Bromurazione selettiva di idrossibenzilalcoli

Durante una nostra ricerca per la sintesi di benzofurani sostituiti è stato necessario adottare un metodo efficiente per la sintesi del 2-idrossibenzilbromuro: questo composto è molto instabile e i metodi di sintesi riportati in letteratura si sono rivelati inefficaci. Nel tentativo di effettuare la bromurazione usando reagenti che fossero efficaci in condizioni blande, è stato sviluppato un metodo di alogenazione, già utilizzato nei nostri laboratori che utilizza il complesso formato tra DMF e TCT

Antigene MYCN Silencing by BGA002 Inhibits SCLC Progression Blocking mTOR Pathway and Overcomes Multidrug Resistance

: Small-cell lung cancer (SCLC) is the most aggressive lung cancer type, and is associated with smoking, low survival rate due to high vascularization, metastasis and drug resistance. Alterations in MYC family members are biomarkers of poor prognosis for a large number of SCLC. In particular, MYCN alterations define SCLC cases with immunotherapy failure. MYCN has a highly restricted pattern of expression in normal cells and is an ideal target for cancer therapy but is undruggable by traditional approaches. We propose an innovative approach to MYCN inhibition by an MYCN-specific antigene-PNA oligonucleotide (BGA002)-as a new precision medicine for MYCN-related SCLC. We found that BGA002 profoundly and specifically inhibited MYCN expression in SCLC cells, leading to cell-growth inhibition and apoptosis, while also overcoming multidrug resistance. These effects are driven by mTOR pathway block in concomitance with autophagy reactivation, thus avoiding the side effects of targeting mTOR in healthy cells. Moreover, we identified an MYCN-related SCLC gene signature comprehending CNTFR, DLX5 and TNFAIP3, that was reverted by BGA002. Finally, systemic treatment with BGA002 significantly increased survival in MYCN-amplified SCLC mouse models, including in a multidrug-resistant model in which tumor vascularization was also eliminated. These findings warrant the clinical testing of BGA002 in MYCN-related SCLC

A Microwave assisted synthesis of benzoxazoles from carboxylic acids

A series of various poly-substituted benzoxazoles were synthesized starting from readily available carboxylic acids. The method is based on TCT (cyanuric chloride)/microwave acid activation and it is characterized by mild conditions, allowing for a wide range of starting materials and functionalization of final products

A Chemoselective, easy bromination of (hydroxymethyl)phenols

A simple and chemoselective method for direct bromination of (hydroxymethyl)phenols via reaction with 2,4,6-trichloro[1,3,5]triazine in N,N-dimethylformamide at room temperature is described. The reaction occurs without affecting the phenolic hydroxy group

A Facile approach to the synthesis of chiral 2-substituted benzofurans

An effective route to chiral optically active 2-substituted benzofurans directly from carboxylic acids is reported. This procedure, which allows the preparation of α-alkyl-2-benzofuranmethanamines from N-protected α-amino acids without sensible racemization phenomena, proceeds in good yields under mild conditions with the help of microwave irradiation

Synthesis of substituted benzofurans via microwave-enhanced catch and release strategy

A microwave-enhanced procedure for the synthesis of substituted benzofurans starting from 2-(1-hydroxyalkyl)-phenols and using triphenylphosphine polystirene resin is reported. The benzofurans are isolated in good to high yields and purities by simple workup. The procedure can be applied to chiral α-alkyl-2-benzofuranmethanamines too

Some recent approaches to the synthesis of 2-substituted benzofurans

In their structural multiplicity and in the extent to which they occur in nature the derivatives of benzofuran are significantly lesser than the isoelectronic analogue indoles. However, these heterocyclic compounds show a variety of pharmacological properties, and change of their structure offers a high degree of diversity that has proven useful for the search of new therapeutic agents. The broad spectrum of pharmacological activity in individual benzofurans indicates that this series of compounds is of an undoubted interest. From this point of view, synthetic methods may be of very useful aid in the production of specific structures characterized by given pharmacological qualities. Moreover from a drug discovery perspective, synthesis of chiral functionalized substituted benzofurans could be more interesting because they might constitute starting materials for the production of biologically active compounds. Taking into account the actual tendency directed toward the development of enantiomerically pure drugs, indeed there is a limited number of papers related to the preparation of enantiomers of benzofuran containing compounds, likely because of difficulties in their preparation with conventional methods. In this context, new approaches seem to expand the potentiality of the synthesis of substituted benzofurans, providing also convenient routes to enantiopure 2-substituted benzofurans

