Syntheses and evaluation of acridone-naphthalimide derivatives for regulating oncogene PDGFR-β expression.

A series of acridone-naphthalimide derivatives were synthesized for enhancing anti-cancer activity. Subsequent evaluation showed that derivative WZZ02 could stabilize oncogene PDGFR-β promoter G-quadruplex and destabilize its corresponding i-motif structure resulting in down-regulation of PDGFR-β gene transcription selectively, which caused tumor cells apoptosis. • PDGFR-β is upregulated in various types of cancers and is a known anti-tumor target. • We synthesized and evaluated various fluorescent acridone-naphthalimide derivatives. • WZZ02 selectively stabilized PDGFRβ promoter G-quadruplex and destabilize its i-motif. • WZZ02 down-regulated PDGFR-β gene expression and inhibited cancer cell proliferation. • WZZ02 exhibited tumor growth inhibition activity in MCF-7 xenograft tumor model. Upregulation of platelet-derived growth factor receptor β (PDGFR-β) has been found to be associated with development of various types of cancers, which has become an attractive target for anti-tumor treatment. Previously, we have synthesized and studied an acridone derivative B19 , which can selectively bind to and stabilize oncogene c-myc promoter i-motif, resulting in down-regulation of c-myc transcription and translation, however its effect on tumor cells apoptosis requires improvement. In the present study, we synthesized a variety of B19 derivatives containing a known anti-cancer fluorescent chromophore naphthalimide for the purpose of enhancing anti-cancer activity. After screening, we found that acridone-naphthalimide derivative WZZ02 could selectively stabilize PDGFR-β promoter G-quadruplex and destabilize its corresponding i-motif structure, without significant interaction to other oncogenes promoter G-quadruplex and i-motif. WZZ02 down-regulated PDGFR-β gene transcription and translation in a dose-dependent manner, possibly due to above interactions. WZZ02 could significantly inhibit cancer cell proliferation, and induce cell apoptosis and cycle arrest. WZZ02 exhibited tumor growth inhibition activity in MCF-7 xenograft tumor model, which could be due to its binding interactions with PDGFR-β promoter G-quadruplex and i-motif. Our results suggested that WZZ02 as a dual G-quadruplex/i-motif binder could be effective on both oncogene replication and transcription, which could become a promising lead compound for further development with improved potency and selectivity. The wide properties for the derivatives of 1,8-naphthalimide could facilitate further in-depth mechanistic studies of WZZ02 through various fluorescent physical and chemical methods, which could help to further understand the function of PDGFR-β gene promoter G-quadruplex and i-motif. [ABSTRACT FROM AUTHOR]