Abstract
A facile synthesis of the C4-substituted isoquinolines 5a-c and 6a-c is described. Commercially available 4-bromoisoquinoline is converted to the α,β-unsaturated esters 8 and 10 on treatment with the appropriate acrylate ester under Heck reaction conditions. The saturated amides 5a-c were obtained from the reaction of ester 9 with the requisite primary amine. Similarly the unsaturated analogues 6a-c were prepared by reacting ester 10 with the appropriate amine. The cytotoxicity of the target molecules was evaluated in two tumour cell lines in vitro. Two compounds, 6b and 6c, showed sufficient activity in the human non-small cell lung cancer line NSCLC-N16-L16 to be worthy of further study.
Highlights
Substituted quinolines and isoquinolines constitute the principal subunits of a large number of linear and angular aromatic “frameworks” with cytotoxic properties (Langer Clin Cancer Res 1999) [1] [2]
We have published the synthesis of the cytotoxic pyrroloquinoline derivatives 1-3 (Fig. 1) (Vlachou Heterocycles 2002) [5] and their isomeric pyrroloisoquinolines 4a-e (Fig. 1) (Vlachou EJPS 2002) [6]
1874-1045/07 appears to influence their cytotoxic potency and DNAbinding affinity. Based on these findings we present the synthesis and biological activity of the C4-substituted isoquinolines 5a-c (Scheme 1) and 6a-c (Scheme 2), which constitute structurally related congeners of 1-4
Summary
Substituted quinolines and isoquinolines constitute the principal subunits of a large number of linear and angular aromatic “frameworks” with cytotoxic properties (Langer Clin Cancer Res 1999) [1] (von Nussbaum JMC 1999) [2]. Based on these findings we present the synthesis and biological activity of the C4-substituted isoquinolines 5a-c (Scheme 1) and 6a-c (Scheme 2), which constitute structurally related congeners of 1-4. For the synthetic plan we had to start with commercially available 4bromoisoquinoline (7), which was reacted with ethyl acrylate under Heck reaction conditions (Sakamoto Heterocycles 1981) [7] to give ,-unsaturated ethyl ester 8 in 79% yield as a single isomer of trans geometry.
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