Conformational flexibility in inorganic molecules increases the possibility of polymorphism [1]. These polymorphic forms differ, in hydrogen bonding interaction, in close-packing motifs and consequently in supramolecular conformations [1]. Many properties such as solubility, bioavailability or pharmacological activity are varied among polymorphs [[1], [2], [3]]. For example, differences in the antiproliferative activity were reported for β and α-L-glutamic acid polymorphs [4]. Generally, different polymorphs are formed by crystallization of substances from a single or mixed solvent [5]. Gu et.al have summarized the physicochemical properties of different solvents which are often used for polymorph screening [[5], [6]]. The isomorphism is a phenomenon where two or more solids crystallize in the same space group and have similar unit cell parameters [[7], [8]]. The isomorphism is observed in the transition-metals, although it is not as common as in the rare-earth elements [8]. There are not many reports published that compare the biological activity of molecular isomorphs.

Mitochondria targeted chemotherapeutics, activate cell apoptosis through intrinsic pathway [[9], [10]]. Positively charged compounds are accumulated in the mitochondrial matrix due to its negative inner membrane potential [9]. Mitochondriotropic lipophilic cations such as triphenylphosphine (TPP), are directed to mitochondria causing loss of mitochondrial membrane permeabilization [[11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]]. Moreover, the non-steroidal anti-inflammatory drugs (NSAIDs), (e.g SalH2 = salicylic acid) are accumulated in the mitochondria where the inflammation mechanism occurs [[12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22]]. DNA interaction with metal complexes, on the other hand, may cause DNA fragmentation. Metal complexes can bind to DNA through either covalent bond where the labile ligand of the metal ion can be replaced by a nitrogen base of DNA such as guanine N7 [13] and/or through non-covalent interactions, such as intercalative, electrostatic or groove binding to DNA helix along major or minor grooves [13]. Such interactions not only prevent replication and transcription of DNA but in the case of groove binding inhibit the topoisomerase activity and subsequent the cell cycle arrest [23]. DNA minor groove binders are a class of anticancer agents highly effective in a variety of human cancers leading to programmed cell death (apoptosis) [24].

Conjugation of the mitochondriotropic agents such as trialkyl derivatives of pnictogens (Ar3E, E = P, As, Sb) with the NSAIDs (aspirin, diclofenac, naproxen, nimesulide, salicylic acid) via silver(I) ions have been evaluated against breast cancer cells positive or negative to hormone receptors [[12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22]]. The conjugates possess higher activity than that of cisplatin, inducing apoptosis through activation of mitochondrial pathway or by interacting with DNA or enzymes such as lipoxygenase [22,25]. A single mode of action is not enough to explain the mechanism of these type of compounds such as auranofin, and its analogues as well as the corresponding one of several Ag-based compounds [14,26]. Thus, their activity is attributed on a multi-target mechanism depending on the nature and lipophilicity of ligands, the mitochondrial pathway, DNA structures, the Nuclear Erythroid Related Factor 2 (NRF2) transcription factor and the inhibition of protein targets such as thioredoxin reductase (TrxR), Poly ADP-ribose polymerase 1 (PARP-1), cysteine proteases or protein tyrosine phosphatases [[26], [27], [28]]. However, it is interesting to investigate whether the conjugation of pnictogen derivatives (Mitochondriotropic agents which are involved in the cell's respiration) with NSAIDs that inhibit inflammation enzymes (located in mitochondrion) using Cu(I) ions as linkers may lead in the development of new anti-proliferative agents.

In the course of our studies for drug design and development of new efficient and targeted chemotherapeutics [[12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22]], the copper(I) polymorphs [Cu(SALH)(TPP)3] (1a and 1b) and the isomorph of 1b, [Ag(SALH)(TPP)3] (2) were prepared. The compounds were characterized by ATR-FT-IR spectroscopic technique in solid state. For the characterization in solution UV–Vis and 1H NMR spectroscopic techniques were employed. The crystal and molecular structures of 1a, 1b and 2 were determined by X-ray crystallography. The in vitro antiproliferative activity of 1–2 was evaluated against the MCF-7 (hormone depended (HD)) and MDA-MB-231 (hormone independent (HI)). The in vitro toxicity and genotoxicity were assessed by cells and micronucleus assay towards MRC-5 cells. The molecular mechanism of action was predicted by the MCF-7 cells morphology and confirmed by DNA fragmentation, Acridine Orange/Ethidium Bromide (AO/EB) staining and mitochondrial membrane permeabilization tests. The ex vivo mechanism of 1–2 was studied towards the calf thymus (CT)-DNA and lipoxygenase (LOX) (an enzyme of the inflammation mechanism).