title: Spiro[(dihydropyrazin-2,5-dione)-6,3'-(2',3'-dihydrothieno[2,3-b]naphtho-4',9'-dione)]-based cytotoxic agents: structure-activity relationship studies on the substituent at N4-position of the diketopiperazine domain.
abstract: Analogues of the previously reported potent cytotoxic spiro[(dihydropyrazine-2,5-dione)-6,3'-(2',3'-dihydrothieno[2,3-b]naphtho-4',9'-dione)] derivatives (3, 3') were prepared to explore new structural requirements at the diketopiperazine domain for the cytotoxic activity. The in vitro activity was evaluated against the MCF-7 human breast carcinoma and SW 620 human colon carcinoma cell lines. The 4-[(2-N, N-dimethyl)amino]ethyl (6i), and the 4-(2-pyrrolydin)ethyl (6l) derivatives emerged as the most potent compounds of this series, with a cytotoxic activity comparable to that of doxorubicin. These compounds, in both racemic and pure enantiomeric forms, showed also a high efficacy in cell lines resistant to doxorubicin (MCF-7/Dx) and in cell lines that were highly resistant to treatment with doxorubicin, such as HEK-293 (kidney), M-14 (melanoma), and HeLa (cervical adenocarcinoma) human cell lines. In addition, the effects on growth and cell cycle progression in CaCo-2 cell line (colon adenocarcinoma) and DNA-binding properties were investigated.
authors.affiliation: Dipartimento di Chimica Farmaceutica e Tossicologica, University of Naples Federico II, 80131 Napoli, Italy.
authors.forename: Isabel
authors.initials: I
authors.lastname: Gomez-Monterrey
authors.forename: Pietro
authors.initials: P
authors.lastname: Campiglia
authors.forename: Alfonso
authors.initials: A
authors.lastname: Carotenuto
authors.forename: Paola
authors.initials: P
authors.lastname: Stiuso
authors.forename: Alessia
authors.initials: A
authors.lastname: Bertamino
authors.forename: Marina
authors.initials: M
authors.lastname: Sala
authors.forename: Claudio
authors.initials: C
authors.lastname: Aquino
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
authors.forename: Silvana
authors.initials: S
authors.lastname: Morello
authors.forename: Aldo
authors.initials: A
authors.lastname: Pinto
authors.forename: Pio
authors.initials: P
authors.lastname: Ianelli
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D054659:Diketopiperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C529802:4-((2-N,N-dimethyl)amino)ethylspiro((dihydropyrazin-2,5-dione)-6,3'-(2',3'-dihydrothieno(2,3-b)naphtho-4',9'-dione)); C529803:4-(2-pyrrolidine)ethylspiro((dihydropyrazin-2,5-dione)-6,3'-(2',3'-dihydrothieno(2,3-b)naphtho-4',9'-dione)); D000970:Antineoplastic Agents; D054659:Diketopiperazines; D009285:Naphthoquinones; D011719:Pyrazines; D004247:DNA