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6 results on '"SETZU G."'

1. Antitumor agents. 1. Synthesis, Biological evaluation and molecular modeling of 5H-pyrido[3,2-a]phenoxazin-5-one, a new actynomicin D analog with potent antiproliferative activity

Author

BOLOGNESE A., CORREALE G., MANFRA M., LAVECCHIA A., MAZZONI O., NOVELLINO E., LA COLLA P., LODDO R., MURGIONI C., PANI A., SERRA I., SETZU G., BARONE, VINCENZO, Bolognese, A., Correale, G., Manfra, M., Lavecchia, A., Mazzoni, O., Novellino, E., Barone, Vincenzo, LA COLLA, P., Loddo, R., Murgioni, C., Pani, A., Serra, I., and Setzu, G.

Published
2002

2. Chiral resolution and molecular modeling investigation of rac-2-cyclopentylthio-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methylpyrimidin-4(3H)-one (MC-1047), a potent anti-HIV-1 reverse transcriptase agent of the DABO class

Author

Quaglia, M. G., Mai, Antonello, Sbardella, G., Artico, Marino, Ragno, Rino, Massa, S., DEL PIANO, D., Setzu, G., Doratiotto, S., and Cotichini, V.

Subjects
Models, Molecular, Anti-HIV Agents, Enantiomeric separation, Binding mode, Non-nucleoside reverse transcriptase inhibitor, Chiral stationary phase, Circular dichroism, Circular Dichroism, Microbial Sensitivity Tests, Pyrimidinones, Cell Line, HIV-1, Humans, Reverse Transcriptase Inhibitors
Abstract

rac-2-Cyclopentylthio-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methylpyrimidin-4(3H)-one (MC-1047) is a potent inhibitor of HIV-1 multiplication in acutely infected cells. MC-1047 racemate has been resolved by chiral HPLC using, as chiral stationary phase (CSP), a commercially available (R,R)-Whelk-01 column. The optical purity and the circular dichroism (CD) of the two resolved enantiomers were determined and their biological activities tested in in vitro assays. Molecular modeling inspection of the binding of (R) and (S) enantiomers to the non-nucleoside binding site (NNBS) of reverse transcriptase (RT) using the defined model of F(2)-S-DABO/RT complex indicates the (R) enantiomer as the more active isomer.

Published
2001

3. Chiral resolution and molecular modeling investigation ofrac-2-cyclopentylthio-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methylpyrimidin-4(3H)-one (MC-1047), a potent anti-HIV-1 reverse transcriptase agent of the DABO class

Author

Quaglia, M.G., primary, Mai, A., additional, Sbardella, G., additional, Artico, M., additional, Ragno, R., additional, Massa, S., additional, del Piano, D., additional, Setzu, G., additional, Doratiotto, S., additional, and Cotichini, V., additional

Published
2001
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5. Antitumor Agents. 1. Synthesis, Biological Evaluation, and Molecular Modeling of 5H-Pyrido[3,2-a]phenoxazin-5-one, a Compound with Potent Antiproliferative Activity

Author

Bolognese, A., Correale, G., Manfra, M., Lavecchia, A., Mazzoni, O., Novellino, E., Barone, V., Pani, A., Tramontano, E., Colla, P. La, Murgioni, C., Serra, I., Setzu, G., and Loddo, R.

Abstract

The iminoquinone is an important moiety of a large number of antineoplastic drugs and plays a significant role in the nucleus of actinomycins, powerful, highly toxic, natural antibiotics that target DNA as intercalating agents. A series of polycyclic iminoquinonic compounds, 2-amino-3H-phenoxazin-3-one (1), 2-amino-1,9-diacetyl-3H-phenoxazin-3-one (2), 2-acetylamino-3H-phenoxazin-3-one (3), 3H-phenoxazin-3-one (4), 5H-pyrido[3,2-a]phenoxazin-5-one (5), and 5H-pyrido[3,2-a]phenothiazin-5-one (6), strictly related to the actinomycin chromophore, were synthesized for developing new anticancer intercalating drugs. The antiproliferative activity of these compounds, evaluated against representative human liquid and solid neoplastic cell lines, showed that 5 and its isoster 6 were the most active compounds inhibiting cell proliferation in a submicromolar range. Compound 5 was also evaluated against KB subclones (KBMDR, KB7D, and KBV20C), which overexpress the MDR1/P-glycoprotein drug efflux pump responsible for drug resistance. All the above KB subclones did not show altered sensitivity to the antiproliferative activity of 5. UV−vis and 1H NMR spectroscopy experiments support the phenoxazinone 5/DNA binding. Molecular mechanics methods were used to build a three-dimensional model of the 5/[d(GAAGCTTC)]2 complex. Electrostatic interactions between the hydrogen of the positively charged pyridine nitrogen of 5 and the negatively charged oxygen atoms (O4‘ and O5‘) of the cytosine C5 residue together with stacking forces contribute to the high antiproliferative activity. The metal(II)-assisted synthesis procedure of 5 is described, and the formation mechanism is proposed.

