Design, synthesis, and cytotoxic evaluation of a new series of 3-substituted spiro[(dihydropyrazine-2,5-dione)-6,3′-(2′,3′- dihydrothieno[2,3-b]naphtho-4′,9′-dione)] derivatives

Isabel Gomez-Monterrey, Pietro Campiglia, Alfonso Carotenuto, Daniela Califano, Claudio Pisano, Loredana Vesci, Teresa Lama, Alessia Bertamino, Marina Sala, Antonio Mazzella Di Bosco, Paolo Grieco, Ettore Novellino

Research output: Contribution to journalArticle

Abstract

A series of 3-substituted spiro[(dihydropyrazine-2,5-dione)-6,3′- (2′,3′-dihydrothieno[2,3-b]naphtho-4′,9′-dione)] derivatives were prepared using an easy synthetic route via condensation of the 3-amino-3-(ethoxycarbonyl)-2,3-dihydrothieno[2,3-b]naphtho-4,9-dione system and amino acids followed by intramolecular lactamization. Amino acids containing alkyl and aryl, linear and cyclic, polar and apolar, and basic and acid residues were incorporated. Evaluation of these analogues against the MCF-7 human breast carcinoma and SW 620 human colon carcinoma cell lines revealed, for the 3S,3′R isomers derived from Pro (7a), Cys (11a), and Met (12a) and the 3R,3′S isomer derived from D-Pro (7c), a cytotoxic potency comparable to or greater than that of doxorubicin. Some of these selected analogues were potent cytotoxic agents in several other sensible and resistant human solid tumor cell lines and may be able to circumvent the multiple-drug-resistance mechanism. In particular, only a partial cross-resistance to the compounds 7, 11, and 12 was observed in selected tumor cell sublines known to be resistant to doxorubicin (MCF-7/Dx and A2780/Dx), whereas a very low level of cross-resistance to compounds 7 and 11 was found in a tumor cell subline selected for resistance to cisplatin (A2780/DDP). In addition, the topoisomerase II inhibition activity and DNA-binding properties were investigated.

Original languageEnglish
Pages (from-to)1787-1798
Number of pages12
JournalJournal of Medicinal Chemistry
Volume50
Issue number8
DOIs
Publication statusPublished - Apr 19 2007

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Cells
Derivatives
Tumors
Doxorubicin
Isomers
Amino Acids
Type II DNA Topoisomerase
Cytotoxins
Multiple Drug Resistance
Tumor Cell Line
Cisplatin
Neoplasms
Colon
Breast Neoplasms
Carcinoma
Cell Line
Condensation
Acids
DNA
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Organic Chemistry

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Design, synthesis, and cytotoxic evaluation of a new series of 3-substituted spiro[(dihydropyrazine-2,5-dione)-6,3′-(2′,3′- dihydrothieno[2,3-b]naphtho-4′,9′-dione)] derivatives. / Gomez-Monterrey, Isabel; Campiglia, Pietro; Carotenuto, Alfonso; Califano, Daniela; Pisano, Claudio; Vesci, Loredana; Lama, Teresa; Bertamino, Alessia; Sala, Marina; Di Bosco, Antonio Mazzella; Grieco, Paolo; Novellino, Ettore.

In: Journal of Medicinal Chemistry, Vol. 50, No. 8, 19.04.2007, p. 1787-1798.

