DNA Metalating–Intercalating Hybrid Agents for the Treatment of Chemoresistant Cancers

Abstract

Nonclassical platinum-based antitumor agents have shown enormous potential in the treatment of chemoresistant cancers. The design of these agents is based on the hypothesis that platinum-containing pharmacophores that react with nuclear DNA in cancer cells radically differently than the clinical agent cisplatin will produce a unique spectrum of biological activity. One such class of molecules are platinum-acridine hybrid agents derived from the prototypical complex [PtCl(en)(ACRAMTU)](NO(3))(2), en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea ("PT-ACRAMTU"). This article summarizes milestones in the development of these agents and reviews critical key concepts that have guided their design and that of related compounds.

Redesigning the DNA‐Targeted Chromophore in Platinum–Acridine Anticancer Agents: A Structure–Activity Relationship Study

“…These previously optimized critical motifs allow strainless intercalation/p-stacking of the chromophore with DNA bases adjacent to the sites of platination. [3] Systematic changes to the chromophore were desired that reduce the electrostatically driven association and promiscuous reactivity of the platinum–acridines with nuclear DNA. The approach involved reducing the cationic charge of the DNA-interacting chromophore and modifying its shape and size.…”

“…[2] To extend the spectrum of activity of the classical anticancer metal, platinum complexes have been introduced as reactive, electrophilic components into multifunctional DNA-targeted therapies, such as platinum–intercalator agents. [3,4] …”

“…The platinum–acridine agents represented by the general structure in Figure 1 form mixed monofunctional-intercalative DNA adducts distinct from the bifunctional cross-links induced by cisplatin [3] and structurally related monofunctional-noninter-calative DNA adducts. [5] The hybrid adducts form at a significantly higher rate and are a more severe form of DNA damage than the classical cross-links.…”

“…[5] The hybrid adducts form at a significantly higher rate and are a more severe form of DNA damage than the classical cross-links. [3] They effectively inhibit DNA synthesis in treated cells and lead to stalled replication forks and DNA double-strand breaks, which elicits responses from specialized DNA damage recognition and repair modules. [6] In addition, the hybrid adducts are significantly more potent inhibitors of RNA polymerase II (Pol II)-mediated transcription than the cross-links.…”

Human Serum Albumin-Delivered [Au(PEt3)]+ Is a Potent Inhibitor of T Cell Proliferation

“…12,13 The dicationic phosphinemodified complex, [Au(PEt 3 )(ACRAMTU)](NO 3 ) 2 (1), inhibited T cell proliferation at concentrations an order of magnitude lower than had previously been observed in human cancer cells by disrupting the mitochondrial Trx/TrxR system. 10 It also demonstrated potent immunosuppressive activity in mice but was mildly toxic to the test animals when injected intraperitoneally.…”