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.
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.
Gomez-Monterrey
Isabel
I
Dipartimento di Chimica Farmaceutica e Tossicologica, University of Naples Federico II, 80131 Napoli, Italy.
Campiglia
Pietro
P
Carotenuto
Alfonso
A
Stiuso
Paola
P
Bertamino
Alessia
A
Sala
Marina
M
Aquino
Claudio
C
Grieco
Paolo
P
Morello
Silvana
S
Pinto
Aldo
A
Ianelli
Pio
P
Novellino
Ettore
E
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
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