracterização estrutural de complexos mono e bimetálicos de paládio e platina com ligantes contendo nitrogênio e enxofre

The synthesis of several mono- and bimetallic platinum and palladium complexes are reported. The monometallic complexes are of the type MCl2(PEt3)2L (L=2-aminothiazol; benzothiazol; 2-imidazolidithione; M=Pt; Pd), and the bimetallic complexes (M2Cl4(PEt3) 2L) are derived from them. Infrared spectroscopic characterization of the monometallic complexes shows that the metal centre are coordinated through the N-endocyclic (L=2-aminothiazol; benzothiazol) and through the sulphur when L=2-imidazolidithione. Coordination of a second metal fragment occurs via the sulphur atom (L=2-aminothiazol; benzothiazol) according to infrared studies. 31P{¹H} NMR spectroscopy suggest that the complexes have a cis- configuration since the ¹J Pt-P are around the value found for this type of compound.

Synthesis, characterization and thermal decomposition of [Pd2 (C²-dmba) (µ-SO4) (SO2)2]

The bridged sulphate complex [Pd2 (C²,dmba) (µ-SO4) (SO2)2] has been obtained by reacting a saturated solution of SO2 in methanol and the cyclometallated compound [Pd(C²,N-dmba)(µ-N3)] 2; (dmba = N,N-dimethylbenzylamine), at room temperature for 24 h. Reaction product was characterized by elemental analysis, NMR comprising 13C{¹H} and ¹H nuclei and I.R. spectrum's measurements. Thermal behavior has been investigated and residual products identified by X-ray powder diffraction.

Synthesis and structure - Activity relationship study of potent cytotoxic analogues of the marine alkaloid Lamellarin D

The marine alkaloid, Lamellarin D (Lam-D), has shown potent cytotoxicity in numerous cancer cell lines, and was recently identified as a potent topoisomerase I inhibitor. A library of open lactone analogs of Lam-D was prepared from a methyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carboxylate scaffold (1) by introducing various aryl groups through sequential and regioselective bromination, followed by Pd(0)-catalyzed Suzuki cross-coupling chemistry. The compounds were obtained in a 24-44% overall yield, and tested in a panel of three human tumor cell lines, MDA-MB- 231 (breast), A-549 (lung), and HT-29 (colon), to evaluate their cytotoxic potential. From these data the SAR study concluded that more than 75% of the open-chain Lam-D analogs tested showed cytotoxicity in a low micromolar GI50 range.

Synthesis and structure - Activity relationship study of potent cytotoxic analogues of the marine alkaloid Lamellarin D

The marine alkaloid, Lamellarin D (Lam-D), has shown potent cytotoxicity in numerous cancer cell lines, and was recently identified as a potent topoisomerase I inhibitor. A library of open lactone analogs of Lam-D was prepared from a methyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carboxylate scaffold (1) by introducing various aryl groups through sequential and regioselective bromination, followed by Pd(0)-catalyzed Suzuki cross-coupling chemistry. The compounds were obtained in a 24-44% overall yield, and tested in a panel of three human tumor cell lines, MDA-MB- 231 (breast), A-549 (lung), and HT-29 (colon), to evaluate their cytotoxic potential. From these data the SAR study concluded that more than 75% of the open-chain Lam-D analogs tested showed cytotoxicity in a low micromolar GI50 range.