Synthesis, Aqueous Reactivity, and Biological Evaluation of Carboxylic Acid Ester-Functionalized Platinum–Acridine Hybrid Anticancer Agents

Abstract

The synthesis of platinum–acridine hybrid agents containing carboxylic acid ester groups is described. The most active derivatives and the unmodified parent compounds showed up to 6-fold higher activity in ovarian cancer (OVCAR-3) and breast cancer (MCF-7, MDA-MB-23) cell lines than cisplatin. Inhibition of cell proliferation at nanomolar concentrations was observed in pancreatic (PANC-1) and non-small cell lung cancer cells (NSCLC, NCI-H460) of 80- and 150-fold, respectively. Introduction of the ester groups did not affect the cytotoxic properties of the hybrids, which form the same monofunctional–intercalative DNA adducts as the parent compounds, as demonstrated in a plasmid unwinding assay. In-line high-performance liquid chromatography and electrospray mass spectrometry (LC-ESMS) shows that the ester moieties undergo platinum-mediated hydrolysis in a chloride concentration-dependent manner to form carboxylate chelates. Potential applications of the chloride-sensitive ester hydrolysis as a self-immolative release mechanism for tumor-selective delivery of platinum–acridines are discussed.

Antiproliferative effects of copper(II)–polypyridyl complexes in breast cancer cells through inducing apoptosis

“…In this relation, a well-known metal complex with anticancer activity is cis-diamminedichloro platinum(II) (cisplatin) which covalently binds to DNA. While the platinum based antitumor agents have vast effect on current cancer therapy (Graham et al 2012), the types of cancer that can be treated with platinum agents are limited and suffer from side effects and resistance phenomena (Boerner and Zaleski 2005;Ott and Gust 2007). In order to get over clinical troubles connected with the relatively limited activity of platinum based agents against the wide spectrum of human malignancies, acquired resistance, and side effects, novel nonplatinum metal-based anticancer complexes have been and are being developed (Ott and Gust 2007;Gust et al 2004;Köpf-Maier 1999;Castonguay et al 2012).…”

Design and cellular studies of a carbon nanotube-based delivery system for a hybrid platinum-acridine anticancer agent

“…5) at a dose that is less than a tenth of the reported dose of cisplatin required for a similar effect on MDA-MB-231 cells. [3] TNBC patients show the highest levels of tumor recurrence, the lowest five-year survival rates of all breast cancer subtypes,[49] and do not benefit from current molecularly targeted therapies. [50] The high activity we establish for P3A1 and P3A1 -MWCNT[1] treatment of TNBC cells offers the possibility of expanding platinum therapy to TNBC patients.…”

“…[3, 4] The acridine group functions as a DNA intercalator that when combined with a platinum moiety, leads to rapid mono-adduct formation with nucleotides near the intercalation site resulting in a more severe form of DNA damage than the cross-links induced by cisplatin. [3–9] PAs also form permanent adducts at significantly higher frequency in genomic DNA than cisplatin resulting in effective inhibition of DNA replication and transcription,[6] which results in submicromolar activity against intrinsically platinum-resistant cancers, including breast cancer, in vitro . [3, 10] Second-generation platinum-acridines are less reactive with non-DNA intracellular nucleophiles, which may contribute to their high potency .…”

“…[3–9] PAs also form permanent adducts at significantly higher frequency in genomic DNA than cisplatin resulting in effective inhibition of DNA replication and transcription,[6] which results in submicromolar activity against intrinsically platinum-resistant cancers, including breast cancer, in vitro . [3, 10] Second-generation platinum-acridines are less reactive with non-DNA intracellular nucleophiles, which may contribute to their high potency . [11] The non-crosslinking DNA damage differs greatly from current clinical agents and is able to circumvent resistance.…”

“…[11] The non-crosslinking DNA damage differs greatly from current clinical agents and is able to circumvent resistance. [3]…”