Antiviral and tumor cell antiproliferative SAR studies on tetracyclic eudistomins. II.
J H van Maarseveen, H W Scheeren, E De Clercq, J Balzarini, C G Kruse
Index: Bioorg. Med. Chem. 5(5) , 955-70, (1997)
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Abstract
In a search for the minimum pharmacophore of the naturally occurring tetracyclic eudistomins, five structural analogues (4-8) were evaluated for their in vitro antiviral and tumor cell antiproliferative activities. For the synthesis of these derivatives both intra- and intermolecular Pictet-Spengler reactions have been used. Opening of the beta-carboline annulated 7-membered D-ring in 6 and 7 resulted in a complete loss of activity. On the other hand, replacement of either the oxygen atom or the sulfur atom in the 7-membered ring by a methylene group in 5 and 8, respectively, is allowed. These results combined with previous SAR data underline the crucial importance of the D-ring in eudistomins as a scaffold for the correct positioning of both basic nitrogen atoms. Also bioisosteric replacement of the bicyclic indole system with a dimethoxyphenyl group, to give the isoquinoline skeleton, is allowed. The tricyclic isoquinoline derivative 4 is, so far, the most promising antiviral analogue; it combines a high potency (MIC at 100 ng/ mL (340 nM)) with high MCC/MIC ratios (ranging from 1000 to 5000 against HSV-1, HSV-2, vaccinia virus, and vesicular stomatitis virus.
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