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CHIARA FRASSINETI

COLLABORATORE DI RICERCA
Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze sede ex-Sc. Biomediche

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Pubblicazioni

2023 - Unexpected Absence of Skeletal Responses to Dietary Magnesium Depletion: Basis for Future Perspectives? [Articolo su rivista]
Ferretti, Marzia; Cavani, Francesco; Lo Vasco, Vincenza Rita; Checchi, Marta; Truocchio, Serena; Davalli, Pierpaola; Frassineti, Chiara; Rizzi, Federica; Palumbo, Carla
abstract

2021 - Magnesium favors the capacity of vitamin d3 to induce the monocyte differentiation of u937 cells [Articolo su rivista]
Parenti, S.; Sandoni, L.; Montanari, M.; Zanocco-Marani, T.; Anesi, A.; Iotti, S.; Manfredini, R.; Frassineti, C.; Davalli, P.; Grande, A.
abstract

The hematopoietic U937 cells are able to differentiate into monocytes, macrophages, or osteoclasts when stimulated, respectively, with vitamin D3 (VD3), phorbol 12-myristate 13-acetate (PMA) or PMA plus VD3. We have previously demonstrated that magnesium (Mg) strongly potentiates the osteoclastic differentiation of U937 cells. In this study, we investigated whether such an effect may be ascribed to a capacity of Mg to modulate the monocyte differentiation of U937 cells and/or to an ability of Mg and VD3 to act directly and independently on the early phases of the osteoclastic differentiation. To address this issue, we subjected U937 cells to an individual and combined treatment with Mg and VD3 and then we analyzed, by flow cytometry and quantitative real-time polymerase chain reaction, the expression of a number of genes related to the early phases of the differentiation pathways under consideration. The results obtained indicated that Mg favors the monocyte differentiation of U937 cells induced by VD3 and at the same time, Mg contrasts the inhibitory effect that VD3 exerts on the osteoclastic differentiation in the absence of PMA. The crucial and articulated role played by Mg in diverse pathways of the osteoclastic differentiation of U973 cells is emphasized.

2019 - Magnesium is a key regulator of the balance between osteoclast and osteoblast differentiation in the presence of vitamin D 3 [Articolo su rivista]
Mammoli, F.; Castiglioni, S.; Parenti, S.; Cappadone, C.; Farruggia, G.; Iotti, S.; Davalli, P.; Maier, J. A. M.; Grande, A.; Frassineti, C.
abstract

Magnesium (Mg) is crucial for bone health. Low concentrations of Mg inhibit the activity of osteoblasts while promoting that of osteoclasts, with the final result of inducing osteopenia. Conversely, little is known about the effects of high concentrations of extracellular Mg on osteoclasts and osteoblasts. Since the differentiation and activation of these cells is coordinated by vitamin D 3 (VD3), we investigated the effects of high extracellular Mg, as well as its impact on VD3 activity, in these cells. U937 cells were induced to osteoclastic differentiation by VD3 in the presence of supra-physiological concentrations (>1 mM) of extracellular Mg. The effect of high Mg concentrations was also studied in human bone-marrow-derived mesenchymal stem cells (bMSCs) induced to differentiate into osteoblasts by VD3. We demonstrate that high extra-cellular Mg levels potentiate VD3-induced osteoclastic differentiation, while decreasing osteoblastogenesis. We hypothesize that Mg might reprogram VD3 activity on bone remodeling, causing an unbalanced activation of osteoclasts and osteoblasts.

2018 - KLF4 mediates the effect of 5-ASA on the b-catenin pathway in colon cancer cells [Articolo su rivista]
Parenti, Sandra; Montorsi, Lucia; Fantini, Sebastian; Mammoli, Fabiana; Gemelli, Claudia; Atene, Claudio Giacinto; Losi, Lorena; Frassineti, Chiara; Calabretta, Bruno; Tagliafico, Enrico; Ferrari, Sergio; Zanocco-Marani, Tommaso; Grande, Alexis
abstract

Mesalazine (5-ASA) is an aminosalicylate anti-inflammatory drug capable of inducing m-protocadherin, a protein expressed by colorectal epithelial cells that is downregulated upon malignant transformation. Treatment with 5-ASA restores m-protocadherin expression and promotes the sequestration of b-catenin to the plasma membrane. Here, we show that 5-ASA–induced m-protocadherin expression is directly regulated by the KLF4 transcription factor. In addition, we suggest the existence of a dual mechanism whereby 5-ASA–mediated b-catenin inhibition is caused by m-protocadherin–dependent sequestration of b-catenin to the plasma membrane and by the direct binding of KLF4 to b-catenin. In addition, we found that 5-ASA treatment suppresses the expression of miR-130a and miR-135b, which target KLF4 mRNA, raising the possibility that this mechanism is involved in the increased expression of KLF4 induced by 5-ASA.

2014 - Internalization and stability of a thymidylate synthase peptide inhibitor in ovarian cancer cells [Articolo su rivista]
Cannazza, Giuseppe; Cazzato, ADDOLORATA STEFANIA; Marraccini, Chiara; Pavesi, Giorgia; Pirondi, Silvia; R., Guerrini; M., Pelà; Frassineti, Chiara; Ferrari, Stefania; Marverti, Gaetano; Ponterini, Glauco; Costi, Maria Paola
abstract

Information on the cellular internalization and stability of the ovarian cancer cell growth inhibitor peptide, LSCQLYQR (LR), is vital for lead optimization. Ad-hoc-synthesized LR/fluorescent-probe conjugates were used to monitor the internalization of the peptide. Mass spectrometry was used to identify adducts resulting from the thiol reactivity of the cysteine residue in LR. A mechanistic model is proposed to explain the observed change in intracellular peptide amount over time. Structural modifications can be foreseen to improve the peptide stability.

2013 - Modulation of the expression of folate cycle enzymes and polyamine metabolism by berberine in cisplatin-sensitive and -resistant human ovarian cancer cells [Articolo su rivista]
Marverti, Gaetano; Ligabue, A; Lombardi, P; Ferrari, Stefania; Monti, Maria Giuseppina; Frassineti, Chiara; Costi, Maria Paola
abstract

Berberine is a natural isoquinoline alkaloid with significant antitumor activity against many types of cancer cells, including ovarian tumors. This study investigated the molecular mechanisms by which berberine differently affects cell growth of cisplatin (cDDP)-sensitive and -resistant and polyamine analogue cross-resistant human ovarian cancer cells. The results show that berberine suppresses the growth of cDDP-resistant cells more than the sensitive counterparts, by interfering with the expression of folate cycle enzymes, dihydrofolate reductase (DHFR) and thymidylate synthase (TS). In addition, the impairment of the folate cycle also seems partly ascribable to a reduced accumulation of folate, a vitamin which plays an essential role in the biosynthesis of nucleic acids and amino acids. This effect was observed in both lines, but especially in the resistant cells, correlating again with the reduced tolerance to this isoquinoline alkaloid. The data also indicate that berberine inhibits cellular growth by affecting polyamine metabolism, in particular through the upregulation of the key catabolic enzyme, spermidine/spermine N1-acetyltransferase (SSAT). In this regard, berberine is shown to stimulate the SSAT induction by the spermine analogue N1, N12 bisethylspermine (BESpm), which alone was also able to downregulate DHFR mRNA more than TS mRNA. We report that the sensitivity of resistant cells to cisplatin or to BESpm is reverted to the levels of sensitive cells by the co-treatment with berberine. These data confirm the intimate inter-relationships between folate cycle and polyamine pathways and suggest that this isoquinoline plant alkaloid could be a useful adjuvant therapeutic agent in the treatment of ovarian carcinoma.

