Facile total synthesis of lysicamine and the anticancer activities of the RuII, RhIII, MnII and ZnII complexes of lysicamine

Abstract

Lysicamine is a natural oxoaporphine alkaloid, which isolated from traditional Chinese medicine (TCM) herbs and has been shown to possess cytotoxicity to hepatocarcinoma cell lines. Reports on its antitumor activity are scarce because lysicamine occurs in plants at a low content. In this work, we demonstrate a facile concise total synthesis of lysicamine from simple raw materials under mild reaction conditions, and the preparation of the Ru(II), Rh(III), Mn(II) and Zn(II) complexes 1–4 of lysicamine (LY). All the compounds were fully characterized by elemental analysis, IR, ESI-MS, 1H and 13C NMR, as well as single-crystal X-ray diffraction analysis. Compared with the free ligand LY, complexes 2 and 3 exhibited superior in vitro cytotoxicity against HepG2 and NCI-H460. Mechanistic studies indicated that 2 and 3 blocked the cell cycle in the S phase by decreasing of cyclins A2/B1/D1/E1, CDK 2/6, and PCNA levels and increasing levels of p21, p27, p53 and CDC25A proteins. In addition, 2 and 3 induced cell apoptosis via both the caspase-dependent mitochondrial pathway and the death receptor pathway. in vivo study showed that 2 inhibited HepG2 tumor growth at 1/3 maximum tolerated dose (MTD) and had a better safety profile than cisplatin.

Ruthenium Complexes as Promising Candidates against Lung Cancer

“…Additional studies have shown that metallodrugs can target CDKs and cycle proteins to block the cell cycle in different phases. For instance, Ru(II), Rh(III), Mn(II), and Zn(II) complexes blocked the cell cycle in the S-phase, thus inhibiting cell proliferation by reducing the levels of cyclins A2/B1/D1/E1, CDK-2/6, and PCNA and increasing the levels of p21, p27, p53, and CDC25A [ 121 ].…”

Protein kinases as therapeutic targets to develop anticancer drugs with natural alkaloids

“…An oxoaporphine alkaloid, lysicamine isolated from Asimina triloba inhibited the growth of hepatoma HepG2 and lung cancer NCI-H460 cells. Lysicamine induced S-phase arrest via down-regulation of the expression of cyclin A2/B1/D1/E1 and CDK2/6 [120]. FLT3, a type III receptor tyrosine kinase acts as a proto-oncogene involved in crucial steps of haematopoiesis such as proliferation, differentiation and survival.…”

Caspase‐3: A primary target for natural and synthetic compounds for cancer therapy

“…Chen and Liang (2010) reported the anticancer activity of metal complex of liriodenine, oxoglaucine and oxoisoaporphine, as more potent to corresponding ligands. Furthermore, Qin et al., (2017) synthesized four metal complexes of lysicamine, that is, [Ru(LY)Cl 2 (DMSO) 2 ]·3H 2 O, [Rh(LY‐OH)Cl 3 CH 3 OH], [Mn(LY) 3 ](ClO 4 ) 2 .3CHCl 3 , and [Zn(LY) 2 (ClO 4 ) 2 ], and reported their cytotoxicity against HepG2 and NCI‐H460 cell lines. Rh and Mn‐metal complex of lysicamine ( 26 ) exhibited higher cytotoxicity against HepG2 and NCI‐H460 (Figure 20).…”