Abstract
Twenty-five sophora alkaloids-cinnamic acid hybrids (including matrine-cinnamic acid hybrids, sophoridine-cinnamic acid hybrids, and sophocarpine-cinnamic acid hybrids) were designed, synthesized, and evaluated in vitro against three human tumor cell lines (HeLa, HepG2 and A549) with cisplatin as a positive control. Some matrine-cinnamic acid and sophoridine-cinnamic acid compounds exhibited potent effect against all three cancer cell lines, such as compounds 5b, 5e, 5g, and 6d. The structure-activity relationship study of the synthesized compounds was also performed. Preliminary mechanistic studies indicated that compounds 5e and 6d could induce apoptosis in HepG2 cell line. Further, compounds 5e and 6d altered mitochondrial membrane potential and produced ROS leading to cell apoptosis of HepG2 cells. Overall, our findings suggested that these compounds may provide promising lead compounds for further development as antitumor agents by structural modification.
Highlights
Matrine, sophoridine, and sophocarpine (Figure 1) are the main extractable alkaloid components in the roots of Sophora flavescens Ait (Fabaceae), a common traditional chinese herb
The synthesis of sophora alkaloids-cinnamic derivatives is outlined in Scheme 1
The Boc protective group was introduced to the 12N-atom of 1 which produced 2 with a yield of 73%, which was used in the following reduction step by LiAlH4 to give 3 [40,41]
Summary
Sophoridine, and sophocarpine (Figure 1) are the main extractable alkaloid components in the roots of Sophora flavescens Ait (Fabaceae), a common traditional chinese herb. Cinnamic acid and its analogues, such as caffeic acid and ferulic acid (Figure 2), are naturally occurring aromatic fatty acids which are widely presented in fruits, coffee, and wine [29] They consist of a common phenyl ring substituted with an acrylic acid group and displayed a variety of biological activities including antitumor effect [30,31,32,33,34]. Mao et al adopted molecular hybridization strategy to produce bergenin-cinnamic acid hybrids and the evaluation of their antitumor activity proved that the hybrid compounds were superior to bergenin [39] These stimulated us to design and synthesize the hybrids of sophora alkaloids and cinnamic acid as antitumor agents by molecular hybridization strategy with improved affinity and efficacy. The most promising molecule was selected for further pharmacological mechanism studies
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