2012 - Distamycin A and derivatives as synergic drugs in cisplatin-sensitive and -resistant ovarian cancer cells. [Articolo su rivista]
Marverti, Gaetano; Guaitoli, Giambattista; Ligabue, Alessio; Frassineti, Chiara; Monti, Maria Giuseppina; P., Lombardi; Costi, Maria Paola
abstract

Acquired resistance to cisplatin (cDDP) is a multifactorial process that represents one of the main problems in ovarian cancer therapy. Distamycin A is a minor groove DNA binder whose toxicity has limited its use and prompted the synthesis of derivatives such as NAX001 and NAX002, which have a carbamoyl moiety and different numbers of pyrrolamidine groups. Their interaction with a B-DNA model and with an extended-TATA box model, [Polyd(AT)], was investigated using isothermal titration calorimetry (ITC) to better understand their mechanism of interaction with DNA and therefore better explain their cellular effects. Distamycin A interactions with Dickerson and Poly[d(AT)6] oligonucleotides show a different thermodynamic with respect to NAX002. The bulkier distamycin A analogue shows a non optimal binding to DNA due to its additional pyrrolamidine group. Cellular assays performed on cDDP-sensitive and -resistant cells showed that these compounds, distamycin A in particular, affect the expression of folate cycle enzymes even at cellular level. The optimal interaction of distamycin A with DNA may account for the down-regulation of both dihydrofolate reductase (DHFR) and thymidylate synthase (TS) and the up-regulation of spermidine/spermine N1-acetyltransferase (SSAT) caused by this compound. These effects seem differently modulated by the cDDP-resistance phenotype. On the contrary, NAX002 which presents a lower affinity to DNA and slightly affected these enzymes, showed a synergic inhibition profile in combination with cDDP. In addition, their combination with cDDP or polyamine analogues increased cell sensitivity to the drugs suggesting that these interactions may have potential for development in the treatment of ovarian carcinoma.

2012 - Folate Receptor Expression and Folate Receptor Targeted Chemotherapy in Cisplatin-sensitive and – resistant Human cancer cell lines Marverti G.a, Pirondi S.a, MarracciniC.a, Frassineti C.a, Helleman J.b, Berns E.M.J.J. b, and Costi, M.P. cThe 4th International Symposium on Folate Receptors and Transporters Cozumel, Mexico October 7 - 11, 2012 [Poster]
Marverti, Gaetano; Pirondi, Silvia; Marraccini, Chiara; Frassineti, Chiara; Costi, Maria Paola
abstract

Folate Receptor Expression and Folate Receptor Targeted Chemotherapy in Cisplatin-sensitive and – resistant Human cancer cell lines Marverti G.a, Pirondi S.a, MarracciniC.a, Frassineti C.a, Helleman J.b, Berns E.M.J.J. b, and Costi, M.P. c aDept. Biomedical Sciences and cDept. Pharmaceutical Sciences, Via Campi 287-183, University of Modena and Reggio Emilia, 41125, Modena, Italy; Dept. of Medical Oncology, bErasmus University Medical Center - Daniel den Hoed Cancer Center, PO Box 2040, 3000 CA, Rotterdam,The Netherlands. Targeted drug delivery systems promise to expand the therapeutic windows of drugs by increasing delivery to the target tissue as well as the target–non-target tissue ratio. Interest in exploiting the folate receptor (FR) for drug targeting applications has rapidly increased because it is a tumor-associated antigen that is overex- pressed in greater than 90% of human ovarian carcinomas and associated with increased biological aggressive- ness of this tumor [1]. The most significant advantage to emerge from studies of FR-mediated delivery has been the surprisingly low level of toxicity to normal tissues which constitute one of the most significant merits of the FR-targeting strategy. Therefore, FR presents an attractive target for tumor-selective drug delivery. The final goal of this research is to analyze the effects of oligopeptides, designed to inhibit thymidylate syn- thase (TS) activity by interfering with its dimerization, without causing TS over-expression and the develop- ment of cellular drug resistance against the traditional TS-targeted compounds. The over-expression of TS and the others folate cycle enzymes, is one of the major mechanisms of resistance to cisplatin (cDDP), encountered in most of resistant human ovarian cancer cell lines [2], accounting for the more efficient DNA repair and syn- thesis. To this aim, we have chosen two cisplatin-sensitive human ovarian cancer cell lines, 2008 and A2780, and their –resistant counterparts, C13* and A2780/CP cell lines, respectively, in order to display and study possi- ble different responses modulated by cDDP-resistance. At first, the cell lines have been tested for their total levels of FR and for functionally active receptors (FR or also other receptors?). The quantification of functional FR by the microfiltration method [3] and by an alterna- tive method, which deduces FR amount from the folic acid (FA) binding to FR [4] indicate that 2008 and C13* cells present a 3-4 fold higher expression of FR than A2780 and A2780/CP cells. However, time-dependent and concentration-dependent studies revealed that despite their higher expression of FR and the higher [3H]folic acid binding capacity, 2008 and C13* cell lines appeared to saturate earlier than A2780 and A2780/CP cell lines since they accumulated less [3H]folic acid at concentrations higher than 150 nM. Substrate specificity studies of the saturable uptake process, revealed that the 30 nM [3H]Folic acid uptake in A2780 cells was more affected than in the resistant line A2780/CP to the presence of 20μM of unlabeled folic acid (FA) and methotrexate (MTX), respectively (I do not understand this sentence, A2780 is more sensitive to unlabeled folic acid and mtx after labeled FA treatment? How do you measure this sensitivity? Do you mean affected/decreased uptake?). On the contrary, 30 nM [3H]Folic acid uptake was unaffected by unlabeled FA and MTX in both 2008 and C13* cell lines.  To evaluate the presence of ATP-dependent process affecting FA uptake, experiments were also performed at 4°C and compared with those at 37°C. The accumulation of [3H]folic acid was greatly reduced at 4°C in comparison to 37°C both in 2008 and C13* cells, whereas only about 6- and 4-fold reductions were detected in A2780 and A2780/CP cells, respectively . These results are, at least partly, in accordance with the competitive uptake studies, since they suggest that in t

