Manuela Rodriquez | University of Salerno Italy (original) (raw)

Papers by Manuela Rodriquez

Molecules

Films and fibers of syndiotactic polystyrene (sPS), being amorphous or exhibiting nanoporous crys... more Films and fibers of syndiotactic polystyrene (sPS), being amorphous or exhibiting nanoporous crystalline (NC) or dense crystalline phases, were loaded with salicylic acid (SA), a relevant non-volatile antimicrobial molecule. In the first section of the paper, sPS/SA co-crystalline (CC) δ form is characterized, mainly by wide angle X-ray diffraction (WAXD) patterns and polarized Fourier transform infrared (FTIR) spectra. The formation of sPS/SA δ CC phases allows the preparation of sPS fibers even with a high content of the antibacterial guest, which is also retained after repeated washing procedures at 65 °C. A preparation procedure starting from amorphous fibers is particularly appropriate because involves a direct formation of the CC δ form and a simultaneous axial orientation. The possibility of tuning drug amount and release kinetics, by simply selecting suitable crystalline phases of a commercially available polymer, makes sPS fibers possibly useful for many applications. In pa...

Cancer Letters, 2014

Breast cancer (BC) displays a high heterogeneity from histology to prognosis, metastatic evolutio... more Breast cancer (BC) displays a high heterogeneity from histology to prognosis, metastatic evolution and treatment responses. We report here a 1 H NMR-based metabolic phenotyping study aiming at identifying coordinated metabolic serum changes associated with advanced metastatic breast cancer (MBC) in comparison to the localized early disease (EBC). A model discriminating EBC and MBC patients is obtained (n = 85: 46 EBC and 39 MBC), and validated with an independent cohort (n = 112: 61 EBC and 51 MBC; 89.8% sensitivity, 79.3% specificity). We identify 9 statistically significant metabolites involved in this discrimination: histidine, acetoacetate, glycerol, pyruvate, glycoproteins (N-acetyl), mannose, glutamate and phenylalanine. This work illustrates the strong potential of NMR metabolic phenotyping for the diagnosis, prognosis, and management of cancer patients.

RSC Advances, 2015

After a SAR study of santacruzamate A, 5 was discovered to selectively inhibit the growth of mali... more After a SAR study of santacruzamate A, 5 was discovered to selectively inhibit the growth of malignant cancer cells.

Pharmaceutics, 2022

The supramolecular structure in peptides’ prolonged-released gel formulations is the most critica... more The supramolecular structure in peptides’ prolonged-released gel formulations is the most critical parameter for the determination of the pharmaceutical profile of the drug. Here, we report our investigation on lanreotide Autogel as a case study. For the first time, we describe the use of the pulsed field gradient (PFG) diffusion-ordered spectroscopy (DOSY) magic-angle spinning NMR to characterize the supramolecular self-assembly and molecular mobility of different samples of lanreotide Autogel formulations prepared according to different formulation protocols. The diffusion coefficient was used to calculate the hydrodynamic radii of supramolecular assemblies and build relative molecular models. DOSY data were integrated with NMR imaging (MRI) measurements and atomic force microscopy (AFM) imaging.

Feline immunodeficiency virus (FIV) is a pathogen that causes an AIDS-like syndrome in domestic c... more Feline immunodeficiency virus (FIV) is a pathogen that causes an AIDS-like syndrome in domestic cats and is extensively used as a model system by which criteria for anti-lentiviral vaccines and drugs development can be tested. Despite little homology sequence, the surface and TM gp of FIV and HIV-1 exhibit a common structural framework and appear to play similar roles in Initiation of cell infection mediating the final event of membrane fusion and virus entry. Recently a 20-mer synthetic peptide spanning amino acids 767 L-G 786 of the membrane-proximal ectodomain of FIV (TM) gp - gp41(767-786)- was found to be endowed with potent antiviral activity. Testing deleted or substituted peptides, the 8-mer gp41(770-777), designated C8, including in the sequence three Trp residues was identified as the minimal sequence needed for full antiviral activity. NMR conformational analysis of gp41(770-777) evidenced the presence of a b-turn conformation centered on the residues 773-776. Here we rep...

