Hydroxamic acids exert various biological effects, as there are examples for antibacterial [1,2] and anticancer [1,3] members in this compound family. These properties are undoubtedly linked to their well-known metal ion-binding ability. As a result of their strong affinity to iron(III), a naturally occurring representative, desferrioxamin B (Desferal) was approved by FDA (U. S. Food and Drug Administration) for chelation therapy in 1968 and is still applied in the clinics [1].

Iron has also a crucial role in cancer cell growth and proliferation, as a consequence, its uptake is more intensified in cancer cells than in normal cells [4], thus hydroxamic acids can cause disruption of the metal ion homeostasis in cancer cells. The iron chelator desferrioxamin B was studied as cancer chemotherapeutic agent, however, the low membrane permeability and short plasma half-life were the main drawbacks of its application [5]. Ribonucleotide reductase is a metalloenzyme with two iron centres in its active site, which makes it also an important target in cancer treatment; 3,4-dihydroxybenzohydroxamic acid is a potent ribonucleotide reductase inhibitor [6].

Other hydroxamic acids such as vorinostat (SAHA), belinostat and panobinostat (Chart 1) were approved by FDA due to their Zn(II)-containing histone deacetylase (HDAC) enzyme inhibitory activity [[7], [8], [9]]. HDAC enzymes have a major role in the transcription and DNA replication [10], thus their inhibition is advantageous in cancer therapy [11]. However, the abovementioned HDAC inhibitors have serious mutagenic activity [12], thus there is still a need for new candidates with improved efficacy having less serious side effects. Several other hydroxamate-based inhibitors are currently participating in clinical phase I-III investigations against various cancer types. These compounds are resminostat, abexinostat, givinostat and AR-42 (REC-2282) (Chart 1) [[13], [14], [15], [16]].

The efficacy of hydroxamic acids can be improved by various methods. Conjugation with other anticancer pharmacophores is a straightforward strategy, and a plethora of examples were reported earlier about the improvement in the inhibition of given enzymes or the cytotoxic activity compared to the parent compound [[17], [18], [19]]. The molecular hybridization with sterane-based compounds may be beneficial, since novel molecules and altered mechanisms of action can be targeted [20], whereas these compounds generally have immense membrane permeability. In this work a hydroxamic acid derivative, 2-hydroxycarbamoylestra-1,3,5(10)-triene-3,17β-diol (E2HA, Chart 2) was evaluated. The development of E2HA is the result of the molecular hybridization of salicylhydroxamic acid (SHA) and estradiol [21].

The substitution at position 2 prevents estrone and estradiol derivatives from binding to estrogen receptors, since this kind of derivation leads to the loss of hormonal effect [[22], [23], [24]]. Experimental results achieved in recent years have shown that some steroid derivatives exert a direct cytostatic effect on cancer cells, in a hormone receptor-independent manner, by inhibiting angiogenesis, tubulin polymerization and upregulating apoptotic pathways [25]. The main advantage of this mode of action is that such compounds may offer a solution for the treatment of hormone-resistant cancers.

Another strategy for improving anticancer activity of a compound is the combination of hydroxamic acids with non-essential metal ions, since they can act through different mechanisms of action and may improve the pharmacokinetic properties, such as better aqueous solubility, optimal lipophilicity or binding to transport protein. Ru(III)-hydroxamate complexes are able to release nitric oxide (NO) [26], then the released NO may be responsible for the cytotoxic effect [27,28]. There are examples for metal complexes with hydroxamic acids exerting strong cytotoxicity, e.g. the [Pt(R,R-cyclohexane-1,2-diamine)2(μ-BHAH−1)]+ complex (BHA = benzohydroxamic acid) displayed remarkable cytotoxicity in cancer cells including cisplatin-resistant ones (IC50 = 4.8 and 5.1 μM in A2780 and A2780cisR, respectively) [29].

In this work, we report the solution and anticancer properties of E2HA, together with the complex formation with essential metal ions (Cu, Fe) and with half-sandwich organometallic cations [Rh(III)(η5-Cp*)(H2O)3]2+ ([RhCp*(H2O)3]2+) and [Ru(II)(η6-p-cymene)(H2O)3]2+ ([RuCym(H2O)3]2+). The parent compound SHA has various coordination modes: SHA is a bidentate ligand bearing (O,O) donor atoms in the complex [Pt(II)(SHAH−2)(PPh3)2]), while it is coordinated via (N−,O−) donor set in the [Pd(II)(SHAH−1)2] and in [IrCp*(SHAH−2)] complexes [[30], [31], [32]]. Our detailed solution studies uncover the coordination behaviour of E2HA in its complexes.