2011 - Characterization of the cell growth inhibitory effects of a novel DNA-intercalating bipyridyl-thiourea-Pt(II) complex in cisplatin-sensitive and-resistant human ovarian cancer cells [Articolo su rivista]
Marverti, Gaetano; Ligabue, Alessio; Montanari, Monica; Guerrieri, Davide; M., Cusumano; M. L., Di Pietro; L., Troiano; DI VONO, Elena; S., Iotti; G., Farruggia; F., Wolf; Monti, Maria Giuseppina; Frassineti, Chiara
abstract

The cellular effects of a novel DNA-intercalatingagent, the bipyridyl complex of platinum(II) with diphenylthiourea, [Pt(bipy)(Ph2-tu)2]Cl2, has been analyzed in thecisplatin (cDDP)—sensitive human ovarian carcinoma cellline, 2008, and its—resistant variant, C13* cells, in which thehighest accumulation and cytotoxicity was found among sixrelated bipyridyl thiourea complexes. We also show here thatthis complex causes reactive oxygen species to form andinhibits topoisomerase II activity to a greater extent in thesensitive than in the resistant line. The impairment of thisenzyme led to DNA damage, as shown by the comet assay.As a consequence, cell cycle distribution has also beengreatly perturbed in both lines. Morphological analysisrevealed deep cellular derangement with the presence of cellular masses, together with increased membrane permeability and depolarization of the mitochondrial membrane. Some of these effects, sometimes differentially evident between the two cell lines, might also be related to the decrease of total cell magnesium content caused by this thiourea complex both in sensitive and resistant cells, though the basal content of this ion was higher in the cDDP-resistant line. Altogether these results suggest that this compound exerts its cytotoxicity by mechanisms partly mediated by the resistance phenotype. In particular, cDDP-sensitive cells were affected mostly by impairing topoisomerase II activity and by increasing membrane permeability and the formation of reactive oxygen species; conversely, mitochondrial impairment appeared to play the most important role in the action of complex F in resistant cells.

2011 - Erratum: Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase (Proceedings of the National Academy of Sciences of the United States of America (2011) 108, 34 (E542-E549) DOI: 10.1073/pnas.1104829108) [Articolo su rivista]
Cardinale, D.; Guaitoli, G.; Tondi, D.; Luciani, R.; Henrich, S.; Salo-Ahen, O. M. H.; Ferrari, S.; Marverti, G.; Guerrieri, D.; Ligabue, A.; Frassineti, C.; Pozzi, C.; Mangani, S.; Fessas, D.; Guerrini, R.; Ponterini, G.; Wade, R. C.; Costi, M. P.
abstract

2011 - Protein–protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase [Articolo su rivista]
Cardinale, Daniela; Guaitoli, Giambattista; Tondi, Donatella; Luciani, Rosaria; S., Henrich; O. M. H., Salo Ahen; Ferrari, Stefania; Marverti, Gaetano; Guerrieri, Davide; Ligabue, Alessio; Frassineti, Chiara; C., Pozzi; S., Mangani; D., Fessas; R., Guerrini; Ponterini, Glauco; R. C., Wade; Costi, Maria Paola
abstract

Human thymidylate synthase is a homodimeric enzyme that playsa key role in DNA synthesis and is a target for several clinicallyimportant anticancer drugs that bind to its active site. We have designed peptides to specifically target its dimer interface. Here we show through X-ray diffraction, spectroscopic, kinetic, and calorimetric evidence that the peptides do indeed bind at the interface of the dimeric protein and stabilize its di-inactive form. The “LR” peptide binds at a previously unknown binding site and shows a previously undescribed mechanism for the allosteric inhibition of a homodimeric enzyme. It inhibits the intracellular enzyme in ovarian cancer cells and reduces cellular growth at low micromolar concentrations in both cisplatin-sensitive and -resistant cells without causing protein overexpression. This peptide demonstrates the potential of allosteric inhibition of hTS for overcoming platinum drug resistance in ovarian cancer.

2010 - Spermidine/spermine N1-acetyltranferasemodulation by novel folate cycle inhibitors in cisplatin-sensitive and -resistanthuman ovarian cancer cell lines [Articolo su rivista]
Marverti, Gaetano; Ligabue, Alessio; Guerrieri, Davide; Paglietti, G; Piras, S; Costi, Maria Paola; Farina, Davide Salvatore Francesco; Frassineti, Chiara; Monti, Maria Giuseppina; Moruzzi, Maria Stella
abstract

Polyamines have been shown to play a role in the growth and survival of several solid tumors, including ovarian cancer. Intracellular polyamine depletion by the inhibition of biosynthesis enzymes or by the induction of the catabolic pathway leads to antiproliferative effects in many different tumor cell lines. Recent studies showed that the thymidylate synthase inhibitor 5-fluorouracil (5-FU) affects polyamine metabolism in colon carcinoma cells through the induction of the key catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT). METHODS: We therefore examined whether combinations of novel folate cycle inhibitors with quinoxaline structure and drugs that specifically target polyamine metabolism, such as diethylderivatives of norspermine (DENSPM) or spermine (BESpm), have synergistic effect in killing cisplatin-sensitive and drug-resistant daughter human ovarian cell lines. RESULTS: Our results showed that simultaneous drug combination or quinoxaline pre-treatment synergistically increased SSAT expression, depleted polyamines, increased reactive oxygen species production, and produced synergistic tumor cell killing in both cell lines. Of note, this combined therapy increased the chemosensitivity of cisplatin-resistant cells and cross-resistant to the polyamine analogues. On the contrary, some pre-treatment regimens of Spm analogues were antagonistic. CONCLUSIONS: These results show that SSAT plays an important role in novel folate cycle inhibitors effects and suggest that their combination with analogues has potential for development as therapy for ovarian carcinoma based on SSAT modulation. Copyright © 2009 Elsevier Inc. All rights reserved.

2009 - Collateral sensitivity to novel thymidylate synthase inhibitors correlates with folate cycle enzymes impairment in cisplatin-resistant human ovarian cancer cells [Articolo su rivista]
Marverti, Gaetano; Ligabue, Alessio; G., Paglietti; P., Corona; S., Piras; G., Vitale; Guerrieri, Davide; Luciani, Rosaria; Costi, Maria Paola; Frassineti, Chiara; Moruzzi, Maria Stella
abstract

The cytotoxicity of two novel folate cycle inhibitors with quinoxalinic structure, 3-methyl-7-trifluoromethyl-2(R)-[3,4,5-trimethoxyanilino]-quinoxaline (453R) and 3-piperazinilmethyl-2[4(oxymethyl)-phenoxy]quinoxaline (311S), was tested against a panel of both cisplatin(cDDP)-sensitive and -resistant carcinoma cell lines. Interestingly, the cisplatin-resistant human ovarian line, C13 cells, exhibited collateral sensitivity towards the two compounds when compared to its sensitive parental 2008 cells. In this resistant line, which showed elevated expression of the folate cycle enzymes, thymidylate synthase (TS) and dihydrofolate reductase (DHFR), due to cisplatin-resistance phenotype, collateral sensitivity correlated with the greater reduction of enzyme expression. In addition, TS and DHFR expression of the other resistant lines, the human ovarian carcinoma A2780/CP cells and the human breast cancer MDA/CH cells, were decreased in accordance with the similar sensitivity or the low level of cross-resistance to these compounds in comparison to their respective parental lines. Noteworthy, unlike 5-fluorouracil, both drugs reduced the level of TS without inducing ternary complex formation with the co-substrate and the nucleotide analogue. Median effect analysis of the interactive effects of cisplatin with the two quinoxalines mainly showed additive or synergistic cell killing, depending on schedules of drug combinations. In particular, synergistic effects were more often obtained, even on the resistant cells, when cisplatin was added at the beginning of the treatment. These results indicate that, despite the possibility of other mechanisms being involved, inhibition of TS cycle enzymes plays an important role in the pharmacology of these compounds, which might also represent a useful component in drug treatment protocols against cDDP-resistant cells.