Some original chimeric structures formed by a hydroxamic acid moiety separated from a steroid nuc... more Some original chimeric structures formed by a hydroxamic acid moiety separated from a steroid nucleus (derived from cholanoic or abietic acids) by a seven atoms linker have been prepared and tested against the 11 HDAC isoforms. The products derived from abietic acid show promising results with a particular activity against Class IIb tubuline deaceyilating HDAC6.

Signal transducer and activator of transcription 3 (STAT3) regulates many critical functions in h... more Signal transducer and activator of transcription 3 (STAT3) regulates many critical functions in human normal and malignant tissues, such as differentiation, proliferation, survival, angiogenesis and immune function. Constitutive activation of STAT3 is implicated in a wide range of human cancers. As such, STAT3 has been studied as a tumor therapeutic target. The last approach using small molecule STAT3 inhibitors has been the most examined so Heterocyles and Carbazole. Heterocyles are an essential class of molecules, assuming a role in many aspect of our life. Indeed heterocyclic nucleus is a common feature of several biomolecule and bioactive compounds including agrochemical products and drugs. In this review we focused on two important class of heterocyclic compounds: carbazoles and NHCs (N-heterocyclic carbenes) and there implications in cancer inhibitions. Carbazoles, prevalent as structural motifs in various synthetic materials and naturally occurring alkaloids, as is known, hav...

La gentamicina è un ben noto antibiotico appartenente alla classe degli amminiglicosidi ed è cost... more La gentamicina è un ben noto antibiotico appartenente alla classe degli amminiglicosidi ed è costituito da quattro molecole strutturalmente estremamente simili -differiscono tra loro per un gruppo metilico- e, pertanto, difficilmente separabili. I gruppi chimici caratterizzanti tutti gli isomeri sono di tipo amminico (porzione farmacoforica) ed alcolico, pertanto, la miscela viene utilizzata come sale solfato ed è caratterizzata da un’elevata idrofilia ed igroscopicità. Numerosi sforzi chimici sono stati effettuati per rendere la gentamicina più maneggevole, anche se in letteretura sono riportati pochi esempi in cui questo obiettivo è stato facilmente raggiunto. In questo lavoro vengono proposte modifiche strutturali al fine di aumentare il grado di lipofilia della gentamicina, richiesto per agevolare il suo inserimento in formulazioni innovative e di ampliare le modalità di somministrazione del farmaco per permetterne l’utilizzo nel trattamento di numerose patologie. La metodica utilizzata prevede uno schema sintetico di tre reazioni quali la protezione dei cinque gruppi amminici con CbzCl (benzil cloroformiato), la successiva protezione dei gruppi ossidrilici con BzCl (benzoil cloruro), la deprotezione dei gruppi amminici mediante idrogenolisi. La scelta dei gruppi protettori è stata effettuata sia per assicurare regioselettività delle reazioni di derivatizzazione sia in base ad una esigenza di tipo pratico volta a rendere la molecola tracciabile nel range UV-visibile e sviluppare metodi LC-MS per una rapida determinazione e separazione delle molecole appartenenti al pattern gentamicinico. Il lavoro sintetico è stato, infatti, strettamente associato a un innovativo studio analitico che ha previsto l’utilizzo di tecniche cromatografiche quali HPLC, LC-MS sia di tipo analitico che preparativo, utilizzando diverse fasi stazionarie come colonne C8/C18 . È stato possibile, dunque, proteggere i gruppi amminici delle molecole appartenenti al pattern gentamicinico, effettuare successivamente la protezione dei gruppi ossidrilici sotto stretto regiocontrollo ed isolare, infine, mediante i metodi HPLC e LC-MS creati, ogni singolo intermedio ottenuto, dati fino ad ora mai riportati in letteratura

