Synthesis and Biological Evaluation of Nitrogen-Containing Goniothalamin Analogues

Goniothalamin, a styryl lactone found in the genus Goniothalamus, has been studied in our group due to its antitumor and anti-inflammatory activity.1–3 In the search for more potent compounds, a series of nitrogen-containing Goniothalamin analogues were synthesized, with modification at both para and meta positions. Two different synthetic routes were developed to incorporate the nitrogen-containing groups into the aromatic ring. Modifications at the meta position were made by acylation of m-aminogoniothalamin, the key-intermediate. Regarding the para position, a Buchwald-Hartwig cross coupling reaction was employed using the homoallylic alcohol, followed by esterification and ring closing metathesis reaction to afford the final lactones. A total of 20 analogues were synthesized and evaluated against MCF-7 (breast cancer), HeLa (cervical cancer) and PNT2 (normal prostate) cell lines. Compounds 4 and 11 were the most interesting analogues showing IC50 (MCF-7) = 2.6 μM and IC50 (HeLa) = 8.2 μM, respectively.