2008 - Collateral sensitivity to novel folate cycle inhibitors enhances cisplatin effectiveness against human ovarian cancer cells. [Abstract in Atti di Convegno]
Marverti, Gaetano; Ligabue, Alessio; Guerrieri, Davide; Costi, Maria Paola; G., Paglietti; Frassineti, Chiara; Moruzzi, Maria Stella
abstract

Presentazione della prima evidenza del binding dei peptidi inibitori della Timidilato sintasi all'interfaccia del dimmelo della Proteina.

2008 - SSAT modulation by putative regulators of folate cycle enzymes expression in cisplatin-sensitive and –resistant human ovarian cancer cell lines. [Abstract in Atti di Convegno]
Marverti, G.; Ligabue, A.; Costi, M. P.; Lombardi, P.; Guerrieri, D.; Frassineti, C.; Monti, M. G.; Moruzzi, M. S.
abstract

SSAT modulation by putative regulators of folate cycle enzymes expression in cisplatin-sensitive and –resistant human ovarian cancer cell lines.Cisplatin (DDP)-resistance confers a deficient expression of spermidine/ spermine N(1)-acetyltransferase (SSAT) gene in response to the spermine analog N(1),N(12)-bis(ethyl)spermine (BESpm) in the DDP-resistant human ovarian carcinoma cell line (C13*), compared with their parental DDP-sensitive 2008 cells.

2008 - Studies on the anti-proliferative effects of novel DNA-intercalating bipyridyl-thiourea-Pt(II) complexes against cisplatin-sensitive and -resistant human ovarian cancer cells [Articolo su rivista]
Marverti, Gaetano; Matteo, Cusumano; Ligabue, Alessio; Maria Letizia Di, Pietro; Pasquale Antonio, Vainiglia; Ferrari, Angela; Bergomi, Margherita; Maria Stella, Moruzzi; Frassineti, Chiara
abstract

Six bipyridyl complexes of platinum(II) with thiourea, with different substituents on thiourea moiety [Pt(bipy)(R,R0NCSNR00,R000)2]Cl2(bipy = 2,20-bipyridine: R = R0 =R00 =R000 = H; R = Me, R0 =R00 =R000 =H;R=n-Bu, R0 =R00 =R000 = H; R = Et, R0 =H,R00 = Et,R000 =H; R=p-tolyl, R0 =R00 =R000 = H; R = phenyl, R0 =H, R00 = phenyl, R000 = H), rationally designed to intercalate into DNA,have been tested against a cisplatin (cDDP)-sensitive human ovarian carcinoma cell line (2008) and its -resistant variant (C13*). We showhere that the anti-proliferative efficacy of these drugs was dependent on molecular structure, since it increased with ancillary ligand bulkinessand hydrophobicity of substituents on thiourea moiety. In particular, the presence of two phenyl groups on thiourea moiety confersan outstanding cytotoxicity. The increasing cell growth inhibition along the series of complexes partially paralleled with drug accumulation,particularly in resistant cells, but not with drug intercalation into DNA since all compounds exerted comparable ethidium bromidedisplacement ability. The cDDP-resistant phenotype seems, at least in part, to be involved in the action of these compounds, since the levelof cross-resistance established for most complexes appeared to be in agreement with the observed impairment of drug accumulation in theresistant subline. These findings indicate that resistance to alkylating agents such as cDDP confers low level of cross-resistance to this classof DNA intercalators, which, however, depending on substituents on thiourea moiety may present remarkable cell growth inhibition evenof resistant cells.

2008 - Synthesis, chemical and biological studies on new Fe3þ-glycosilated b-diketo complexes for the treatment of iron deficiency [Articolo su rivista]
Beatrice, Arezzini; Marco, Ferrali; Ferrari, Erika; Frassineti, Chiara; Lazzari, Sandra; Marverti, Gaetano; Ferdinando, Spagnolo; Saladini, Monica
abstract

A simple synthetic pathway to obtain glycosilated b-diketo derivatives is proposed. These compounds show a good iron(III) affinity thereforewe may suggest the use of their Fe3þ-complexes as oral iron supplements in the treatment of anaemia. The glycosilated compounds (6-GlcH, 6-GlcOH and 6-GlcOCH3) are characterized by means of spectroscopic (UV, 1H and 13C NMR) and potentiometric techniques; they have a good water solubility, are kinetically stable in physiological condition (t1/2 > 100 h) and show a low cytotoxicity also in high concentrations (IC50 > 400 mM). They are able to bind Fe3þ ion in acid condition (pHw2) forming complex species thermodynamically more stable than those of other ligands commonly used in the treatment of iron deficiency. The iron complexes show also a good kinetic stability both in acidic and physiological pH and have a good lypophilicity (log P > 0.7) that suggests an efficient gastrointestinal absorption in view of their possible use in oral therapy. In addition they demonstrate a poor affinity for competitive biological metal ion such as Ca2þ, and in particular 6-GlcOCH3 is able to inhibit lipid peroxidation.

2006 - Glucosyl curcuminoid derivatives: Fe(III) and Ga(III) chelating agents with anti-cancer properties [Relazione in Atti di Convegno]
Ferrari, Erika; Frassineti, Chiara; Lazzari, Sandra; Marverti, Gaetano; Grandi, Romano; Saladini, Monica
abstract

...

2006 - Glucosyl curcuminoid derivatives: Fe(III) and Ga(III) chelating agents with anti-cancer properties [Relazione in Atti di Convegno]
Ferrari, Erika; Frassineti, Chiara; Lazzari, Sandra; Marverti, Gaetano; Grandi, Romano; Saladini, Monica
abstract

...