Molecules, 2021

N6-Isopentenyladenosine (i6A) is a naturally occurring modified nucleoside displaying in vitro an... more N6-Isopentenyladenosine (i6A) is a naturally occurring modified nucleoside displaying in vitro and in vivo antiproliferative and pro-apoptotic properties. In our previous studies, including an in silico inverse virtual screening, NMR experiments and in vitro enzymatic assays, we demonstrated that i6A targeted farnesyl pyrophosphate synthase (FPPS), a key enzyme involved in the mevalonate (MVA) pathway and prenylation of downstream proteins, which are aberrant in several cancers. Following our interest in the anticancer effects of FPPS inhibition, we developed a panel of i6A derivatives bearing bulky aromatic moieties in the N6 position of adenosine. With the aim of clarifying molecular action of N6-benzyladenosine analogs on the FPPS enzyme inhibition and cellular toxicity and proliferation, herein we report the evaluation of the N6-benzyladenosine derivatives’ (compounds 2a–m) effects on cell viability and proliferation on HCT116, DLD-1 (human) and MC38 (murine) colorectal cancer c...

Farnesyl Pirophosphate Synthase (FPPS) is a key enzyme in the mevalonate, isoprenoid biosynthesis... more Farnesyl Pirophosphate Synthase (FPPS) is a key enzyme in the mevalonate, isoprenoid biosynthesis pathway. FPPS is nowadays the target of bisphosphonates drugs used in osteoporosis disease, nevertheless it is studied as target for anti-cancer therapeutics. N6-Isopentenyladenosine (i6A) is a modified nucleoside exhibiting anti-tumor effects on human and murine cells. Growing biochemical evidence demonstrate the involvement of FPPS protein in i6A anti-tumor action. We previously demonstrated that i6A interacts with FPPS binding site with K D of ~1mM. This interaction corresponded to a modest inhibition of FPPS enzymatic activity. By STD NMR approaches, here we screened newly synthesized analogs of i6A, designed on the basis of i6A-FPPS interaction data. i6A analogues interact with FPPS exhibiting binding mode very similar to i6A. The binding of i6A analogues highlighted the importance of N6-adenosine substituent in the interaction with FPPS binding site. Ideed, introduction on adenosine scaffold of a benzyl moiety induces a significant improvement of interaction with FPPS target. The altered expression of isoprenoid pathway and in particular of FPPS we found in glioma cells and tissue, allowed them to be targeted by the isoprenoid derivatives. As expected CM223 is more effective than i6A in selectively targeting U87 glioma cells but not normal human astrocytes (NHA). This is achieved by the introduction of intrinisc pathway of apoptosis adn inhibition of proliferation along a portein prenylation blockung ad shown by the increase levels of unprenylated Ras and Rap1A. These open the perspective that a modification of the newly introduced benzyl portion of the i6A molecule, may lead to more active molecules in glioma pharmacological research

Design, synthesis and biological evaluation of simplified linear and cyclic peptidomimetic analog... more Design, synthesis and biological evaluation of simplified linear and cyclic peptidomimetic analogues of FR235222 (1), natural immunosuppressant and HDAC inhibitor, bearing hydroxyketone moiety as more stable zinc binding group, have been reported. Linear dipeptides (6a-b) show significant antiproliferative activities and are chosen to be promising lead compounds for further optimization, in order to elucidate molecule-enzyme surface recognition.

Pharmaceuticals, 2020

Ganoderma lucidum or Reishi is recognized as the most potent adaptogen present in nature, and its... more Ganoderma lucidum or Reishi is recognized as the most potent adaptogen present in nature, and its anti-inflammatory, antioxidant, immunomodulatory and anticancer activities are well known. Moreover, lately, there has been an increasing interest from pharmaceutical companies in antiaging G. lucidum-extract-based formulations. Nevertheless, the pharmacological mechanisms of such adaptogenic and regenerative actions remain unclear. The present investigation aimed to explore its molecular and cellular effects in vitro in epidermal keratinocyte cultures by applying liquid chromatography coupled to ion trap time-of-flight mass spectrometry (LCMS-IT-TOF) for analysis of ethanol extracts using ganoderic acid-A as a reference compound. The G. lucidum extract showed a keratinocyte proliferation induction accompanied by an increase of cyclic kinase protein expressions, such as CDK2 and CDK6. Furthermore, a noteworthy migration rate increase and activation of tissue remodelling factors, such as...

