Cytotoxicity mechanisms of pyrazino[1,2-b]isoquinoline-4-ones and SAR studies.
The cytotoxicity showed by 1b, an interesting representant of the title compounds, for HT-29 human colon cancer cells (CI(50) value of 1.95 x 10(-7)M) has been related to the induced cell death at the G2 phase and not to DNA damage. This compound promotes the degradation of components of the G2/M checkpoint machinery, in particular cdc2, Cyclin B1 and Wee1, which represents a novel mechanism of cytotoxicity. Degradation of Wee1 seems to be mediated by proteasome activity but degradation of cdc2 has to occur through a different mechanism. The activity of 1b on G2 cell cycle components suggests that tumor cells that are arrested in G2/M by anticancer drugs like cisplatin could be targeted by compound 1b, increasing the apoptosis induction, and that their optimized analogs might be useful in the treatment of colon cancer through combination therapies with cisplatin or other anticancer drugs that affect the cytoskeleton integrity such as taxol and taxotere. SAR studies with compounds obtained by manipulation of the N(2) and C(4)-functional groups and the C(6)-chain of compound 1b have confirmed the importance of these structural features in the in vitro antitumor activity. Fused oxazolidine derivatives as compound 5 were inactive, and the lack of activity found in the replacement of the C(4)-lactam by a cyanoamine function, as in compounds 8-10, could be explained considering that their all-syn relative configuration makes them too stable to generate alkylating iminium species.
Ortín
Irene
I
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
González
Juan Francisco
JF
Cuesta
Elena de la
Ede L
Manguan-García
Cristina
C
Perona
Rosario
R
Avendaño
Carmen
C
D017209:Apoptosis / Q000502:physiology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D016195:G2 Phase / Q000502:physiology*; D019073:HT29 Cells; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
D018797:Cell Cycle Proteins; D007546:Isoquinolines; D011719:Pyrazines