Stabilization of G-Quadruplex DNA, Inhibition of Telomerase Activity, and Tumor Cell Apoptosis by Organoplatinum(II) Complexes with Oxoisoaporphine

Abstract

Two G-quadruplex ligands [Pt(L(a))(DMSO)Cl] (Pt1) and [Pt(L(b))(DMSO)Cl] (Pt2) have been synthesized and fully characterized. The two complexes are more selective for SK-OV-3/DDP tumor cells versus normal cells (HL-7702). It was found that both Pt1 and Pt2 could be a telomerase inhibitor targeting G-quadruplex DNA. This is the first report demonstrating that telomeric, c-myc, and bcl-2 G-quadruplexes and caspase-3/9 preferred to bind with Pt2 rather than Pt1, which also can induce senescence and apoptosis. The different biological behavior of Pt1 and Pt2 may correlate with the presence of a 6-hydroxyl group in L(b). Importantly, Pt1 and Pt2 exhibited higher safety in vivo and more effective inhibitory effects on tumor growth in the HCT-8 and NCI-H460 xenograft mouse model, compared with cisplatin. Taken together, these mechanistic insights indicate that both Pt1 and Pt2 display low toxicity and could be novel anticancer drug candidates.

Synthesis of acyl oleanolic acid-uracil conjugates and their anti-tumor activity

“…This assay was carried out according to a description in a published study [35]. Cells were seeded at a concentration of 5 × 10 4 cell/mL in a volume of 2 mL on a sterile cover slip in six-well tissue culture plates.…”

“…This assay was carried out according to a description in a published study [35]. Cells grown on a sterile cover slip in six-well tissue culture plates were treated with compound for a certain range of time.…”

“…This assay was carried out according to a description in a published study [35]. The induced apoptosis was assayed by the Annexin V-FITC Apoptosis Detection kit (Beyotime, China), according to the manufacturer’s instructions.…”

“…According to a description in a published study [35], the measurement of the caspase-3 and caspase-9 activities was performed by a CaspGLOW™ Fluorescein Active Caspase-3 and Caspase-9 Staining Kit. The prepared Hep-G2 cells were harvested at a density of 1 × 10 6 cells/mL in RPMI 1640 medium supplemented with 10% FCS.…”

Preparation of 6/8/11-Amino/Chloro-Oxoisoaporphine and Group-10 Metal Complexes and Evaluation of Their in Vitro and in Vivo Antitumor Activity

“…It has been reported that alkaloids are an important source of G-quadruplex ligands, and they also exhibit significant anticancer bioactivities41. Nevertheless, there are only a few reported metal complexes with alkaloids as G-quadruplex ligands4243. To combine the anticancer activity of group-10 metal complexes and those of alkaloids, we synthesized group-10 metal complexes with oxoisoaporphine ligands (6-amino-oxoisoaporphine, L a ; 8-amino-oxoisoaporphine, L b ; 8-chloro-oxoisoaporphine, L c ; and 10-chloro-11-amino-oxoisoaporphine, L d )444546.…”