Journal of Pharmaceutical and Biomedical Analysis, 2018

Cancers affecting the salivary glands have been an increasing incidence. Salivary gland cancer is... more Cancers affecting the salivary glands have been an increasing incidence. Salivary gland cancer is not detected until it reaches an advanced stage, which would generally result in a poor prognosis and survival rate. Therefore, early detection as well as the screening of high risk populations with precancerous lesions remains an unmet medical need. In the present work, we present a NMR-based metabolomic study of the saliva of patients suffering from salivary gland tumours. Analysis of data was done using a combined approach based on PRICONA quantitative analysis and statistical multivariate analysis. Interestingly, both the analytical methods indicate that individuals affected by parotid tumour have a characteristic metabolomic profile characterized by abnormalities in the concentration of several aminoacids. Among these the most significant are those relative to Alanine and Leucine suggestive of an alteration in the metabolic pathways of glycogenic aminoacids and ketone bodies. Our data, describing the preliminary metabolomics fingerprint of parotid tumour, are consistent with the recent view that oncogenic signalling corresponds to alteration in the metabolism of nutrient pull (Vander Heiden et al., 2009), rather than to a single metabolite.

Bioorganic Chemistry, 2019

Farnesyl pyrophosphate synthase (FPPS) is a crucial enzyme for the synthesis of isoprenoids and t... more Farnesyl pyrophosphate synthase (FPPS) is a crucial enzyme for the synthesis of isoprenoids and the key target of nitrogen-containing bisphosphonates (N-BPs). N-BPs are potent and selective FPPS inhibitors that are used in the treatment of bone-related diseases, but have poor pharmacokinetic properties. Given the key role played by FPPS in many cancer-related pathways and the pharmacokinetic limits of N-BPs, hundreds of molecules have been screened to identify new FPPS inhibitors characterized by improved drug-like properties that are useful for broader therapeutic applications in solid, non-skeletal tumours. We have previously shown that N6-isopentenyladenosine (i6A) and its related compound N6-benzyladenosine (2) exert anti-glioma activity by interfering with the mevalonate pathway and inhibiting FPPS. Here, we report the design and synthesis of a panel of N6-benzyladenosine derivatives (compounds 2a-m) incorporating different chemical moieties on the benzyl ring. Compounds 2a-m show in vitro antiproliferative activity in U87MG glioma cells and, analogous to the bisphosphonate FPPS inhibitors, exhibit immunogenic properties in ex vivo γδ T cells from stimulated peripheral blood mononuclear cells (PBMCs). Using saturation transfer difference (STD) and quantitative 1H nuclear magnetic resonance (NMR) experiments, we found that 2f, the N6-benzyladenosine analogue that includes a tertbutyl moiety in the para position of the benzyl ring, is endowed with increased FPPS binding and inhibition compared to the parent compounds i6A and 2. N6-benzyladenosine derivatives, characterized by structural features that are significantly different from those of N-BPs, have been confirmed to be promising chemical scaffolds for the development of non N-BP FPPS inhibitors, exerting combined cytotoxic and immunostimulatory activities.

Journal of enzyme inhibition and medicinal chemistry, 2018

Synthetic or natural carbazole derivatives constitute an interesting class of heterocycles, which... more Synthetic or natural carbazole derivatives constitute an interesting class of heterocycles, which showed several pharmaceutical properties and occupied a promising place as antitumour tools in preclinical studies. They target several cellular key-points, e.g. DNA and Topoisomerases I and II. The most studied representative, i.e. Ellipticine, was introduced in the treatment of metastatic breast cancer. However, because of the onset of dramatic side effects, its use was almost dismissed. Many efforts were made in order to design and synthesise new carbazole derivatives with good activity and reduced side effects. The major goal of the present study was to synthesise a series of new N-thioalkylcarbazole derivatives with anti-proliferative effects. Two compounds, 5a and 5c, possess an interesting anti-proliferative activity against breast and uterine cancer cell lines without affecting non-tumoural cell lines viability. The most active compound (5c) induces cancer cells death triggering...