2005 - Quantitative mathematical expressions for accurate in vivo assessment of cytosolic [ADP] and Delta G of ATP hydrolysis in the human brain and skeletal muscle [Articolo su rivista]
S., Iotti; Frassineti, Chiara; A., Sabatini; A., Vacca; B., Barbiroli
abstract

Magnetic Resonance Spectroscopy affords the possibility of assessing in vivo the thermodynamic status of living tissues. The main thermodynamic variables relevant for the knowledge of the health of living tissues are: Delta G of ATP hydrolysis and cytosolic [ADP], the latter as calculated from the apparent equilibrium constant of the creatine kinase reaction. In this study we assessed the stoichiometric equilibrium constant of the creatine kinase reaction by in vitro P-31 NMR measurements and computer calculations resulting to be: logK(CK)=8.00 +/- 0.07 at T=310 K and ionic strength I=0.25 M. This value refers to the equilibrium: PCr2- + ADP(3-) + H+ = Cr + ATP(4-) We also assessed by computer calculation the stoichiometric equilibrium constant of ATP hydrolysis obtaining the value: logK(ATP-hyd)= -12.45 at T=310 K and ionic strength I=0.25 M, which refers to the equilibrium: ATP(4-) + H2O = ADP(3-) + PO43- + 2H(+) Finally, we formulated novel quantitative mathematical expressions of Delta G of ATP hydrolysis and of the apparent equilibrium constant of the creatine kinase reaction as a function of total [PCr], pH and pMg, all quantities measurable by in Vivo (31)p MRS. Our novel mathematical expressions allow the in vivo assessment of cytosolic [ADP] and Delta G of ATP hydrolysis in the human brain and skeletal muscle taking into account pH and pMg changes occurring in living tissues both in physiological and pathological conditions.

2003 - Complexation of HEPES buffer solutions with metal ions. [Abstract in Atti di Convegno]
Frassineti, Chiara; P., Gans; S., Iotti; P., Mariani; A., Sabatini; A., Vacca; S., Ghelli
abstract

CHOICE OF BUFFER SOLUTION TO USE FOR IN VITRO INVESTIGATION OF BIOCHEMICAL SYSTEMS

2003 - DISCO - a general computer program for the computation of acid dissociation constants of polyprotic molecules in water and biological fluids from nuclear magnetic resonance data: application to polyamines. [Articolo su rivista]
F., Renieri; C., Guillou; Frassineti, Chiara; S., Ghelli
abstract

A new computer program, DISCO, running under Windows, has been developed under the project CSA98P22 falling within theCompetitive Support Activities initiative launched within the EU 4th Framework Programme. DISCO allows the calculation of thestepwise acid dissociation constants of polyprotic molecules in water and in complex media (i.e., biofluids, etc.) from nuclearmagnetic resonance (NMR) data (chemical shifts) by means of two derivative-free methods: Pit-mapping and Simplex. DISCOperformances were tested using simulated—unaffected by experimental error—data sets, for systems having up to seven equilibriumconstants and experimental NMR data of spermine, 6-monofluorospermine, and 6,6-difluorospermine, dissolved in D2O and inphysiological solution (D2O/NaCl). Results demonstrated that (i) DISCO enables the determination of pKA values with high precisioneven when small-sized raw data sets are employed, when chemical shifts are measured with low precision (the usual conditionin biofluids due to the impossibility to obtain narrow line shape), and when the guess solution, necessary as an initial step of themathematical iterative process, is fixed within a large interval of variation; (ii) DISCO always converges to the root; (iii) DISCOpermits the calculation of pKA values which lie within the observed pH range, independent of the narrowness of the pH range.

2003 - Determination of protonation constants of some fluorinated polyamines by means of C-13 NMR data processed by the new computer program HypNMR2000. Protonation sequence in polyamines [Articolo su rivista]
Frassineti, Chiara; L., Alderighi; P., Gans; A., Sabatini; A., Vacca; S., Ghelli
abstract

The pK(a) values of 6-fluoro-4,8-diazadodecane-1,12-diamine (6-fluorospermine) (1), 6,6-difluoro-4,8-diazadodecane-1,12-diamine (6,6-difluorospermine) (2), 6-fluoro-4-azaoctane-1,8-diamine (6-fluorospermidine) (3) and 6,6-difluoro-4-azaoctane-1,8-diamine (6,6-difluorospermidine) (4) in D2O solution have been determined at 40degreesC from C-13 NMR chemical shifts data using the new computer program HypNMR2000. The enthalpies of protonation of compounds 1-4 and the parent amines spermine (5) and spermidine (6) have been determined from microcalorimetric titration data. The values of DeltaHdegrees were used to derive basicity constants relative to 25degreesC. The NMR data have been analysed by two different methods to obtain information on the protonation sequence in the polyamines 1-5. The protonation sequence for spermine is related to its biological activity.

2002 - Complex formation equilibria of phosphocreatine with sodium, potassium and magnesium ions [Articolo su rivista]
F., Cecconi; Frassineti, Chiara; P., Gans; S., Iotti; S., Midollini; A., Sabatini; A., Vacca
abstract

The formation of complexes between phosphocreatine, H2O3PNHC(=NH)N(CH3)CH2CO2H, and the ions Na+, K+ and Mg2+ have been investigated under physiological conditions (aqueous solution, T=37degreesC and I=0.25 mol dm(-3)) by means of P-31 NMR spectroscopy. Only 1:1 complexes have been identified. Stability constants have been determined with the aid of the new computer program HYPNMR-2000. log(10) K values were found to be -0.5(2),-0.3(2) and 1.43(3), respectively. The formation constant for the potassium complex is two orders of magnitude less that the literature value.

2001 - Reassessment of the apparent equilibrium constant of the creatine kinase reaction for accurate in vivo assessment of [ADP] by 31P-MRS in the human brain and skeletal muscle. [Abstract in Atti di Convegno]
Iotti, S.; Sabatini, A.; Vacca, A.; Frassineti, Chiara; Barbiroli, B.
abstract

THE CHEMICAL MODEL IS BASED ON THREE LIGANDS ATP, ADP E PCr AND 4 LEWIS ACIDS: Na+, K+ Mg2+ H+ AS BASIC SPECIES

2000 - In vivo P-31-MRS assessment of cytosolic [Mg2+] in the human skeletal muscle in different metabolic conditions [Articolo su rivista]
S., Iotti; Frassineti, Chiara; L., Alderighi; A., Sabatini; A., Vacca; B., Barbiroli
abstract

Cytosolic free [Mg2+] can be assessed in vivo by P-31-MRS from the chemical shift of beta-ATP. The reliability of in vivo measurements depends on the availability of appropriate in vitro calibration curves obtained by using solutions that mimic the in vivo cytosolic conditions as far as possible, We build a semi-empiric equation that correlates the chemical shift of beta-ATP to free [Mg2+] taking into account the amount of Mg2+ bound to all other ligands in solution. Our experiments resulted in a reliable ten-parameters equation directly usable to assess the cytosolic free [Mg2+] of human skeletal muscle at rest, during work and recovery. Our experiments also resulted in a new equation that allows the assessment of cytosolic pH from the chemical shift of Pi laking into account the measured free [Mg2+]. To perform simultaneous calculation of free [Mg2+] and pH in the skeletal muscle in different metabolic conditions we developed a specific software package available on Internet (http://www.unibo.it/bioclin) together with another program based on the equation previously obtained to calculate cytosolic free [Mg2+] in the human brain. The reliability and effectiveness of our equations and software were tested on the calf muscles of healthy volunteers at rest, during work and recovery. (C) 2000 Elsevier Science Inc. All rights reserved.