Research output: Contribution to journalArticle

Gomez-Monterrey, I, Campiglia, P, Carotenuto, A, Califano, D, Pisano, C, Vesci, L, Lama, T, Bertamino, A, Sala, M, Di Bosco, AM, Grieco, P & Novellino, E 2007, 'Design, synthesis, and cytotoxic evaluation of a new series of 3-substituted spiro[(dihydropyrazine-2,5-dione)-6,3′-(2′,3′- dihydrothieno[2,3-b]naphtho-4′,9′-dione)] derivatives', Journal of Medicinal Chemistry, vol. 50, no. 8, pp. 1787-1798. https://doi.org/10.1021/jm0612158
Gomez-Monterrey, Isabel ; Campiglia, Pietro ; Carotenuto, Alfonso ; Califano, Daniela ; Pisano, Claudio ; Vesci, Loredana ; Lama, Teresa ; Bertamino, Alessia ; Sala, Marina ; Di Bosco, Antonio Mazzella ; Grieco, Paolo ; Novellino, Ettore. / Design, synthesis, and cytotoxic evaluation of a new series of 3-substituted spiro[(dihydropyrazine-2,5-dione)-6,3′-(2′,3′- dihydrothieno[2,3-b]naphtho-4′,9′-dione)] derivatives. In: Journal of Medicinal Chemistry. 2007 ; Vol. 50, No. 8. pp. 1787-1798.
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abstract = "A series of 3-substituted spiro[(dihydropyrazine-2,5-dione)-6,3′- (2′,3′-dihydrothieno[2,3-b]naphtho-4′,9′-dione)] derivatives were prepared using an easy synthetic route via condensation of the 3-amino-3-(ethoxycarbonyl)-2,3-dihydrothieno[2,3-b]naphtho-4,9-dione system and amino acids followed by intramolecular lactamization. Amino acids containing alkyl and aryl, linear and cyclic, polar and apolar, and basic and acid residues were incorporated. Evaluation of these analogues against the MCF-7 human breast carcinoma and SW 620 human colon carcinoma cell lines revealed, for the 3S,3′R isomers derived from Pro (7a), Cys (11a), and Met (12a) and the 3R,3′S isomer derived from D-Pro (7c), a cytotoxic potency comparable to or greater than that of doxorubicin. Some of these selected analogues were potent cytotoxic agents in several other sensible and resistant human solid tumor cell lines and may be able to circumvent the multiple-drug-resistance mechanism. In particular, only a partial cross-resistance to the compounds 7, 11, and 12 was observed in selected tumor cell sublines known to be resistant to doxorubicin (MCF-7/Dx and A2780/Dx), whereas a very low level of cross-resistance to compounds 7 and 11 was found in a tumor cell subline selected for resistance to cisplatin (A2780/DDP). In addition, the topoisomerase II inhibition activity and DNA-binding properties were investigated.",
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T1 - Design, synthesis, and cytotoxic evaluation of a new series of 3-substituted spiro[(dihydropyrazine-2,5-dione)-6,3′-(2′,3′- dihydrothieno[2,3-b]naphtho-4′,9′-dione)] derivatives

AU - Gomez-Monterrey, Isabel

AU - Campiglia, Pietro

AU - Carotenuto, Alfonso

AU - Califano, Daniela

AU - Pisano, Claudio

AU - Vesci, Loredana

AU - Lama, Teresa

AU - Bertamino, Alessia

AU - Sala, Marina

AU - Di Bosco, Antonio Mazzella

AU - Grieco, Paolo

AU - Novellino, Ettore

PY - 2007/4/19

Y1 - 2007/4/19

N2 - A series of 3-substituted spiro[(dihydropyrazine-2,5-dione)-6,3′- (2′,3′-dihydrothieno[2,3-b]naphtho-4′,9′-dione)] derivatives were prepared using an easy synthetic route via condensation of the 3-amino-3-(ethoxycarbonyl)-2,3-dihydrothieno[2,3-b]naphtho-4,9-dione system and amino acids followed by intramolecular lactamization. Amino acids containing alkyl and aryl, linear and cyclic, polar and apolar, and basic and acid residues were incorporated. Evaluation of these analogues against the MCF-7 human breast carcinoma and SW 620 human colon carcinoma cell lines revealed, for the 3S,3′R isomers derived from Pro (7a), Cys (11a), and Met (12a) and the 3R,3′S isomer derived from D-Pro (7c), a cytotoxic potency comparable to or greater than that of doxorubicin. Some of these selected analogues were potent cytotoxic agents in several other sensible and resistant human solid tumor cell lines and may be able to circumvent the multiple-drug-resistance mechanism. In particular, only a partial cross-resistance to the compounds 7, 11, and 12 was observed in selected tumor cell sublines known to be resistant to doxorubicin (MCF-7/Dx and A2780/Dx), whereas a very low level of cross-resistance to compounds 7 and 11 was found in a tumor cell subline selected for resistance to cisplatin (A2780/DDP). In addition, the topoisomerase II inhibition activity and DNA-binding properties were investigated.

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