British Journal of Pharmacology, 2017

BACKGROUND AND PURPOSE N 6-Isopentenyladenosine (i6A) is a modified nucleoside exerting in vitro ... more BACKGROUND AND PURPOSE N 6-Isopentenyladenosine (i6A) is a modified nucleoside exerting in vitro and in vivo antiproliferative effects. We previously demonstrated that the actions of i6A correlate with the expression and activity of farnesyl pyrophosphate synthase (FPPS), a key enzyme involved in the mevalonate (MVA) pathway, which is aberrant in brain cancer. To develop new anti-glioma strategies, we tested related compounds exhibiting greater activity than i6A. EXPERIMENTAL APPROACH We designed and synthesized i6A derivatives characterized by the introduction of diverse chemical moieties in the N6 position of adenosine and tested for their efficacy in U87 cells and in primary glioma cultures, derived from patients. NMR-based structural analysis, molecular docking calculations and siRNA mediated knockdown were used to clarify the molecular basis of their action, targeting FPPS protein. KEY RESULTS CM223, the i6A derivative including a benzyl moiety in N6 position of adenine, showed marked activity in selectively targeting glioma cells, but not normal human astrocytes. This was due to induction of intrinsic pathways of apoptosis and inhibition of proliferation, along with blockade of FPPS-dependent protein prenylation, which counteracted oncogenic signalling mediated by EGF receptors. CONCLUSION AND IMPLICATIONS The biological effects together with structural data on interaction of CM223 with FPPS, provided additional evidence for the correlation of the i6A/CM223 antitumor activity with FPPS modulation. Because the MVA pathway is an important promising target, CM223 and its derivatives should be considered interesting active molecules in antiglioma research.

Scientific Reports, 2016

A broad biophysical analysis was performed to investigate the molecular basis of the neuroprotect... more A broad biophysical analysis was performed to investigate the molecular basis of the neuroprotective action of Curcuma longa extracts in Alzheimer’s disease. By combining circular dichroism and electron paramagnetic resonance experiments with molecular modeling calculations, the minor components of Curcuma longa extracts, such as demethoxycurcumin (2, DMC), bisdemethoxycurcumin (3, BDMC) and cyclocurcumin (4, CYC), were analyzed in a membrane environment mimicking the phospholipid bilayer. Our study provides the first evidence on the relative role of single curcuminoids interacting with Aβ-peptide. When the CYC and curcumin metabolite tetrahydrocurcumin (5, THC) were inserted into an anionic lipid solution, a significant modification of the Aβ CD curves was detected. These data were implemented by EPR experiments, demonstrating that CYC reaches the inner part of the bilayer, while the other curcuminoids are localized close to the membrane interface. Computational studies provided a ...

Future Medicinal Chemistry, 2016

Background: For long time Alzheimer's disease has been attributed to a cholinergic deficit. M... more Background: For long time Alzheimer's disease has been attributed to a cholinergic deficit. More recently, it has been considered dependent on the accumulation of the amyloid beta peptide (Aβ), which promotes neuronal loss and impairs neuronal function. Results/methodology: In the present study, using biophysical and biochemical experiments we tested the hypothesis that in addition to its role as a neurotransmitter, acetylcholine may exert its action as an anti-Alzheimer agent through a direct interaction with Aβ. Conclusion: Our data provide evidence that acetylcholine favors the soluble peptide conformation and exerts a neuroprotective effect against the neuroinflammatory and toxic effects of Aβ. The present paper paves the way toward the development of new polyfunctional anti-Alzheimer therapeutics capable of intervening on both the cholinergic transmission and the Aβ aggregation.

Tetrahedron Letters, 2015

ABSTRACT