1997 - Coenzyme Q(10) improves mitochondrial respiration in patients with mitochondrial cytopathies. An in vivo study on brain and skeletal muscle by phosphorus magnetic resonance spectroscopy [Articolo su rivista]
B., Barbiroli; Frassineti, Chiara; P., Martinelli; S., Iotti; R., Lodi; P., Cortelli; P., Montagna
abstract

With phosphorus magnetic resonance spectroscopy (P-31-MRS) we studied in vivo the effect of six-month coenzyme Q(10) treatment on the efficiency of brain and skeletal muscle mitochondrial respiration in six patients with different mitochondrial cytopathies. Before CoQ we found a low phosphocreatine content (average of 25% decrease from controls) in the occipital lobes of all patients. Calculated [ADP] and the relative rate of ATP synthesis were high (as an average, 57% and 16% above control group respectively), whereas the cytosolic phosphorylation potential was low (as an average, 60% of control value). P-31-MRS also revealed an average of 29% reduction of the mitochondrial function in the skeletal muscle of patients compared with controls. After a six-month treatment with 150 mg CoQ(10)/day all brain variables were remarkably improved in all patients, returning within the control range in all cases. Treatment with CoQ also improved the muscle mitochondrial functionality enough to reduce the average deficit to 56% of the control group. These in vivo findings show the beneficial effect of CoQ in patients with mitochondrial cytopathies, and are consistent with the view that increased CoQ concentration in the mitochondrial membrane increases the efficiency of oxidative phosphorylation independently of enzyme deficit.

1997 - Myofibrils of skeletal muscle: the activity coefficient of orthophosphate [Articolo su rivista]
E., Grazi; R., Adami; E., Magri; G., Trombetta; Frassineti, Chiara
abstract

In the myofibrils of skeletal muscle, at 22 degrees C, pH 7.1 and at the physiological protein osmotic pressure of 1.8x10(5) dynes/cm(2) orthophosphate behaves quite ideally, the activity coefficient being 0.85. Under the same conditions and at saturation, 2.67 mu moles of orthophosphate are bound per gram of dry myofibrils, with a dissociation constant of 7x10(-5) molal. Work is in progress to determine the activity coefficients of adenine nucleotide analogues. This work is needed to assess the actual value of the free energy of hydrolysis of ATP in muscle.

1996 - Effect of oral phosphocreatinine on human skeletal muscle shown by in vivo P-31-NMR [Articolo su rivista]
Frassineti, Chiara; Iotti, S; Lodi, Renzo; Zaniol, P; Barbiroli, B.
abstract

We used the non-invasive method of in vivo phosphorus magnetic resonance spectroscopy to investigate the effect of oral administration of phosphocreatinine on muscle energy metabolism during graded work and post-exercise recovery in humans. Phosphocreatinine administration results in a smaller depletion of phosphocreatine at high work rates accompanied by a smaller cytosolic acidification during work and recovery. Our findings suggest that oral phosphocreatinine increases the readily available energy for muscle contraction by interfering directly or indirectly with the reaction equilibria involving phosphocreatine.

1996 - In vivo assessment of free magnesium concentration in human brain by P-31 MRS. A new calibration curve based on a mathematical algorithm [Articolo su rivista]
S., Iotti; Frassineti, Chiara; L., Alderighi; A., Sabatini; A., Vacca; B., Barbiroli
abstract

Free cytosolic [Mg2+] can be assessed in vivo by P-31 MRS from the chemical shift of beta-ATP which in turn depends on the fraction of total ATP complexed to Mg2+ ions, The reliability of these in vive measurements depends on the availability of an appropriate in vitro calibration to determine the limits of chemical shifts of unbound ATP and Mg-ATP complexes, using solutions that mimic the in vive cytosolic conditions as far as possible, We used an algorithm and software to allow a quantitative definition of the Mg2+-binding molecules to build a semi-empirical equation that correlates the chemical shift of the beta-ATP signal to the [Mg2+] taking into account the amount of Mg2+ bound to all other constituents in solution, Our experiments resulted in a simple and reliable equation directly usable to assess in vive the free cytosolic magnesium concentration of human brain by P-31 MRS. Our method is also flexible enough to make it suitable for in vive measurements of [Mg2+] in other organs and tissues.

1996 - Inhibition of cell growth by accumulated spermine is associated with a transient alteration of cell cycle progression [Articolo su rivista]
Monti, M. G.; Pernecco, L.; Manfredini, R.; Frassineti, C.; Barbieri, D.; Marverti, G.; Ghiaroni, S.
abstract

Exposure of HL-60 cells to millimolar levels of spermine resulted in the inhibition of cell growth. Flow cytometry revealed that the addition of exogenous spermine prevented the accumulation of cells in the S and G2/M phases of the cell cycle as observed in the control cells. High intracellular levels of spermine completely suppressed the early onset of ornithine decarboxylase activity and, consequently, the intracellular increase in spermidine and putrescine. On the other hand, the addition of exogenous spermidine or putrescine also abolished ornithine decarboxylase activity, but in this case neither the growth of spermidine or putrescine-treated cells nor the cell cycle phase distribution was affected. In the latter cells, intracellular levels of spermidine were not significantly different from control ones. These results suggest that the addition of exogenous spermine inhibits cell proliferation by hindering the increase in cellular spermidine needed to accelerate the G, to S phase transition.

1995 - Defective brain and muscle energy metabolism shown by in vivo 31P-Magnetic Resonance Spectroscopy in non-affected carriers of 11778 mtDNA mutation. [Articolo su rivista]
B., Barbiroli; P:, Montagna; P., Cortelli; S., Iotti; R., Lodi; P., Barboni; L., Monari; E., Lugaresi; Frassineti, Chiara; P., Zaniol
abstract

In vivo phosphorus magnetic resonance spectroscopy (P-31-MRS) showed defective brain and muscle energy metabolism in three affected siblings in a family with Leber's hereditary optic neuropathy (LHON) with the 11778 mtDNA mutation. We studied 14 nonaffected members of the same pedigree by P-31-MRS and molecular genetics. Nine of 14 individuals studied had the 11778 mtDNA mutation, with various degrees of heteroplasmy. A decreased brain energy reserve, as shown by low phosphocreatine content and phosphorylation potential and high [ADP], was present in eight of these nine subjects with the 11778 mutation. A low rate of postexercise phosphocreatine recovery in muscle was present in six of the nine mutated individuals, Normal MRS findings in the brain of one and the muscle of three carriers were accompanied by a low percentage of mutated mtDNA All subjects without mutation had normal brain and muscle MRS. (31)p-MRS disclosed defective bioenergetics in the brain or muscle or both of all asymptomatic carriers studied from our pedigree.

