Iodide Analogs of Arsenoplatins—Potential Drug Candidates for Triple Negative Breast Cancers

Abstract

Patients with triple negative breast cancers (TNBCs)—highly aggressive tumors that do not express estrogen, progesterone, and human epidermal growth factor 2 receptors—have limited treatment options. Fewer than 30% of women with metastatic TNBC survive five years after their diagnosis, with a mortality rate within three months after a recurrence of 75%. Although TNBCs show a higher response to platinum therapy compared to other breast cancers, drug resistance remains a major obstacle; thus, platinum drugs with novel mechanisms are urgently needed. Arsenoplatins (APs) represent a novel class of anticancer agents designed to contain the pharmacophores of the two FDA approved drugs cisplatin and arsenic trioxide (As2O3) as one molecular entity. Here, we present the syntheses, crystal structures, DFT calculations, and antiproliferative activity of iodide analogs of AP-1 and AP-2, i.e., AP-5 and AP-4, respectively. Antiproliferative studies in TNBC cell lines reveal that all AP family members are more potent than cisplatin and As2O3 alone. DFT calculations demonstrate there is a low energy barrier for hydrolysis of the platinum-halide bonds in arsenoplatins, possibly contributing to their higher cytotoxicities compared to cisplatin.

Discrete Platinum(II/IV)–Arsenito Clusters with Pt–As and Pt–O Bonding: [PtIV(As3O6)2]2–, [Pt4II(H2AsO3)6(HAsO3)2]2–, and [Pt2IIAs6W4O28]10–

“…A few examples exist wherein the As III ion of the trigonal–pyramidal As III O 3 group is bound to (i) a Cu + (d 10 ) ion to form a tetrahedral unit {Cu I (As III O 3 )­Cl 3 } comprising Cu I –As III bonds (∼2.34 Å) and (ii) a low-spin Fe II (d 6 ) ion to forming an octahedral unit {Fe II (As III O 3 ) 6 } comprising Fe II –As III bonds (∼2.40 Å) . The only known examples for platinum are a family of mononuclear arsenito–platinum­(II) complexes such as [Pt II (μ-NHC­(CH 3 )­O) 2 ClAs III (OH) 2 ] comprising Pt II –As III bonds (∼2.27 Å), which represent a novel class of anticancer agents …”

Reactions of Arsenoplatin-1 with Protein Targets: A Combined Experimental and Theoretical Study

“…Interestingly, the replacement of chloride in AP-1 with iodide did not hamper its cytotoxicity, thus proving that the Pt–As core is the “true” cytotoxic metal scaffold. 23 …”

“…22 Interestingly, the replacement of chloride in AP-1 with iodide did not hamper its cytotoxicity, thus proving that the Pt−As core is the "true" cytotoxic metal scaffold. 23 Given the differences in the mechanism of action of arsenoplatin compared to cisplatin, it is plausible to assume that the interactions with proteins may play a prominent part in the action mode of AP-1. To the best of our knowledge, there are only two investigations of the reactivity of AP-1 with proteins.…”

Medicinal Hypervalent Tellurium Prodrugs Bearing Different Ligands: A Comparative Study of the Chemical Profiles of AS101 and Its Halido Replaced Analogues

“…Indeed, it has been widely exploited in recent years obtaining important hints and can be easily used for both metal- as well as metalloid-based drugs. In fact, on the one hand, the comparative analysis of a halide-bearing parent inorganic drug and its halido-replaced counterparts may provide relevant mechanistic information on the role of the halides in terms of desired pharmacological effects [ 30 , 31 ]. On the other hand, the modulation of certain parameters may lead to the preparation of pharmacologically-improved analogues endowed with properties that are sometimes even ameliorated with respect to the original compound [ 17 , 31 , 32 ].…”

“…In fact, on the one hand, the comparative analysis of a halide-bearing parent inorganic drug and its halido-replaced counterparts may provide relevant mechanistic information on the role of the halides in terms of desired pharmacological effects [ 30 , 31 ]. On the other hand, the modulation of certain parameters may lead to the preparation of pharmacologically-improved analogues endowed with properties that are sometimes even ameliorated with respect to the original compound [ 17 , 31 , 32 ]. For instance, through these modifications, it is possible to change and control some features including the conversion of compounds in the active species that, in turn, may impact the cellular uptake, the bioavailability and other relevant biological aspects [ 33 ].…”