A Novel MYCN-Specific Antigene Oligonucleotide Deregulates Mitochondria and Inhibits Tumor Growth in MYCN-Amplified Neuroblastoma

Approximately half of high-risk neuroblastoma is characterized by MYCN amplification. N-Myc promotes tumor progression by inducing cell growth and inhibiting differentiation. MYCN has also been shown to play an active role in mitochondrial metabolism, but this relationship is not well understood. Although N-Myc is a known driver of the disease, it remains a target for which no therapeutic drug exists. Here, we evaluated a novel MYCN-specific antigene PNA oligonucleotide (BGA002) in MYCN-amplified (MNA) or MYCN-expressing neuroblastoma and investigated the mechanism of its antitumor activity. MYCN mRNA and cell viability were reduced in a broad set of neuroblastoma cell lines following BGA002 treatment. Furthermore, BGA002 decreased N-Myc protein levels and apoptosis in MNA neuroblastoma. Analysis of gene expression data from patients with neuroblastoma revealed that MYCN was associated with increased reactive oxygen species (ROS), downregulated mitophagy, and poor prognosis. Inhibition of MYCN caused profound mitochondrial damage in MNA neuroblastoma cells through downregulation of the mitochondrial molecular chaperone TRAP1, which subsequently increased ROS. Correspondingly, inhibition of MYCN reactivated mitophagy. Systemic administration of BGA002 downregulated N-Myc and TRAP1, with a concomitant decrease in MNA neuroblastoma xenograft tumor weight. In conclusion, this study highlights the role of N-Myc in blocking mitophagy in neuroblastoma and in conferring protection to ROS in mitochondria through upregulation of TRAP1. BGA002 is a potently improved MYCN-specific antigene oligonucleotide that reverts N-Myc-dysregulated mitochondrial pathways, leading to loss of the protective effect of N-Myc against mitochondrial ROS. Significance: A second generation antigene peptide oligonucleotide targeting MYCN induces mitochondrial damage and inhibits growth of MYCN-amplified neuroblastoma cells

The MYCN inhibitor BGA002 restores the retinoic acid response leading to differentiation or apoptosis by the mTOR block in MYCN-amplified neuroblastoma

Background Neuroblastoma is a deadly childhood cancer, and MYCN-amplified neuroblastoma (MNA-NB) patients have the worst prognoses and are therapy-resistant. While retinoic acid (RA) is beneficial for some neuroblastoma patients, the cause of RA resistance is unknown. Thus, there remains a need for new therapies to treat neuroblastoma. Here we explored the possibility of combining a MYCN-specific antigene oligonucleotide BGA002 and RA as therapeutic approach to restore sensitivity to RA in NB. Methods By molecular and cellular biology techniques, we assessed the combined effect of the two compounds in NB cell lines and in a xenograft mouse model MNA-NB. Results We found that MYCN-specific inhibition by BGA002 in combination with RA (BGA002-RA) act synergistically and overcame resistance in NB cell lines. BGA002-RA also reactivated neuron differentiation (or led to apoptosis) and inhibited invasiveness capacity in MNA-NB. Moreover, we found that neuroblastoma had the highest level of mRNA expression of mTOR pathway genes, and that BGA002 led to mTOR pathway inhibition followed by autophagy reactivation in MNA-NB cells, which was strengthened by BGA002-RA. BGA002-RA in vivo treatment also eliminated tumor vascularization in a MNA-NB mouse model and significantly increased survival. Conclusion Taken together, MYCN modulation mediates the therapeutic efficacy of RA and the development of RA resistance in MNA-NB. Furthermore, by targeting MYCN, a cancer-specific mTOR pathway inhibition occurs only in MNA-NB, thus avoiding the side effects of targeting mTOR in normal cells. These findings warrant clinical testing of BGA002-RA as a strategy for overcoming RA resistance in MNA-NB