1995 - NUCLEAR-MAGNETIC-RESONANCE AS A TOOL FOR DETERMINING PROTONATION CONSTANTS OF NATURAL POLYPROTIC BASES IN SOLUTION [Articolo su rivista]
Frassineti, Chiara; Ghelli, Stefano; P., Gans; A., Sabatini; Moruzzi, Maria Stella; A., Vacca
abstract

The acid-base properties of the tetramine 1,5,10,14-tetraazatetradecane H2N(CH2)(3)NH(CH2)(4)NH(CH2)(3)NH2 (spermine) in deuterated water have been studied at 40 degrees C at various pD values by means of NMR spectroscopy. Both one-dimensional C-13{H-1} spectra and two-dimensional H-1/C-13 heterocorrelation spectra with inverse detection have been recorded. A calculation procedure of general validity has been developed to unravel the effect of rapid exchange between the various species in equilibrium as a function of pD of the solution. The method of calculation used in this part of the new computer program, HYPNMR, is independent of the equilibrium model. HYPNMR has been used to obtain the basicity constants of spermine with respect to the D+ cation at 40 degrees C. Calculations have been performed using either C-13{H-1} or H-1/C-13 data individually, or using both sets of data simultaneously. The results of the latter calculations were practically the same as the results obtained with the single data sets; the calculated errors on the refined parameters were a little smaller. After appropriate empirical corrections for temperature effects and for the presence of DC in contrast to Hi, the calculated constants are compared with spermine protonation constants which have been determined previously both from potentiometric and NMR data.

1995 - The effect of spermine on calcium requirement for protein kinase C association with phospholipid vesicles. [Articolo su rivista]
Moruzzi, Maria Stella; Marverti, Gaetano; Piccinini, Giorgio; Frassineti, Chiara; Monti, Maria Giuseppina
abstract

We have previously reported that polyamines interfere with protein kinase C-membrane interactions. ...

1994 - MUSCLE PHOSPHOGLYCERATE MUTASE (PGAM) DEFICIENCY IN THE 1ST CAUCASIAN PATIENT - BIOCHEMISTRY, MUSCLE CULTURE AND P-31-MR SPECTROSCOPY [Articolo su rivista]
G., Vita; A., Toscano; N., Bresolin; G., Meola; F., Fortunato; A., Baradello; B., Barbiroli; Frassineti, Chiara; Zaniol, Paolo; C., Messina
abstract

Muscle phosphoglycerate mutase (PGAM) deficiency has been so far identified in only six patients, five of these being African Americans. We report the results of clinical, morphological, biochemical, muscle culture and P-31-MR spectroscopy studies in the first Caucasian patient with muscle PGAM deficiency. A 23-year-old man had a 10-year history of cramps after physical exertion with one episode of pigmenturia. Neurological examination and EMG study were normal. ECG and echocardiography revealed hypertrophy of the interventricular septum and slight dilatation of the left chambers of the heart. Muscle biopsy revealed increased glycogen content and some accumulation of mitochondria. Muscle PGAM activity was markedly decreased (6.5% and 9.7% of control value in two different biopsies). Citrate synthase and other mitochondrial respiratory chain enzyme activities were much higher than normal. In contrast to the marked decrease of PGAM activity observed in muscle biopsy, total enzyme activity in the patient's aneural muscle culture was normal, being represented exclusively by BB isoenzyme. The deficiency of PGAM-MM isoenzyme was reproduced in the patient's innervated muscle culture. Muscle P-31-MR spectroscopy showed accumulation of phosphomonoesters only on fast ''glycolytic'' exercise. On ''aerobic'' exercise, V(max), calculated from the work-energy cost transfer function, showed an increase consistent with the morphological and biochemical evidence of mitochondrial proliferation. This might represent a sort of compensatory aerobic effort in an attempt to restore muscle power.

1994 - P-31-MAGNETIC RESONANCE SPECTROSCOPY IN MIGRAINE WITHOUT AURA [Articolo su rivista]
P., Montagna; P., Cortelli; L., Monari; G., Pierangeli; P., Parchi; R., Lodi; S., Iotti; Frassineti, Chiara; Zaniol, Paolo; E., Lugaresi; B., Barbiroli
abstract

We investigated 22 patients with migraine without aura, all drug-free and in headache-free periods, by means of P-31-magnetic resonance spectroscopy (MRS) of brain and muscle. Brain P-31-MRS showed significantly low phosphocreatine, increased adenosine diphosphate, and decreased phosphorylation potential. There was a slow rate of phosphocreatine recovery after exercise in the muscle of 12 of 22 patients. Energy metabolism is abnormal in migraine without aura, as previously demonstrated in patients with migraine stroke and migraine with aura.

1993 - Effect of Spermine on Membrane-Associated and Membrane-Inserted Forms of Protein Kinase C [Articolo su rivista]
Moruzzi, Maria Stella; Marverti, Gaetano; G., Piccinini; Frassineti, Chiara; Monti, Maria Giuseppina
abstract

Protein kinase C is reported to exist in two membrane-bound states: a reversible one which can be dissociated by calcium chelators (membrane-associated form) and an irreversible one which is chelator stable (membrane-inserted form). In the present work the effects of a naturally occurring polyamine (spermine) on the membrane-associated and membrane-inserted forms of protein kinase C were investigated using a reconstituted system consisting of partially purified protein kinase C from rat brain and phospholipid vesicles of defined composition. The active membrane-bound complex was conveniently determined by its ability to bind radioactive phorbol ester with an exact 1:1 stoichiometry. Our experimental data show that, in the absence of calcium ions, the amount of enzyme bound to phospholipids vesicles was dramatically reduced by the presence of spermine whereas the PDBu binding affinity was not significantly affected. The addition of the divalent cation increased the affinity of phorbol ester for the active complex but had no effect on N(max); spermine added in this experimental conditions was no longer able to decrease the total number of enzyme molecules bound to liposomes. Moreover gel filtration experiments of the protein kinase C-phospholipids complex formed in the presence of calcium, indicated that polyamine added during the association process was able to reduce the extent of enzyme insertion into liposomes. Since the increase in phospholipid concentration resulted in a higher level of non-dissociable protein kinase C-liposomes complex we propose that spermine, complexing to membrane binding sites both in the absence and in the presence of Ca++, could promote binding conditions that oppose to the formation of the inserted form of the enzyme. As a consequence the distribution between the reversible and the irreversible membrane-bound forms of protein kinase C is affected.

1993 - IN-VIVO ASSESSMENT OF MITOCHONDRIAL FUNCTIONALITY IN HUMAN GASTROCNEMIUS-MUSCLE BY P-31 MRS - THE ROLE OF PH IN THE EVALUATION OF PHOSPHOCREATINE AND INORGANIC-PHOSPHATE RECOVERIES FROM EXERCISE [Articolo su rivista]
S., Iotti; R., Lodi; Frassineti, Chiara; Zaniol, Paolo; B., Barbiroli
abstract

In this study we compared the kinetics of phosphocreatine (PCr) and P(i) recovery, and their dependency on cytosolic pH in 38 normal individuals. Spectra were acquired during rest, work and recovery. A time resolution of 10 s was used to obtain detailed information. The kinetics of PCr and P(i) recovery almost overlapped when the lowest value of cytosolic pH reached during recovery (termed the minimum pH) was < 6.95, while they were completely dissociated when the minimum pH was > 6.95. This result is interpreted as indirect in vivo evidence of the kinetic control exerted by ADP on mitochondrial oxidation. Our results represent a rationale for new experimental conditions to be used in clinical routine studies of pathologies due to primary or secondary mitochondrial malfunction.

