jm970675l_si_001.pdf (165.44 kB)
Download filed-Fused [1]Benzazepines with Selective in Vitro Antitumor Activity: Synthesis and Structure−Activity Relationships
journal contribution
posted on 1998-03-24, 00:00 authored by Andreas Link, Conrad KunickThe synthesis of novel
quinolino[3,2-d][1]benzazepines and
pyrido[3,2-d][1]benzazepines
is
described. The in vitro antitumor activity of the compounds has
been tested in the antitumor
screening of the National Cancer Institute (NCI). Several
2,4-diarylpyrido[3,2-d][1]benzazepin-6-ones and -thiones turned out to exhibit considerable cytotoxicity for
tumor cells. For studies
of SAR within these series, substituents were introduced into the
aromatic rings of the parent
systems. Compounds from the thiolactam series tended to show
higher potency than the
corresponding lactams. Prominent compounds with noteworthy
activity and remarkable
selectivity for renal cancer cell lines are the lactams 10c,
10g, and 10h and the
corresponding
thiolactams 11c, 11g, and 11h.
Methylation of the azepine nitrogen leads to complete loss
of
activity, whereas annelation of a triazolo ring at the lactam site or
transformation of the
thiolactam function to a thiolactim ether results in decreased
antitumor activity and selectivity.
Consequently, the secondary lactam or thiolactam structure of the
seven-membered ring has
to be regarded as essential for selective antitumor
activity.