Published
2002
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6. Antitumor Agents. 1. Synthesis, Biological Evaluation and Molecular Modeling of 5H-pyrido[3,2-a]phenoxazin-5-one, a Compound with Potent Antiproliferative Activity

Author

Gaetano Correale, Alessandra Pani, Enzo Tramontano, Adele Bolognese, Michele Manfra, Roberta Loddo, Mazzoni O, Chiara Murgioni, Ettore Novellino, Ilaria Serra, Antonio Lavecchia, Giovanna Setzu, Paolo La Colla, Vincenzo Barone, Bolognese, Adele, Correale, G., Manfra, M., Lavecchia, Antonio, Mazzoni, O., Novellino, Ettore, Barone, V., LA COLLA, P., Loddo, R., Murgioni, C., Pani, A., Serra, I., Bolognese, A., Lavecchia, A., Mazzoni, Orazio, Novellino, E., Tramontano, E., Setzu, G., Correale, G, Manfra, M, Lavecchia, A, Mazzoni, O, Novellino, E, Barone, V, Pani, A, Tramontano, E, LA COLLA, P, Murgioni, C, Serra, I, and Setzu, G

Subjects
Models, Molecular, Magnetic Resonance Spectroscopy, Molecular model, Stereochemistry, Antineoplastic Agents, Chemical synthesis, Structure-Activity Relationship, chemistry.chemical_compound, Oxazines, Drug Discovery, Tumor Cells, Cultured, Humans, Structure–activity relationship, Moiety, Cytotoxicity, DNA, Intercalating Agents, Thiazoles, chemistry, Drug Resistance, Neoplasm, Molecular Medicine, Neoplastic cell, Spectrophotometry, Ultraviolet, Efflux, Drug Screening Assays, Antitumor, Cell Division
Abstract

The iminoquinone is an important moiety of a large number of antineoplastic drugs and plays a significant role in the nucleus of actinomycins, powerful, highly toxic, natural antibiotics that target DNA as intercalating agents. A series of polycyclic iminoquinonic compounds, 2-amino-3H-phenoxazin-3-one (1), 2-amino-1,9-diacetyl-3H-phenoxazin-3-one (2), 2-acetylamino-3H-phenoxazin-3-one (3), 3H-phenoxazin-3-one (4), 5H-pyrido[3,2-a]phenoxazin-5-one (5), and 5H-pyrido[3,2-a]phenothiazin-5-one (6), strictly related to the actinomycin chromophore, were synthesized for developing new anticancer intercalating drugs. The antiproliferative activity of these compounds, evaluated against representative human liquid and solid neoplastic cell lines, showed that 5 and its isoster 6 were the most active compounds inhibiting cell proliferation in a submicromolar range. Compound 5 was also evaluated against KB subclones (KBMDR, KB7D, and KBV20C), which overexpress the MDR1/P-glycoprotein drug efflux pump responsible for drug resistance. All the above KB subclones did not show altered sensitivity to the antiproliferative activity of 5. UV-vis and (1)H NMR spectroscopy experiments support the phenoxazinone 5/DNA binding. Molecular mechanics methods were used to build a three-dimensional model of the 5/[d(GAAGCTTC)]2 complex. Electrostatic interactions between the hydrogen of the positively charged pyridine nitrogen of 5 and the negatively charged oxygen atoms (O4' and O5') of the cytosine C5 residue together with stacking forces contribute to the high antiproliferative activity. The metal(II)-assisted synthesis procedure of 5 is described, and the formation mechanism is proposed.

Published
2002

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