1993 - Relationship Between Spermine and Calcium on the Activation Process of Protein Kinase C. [Articolo su rivista]
Moruzzi, Maria Stella; Marverti, Gaetano; Piccinini, Giorgio; Frassineti, Chiara; Monti, Maria Giuseppina
abstract

Relationship Between Spermine and Calcium on the Activation Process of Protein Kinase C.

1992 - CORRELATION AND MULTIVARIATE ANALYSES OF SPECTROSCOPIC AND DIHYDROPTEROATE SYNTHASE INHIBITORY ACTIVITY DATA IN 4-AMINOARYL (MULTISUBSTITUTED ARYL) SULFONES [Articolo su rivista]
Cocchi, Marina; Iarossi, Dario; Frassineti, Chiara; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

Nuclear magnetic resonance (H-1 and C-13), vibrational spectroscopy, and quantum chemical calculations (complete neglect of differential overlap/2 [CNDO/2]) have been used to investigate 20 biologically active title compounds, inhibitors of the dihydropteroate synthase. The data obtained have been comparatively analyzed by correlation and multivariate analyses. The results obtained show that also in the case of multisubstitution the electronic effect can be rationalized in terms of electronic charge perturbations which are transmitted from the multisubstituted aryl ring to the common biofunctional moiety 4-NH2-C6H4-SO2- trough the SO2 group, mainly via hyperconjugation. Good predictions of both spectroscopic and biological data are obtained by the partial least squares method using quantum chemical descriptors.

1991 - Correlation and Multivariate Analyses of the Spectroscopic Data in 4'-Substituted 4-Nitro-difhenylsulfones [Articolo su rivista]
Cocchi, Marina; Iarossi, Dario; Frassineti, Chiara; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

Molecular descriptors such as quantum chemical indices, substituent constants, substituent chemical shifts values of monosubstituted benzenes, and different data analyses (linear regression, dual substituent parameters, and multivariate analysis) have been comparatively used in order to rationalize the electronic substituent effects and to predict C-13 nuclearmagnetic resonance (NMR) and vibrational spectroscopy (IR) data of the 14 title compounds. The results have been compared with those previously obtained for the biologically active 4'-substituted 4-aminodiphenylsulfones, inhibitors of the dihydropteroate synthase enzyme. Both the 4-nitro and the 4-amino sulfone series show similar transmission of the electronic substituent effects through the C(1)-SO2-C(1') moiety by a hyperconjugative mechanism. Good predictions of the spectroscopic data are obtained with the different models considered. However, the partial least-squares method and principal componenent analysis seem to be the most powerful predictive tools.

1989 - A Theoretical Study of Conformation-Electronic Structure Relationships in Benzensulfonamide Inhibitors of Carbonic Anhydrase Enzyme. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Cocchi, Marina; Frassineti, Chiara
abstract

A Theoretical Study of Conformation-Electronic Structure Relationships in Benzensulfonamide Inhibitors of Carbonic Anhydrase Enzyme.

1989 - Comparative QSAR Analysis in Dihydropteroate Synthase Inhibition by Sulphones. Design of Some New Derivatives with Improved Petency. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Iarossi, Dario; Frassineti, Chiara; Menziani, Maria Cristina; Cocchi, Marina; Cennamo, Carlo
abstract

Comparative QSAR Analysis in Dihydropteroate Synthase Inhibition by Sulphones. Design of Some New Derivatives with Improved Petency.

1989 - Quantitative Structure-Activity Relationships in Dihydropteroate Synthase Inhibition by Multisubstituted Sulfones. Design and Synthesis of Some New Derivatives with Improved Potency. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Iarossi, Dario; Folli, Ugo; Frassineti, Chiara; Menziani, Maria Cristina; Cennamo, Carlo
abstract

Quantitative Structure-Activity Relationships in Dihydropteroate Synthase Inhibition by Multisubstituted Sulfones. Design and Synthesis of Some New Derivatives with Improved Potency.

1988 - Multinuclear NMR and Vibrational Spectroscopy Studies of the Substituent Effects in Benzensulfonamide Inhibitors of the Enzyme Carbonic Anhydrase. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Iarossi, Dario; Menziani, Maria Cristina; Frassineti, Chiara; Benedetti, Adriano
abstract

Multinuclear NMR and Vibrational Spectroscopy Studies of the Substituent Effects in Benzensulfonamide Inhibitors of the Enzyme Carbonic Anhydrase.

1987 - A Quantum Chemical QSAR Analysis of Carbonic Anhydrase Inhibition by Heterocyclic Sulfonamides. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Cocchi, Marina; Frassineti, Chiara
abstract

A Quantum Chemical QSAR Analysis of Carbonic Anhydrase Inhibition by Heterocyclic Sulfonamides.

1987 - Quantitative Structure-Activity Analysis in Dihydropteroate Synthase Inhibition by Sulphones. Comparison with Sulfanilamides. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Iarossi, Dario; Menziani, Maria Cristina; V., Caiolfa; Frassineti, Chiara; Cennamo, Carlo
abstract

Quantitative Structure-Activity Analysis in Dihydropteroate Synthase Inhibition by Sulphones. Comparison with Sulfanilamides.

1985 - A Quantum Chemical QSAR Study of Carbonic Anhydrase Inhibition by Sulfonamides. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Frassineti, Chiara
abstract

A Quantum Chemical QSAR Study of Carbonic Anhydrase Inhibition by Sulfonamides.

1985 - Experimental and Theoretical Study of Electronic Substituent Effects in 4-Aminoaryl (4-Substituted Aryl) Sulphones. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Folli, Ugo; Iarossi, Dario; Frassineti, Chiara
abstract

Experimental and Theoretical Study of Electronic Substituent Effects in 4-Aminoaryl (4-Substituted Aryl) Sulphones.

1983 - A Theoretical Study of the Structure-Activity Relationship in Diarylsulphones. Comparison with Sulfa Drugs. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Frassineti, Chiara
abstract

A Theoretical Study of the Structure-Activity Relationship in Diarylsulphones. Comparison with Sulfa Drugs.

1981 - Structure-Activity Relationship in Dihydropteroate Synthase Inhibition by Sulfanilamides. Comparison with the Antibacterial Activity. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Rastelli, Augusto; Frassineti, Chiara; Cennamo, Carlo
abstract

Structure-Activity Relationship in Dihydropteroate Synthase Inhibition by Sulfanilamides. Comparison with the Antibacterial Activity.