International Journal of Molecular Sciences Article Theoretical Prediction of Dual-Potency Anti-Tumor Agents: Combination of Oxoplatin with Other FDA-Approved Oncology Drugs José Pedro Cerón-Carrasco Reconocimiento y Encapsulación Molecular, Universidad Católica San Antonio de Murcia Campus los Jerónimos, 30107 Murcia, Spain; [email protected] Received: 16 April 2020; Accepted: 2 July 2020; Published: 3 July 2020 Abstract: Although Pt(II)-based drugs are widely used to treat cancer, very few molecules have been approved for routine use in chemotherapy due to their side-effects on healthy tissues. A new approach to reducing the toxicity of these drugs is generating a prodrug by increasing the oxidation state of the metallic center to Pt(IV), a less reactive form that is only activated once it enters a cell. We used theoretical tools to combine the parent Pt(IV) prodrug, oxoplatin, with the most recent FDA-approved anti-cancer drug set published by the National Institute of Health (NIH). The only prerequisite imposed for the latter was the presence of one carboxylic group in the structure, a chemical feature that ensures a link to the coordination sphere via a simple esterification procedure. Our calculations led to a series of bifunctional prodrugs ranked according to their relative stabilities and activation profiles. Of all the designed molecules, the combination of oxoplatin with aminolevulinic acid as the bioactive ligand emerged as the most promising strategy by which to design enhanced dual-potency oncology drugs. Keywords: cancer; drug design; organometallics; platinum-based drugs; bifunctional compounds; theoretical tools 1. Introduction The unexpected discovery of the bioactivity of Pt salts by Rosenberg about 60 years ago opened the door to a new type of cancer treatment: chemotherapy with transition metals [1]. Unfortunately, only three anti-cancer drugs are routinely used in hospitals—the original cisplatin and two derivatives, carboplatin and oxoplatin [2]. Figure1 shows that the final step in the action of cisplatin-like drugs is an attack on the cell’s DNA, which eventually blocks cell replication by disrupting the natural double helix architecture of the DNA molecule [3]. The cisplatin derivatives were not specifically designed to target cancer cells, and they react with a wide spectrum of biomolecules present in the extracellular media, which is the source of the undesirable side-effects associated with this type of chemotherapy [4]. With the aim of minimizing the risks of chemotherapy related to the high reactivity of the classical Pt(II) salts, Sadler and co-workers proposed increasing the oxidation state of the Pt to the less reactive Pt(IV) by inserting additional axial ligands into the parent cisplatin structure [5]. Figure1 shows how the parent Pt(IV) prodrug, oxoplatin, is less toxic than the cisplatin-like drugs because it does not react in the extracellular region. Simultaneously, oxoplatin presents valuable pharmacokinetics and can be self-activated by redox reactions once it has reached the intracellular medium. The driving force for oxoplatin activation is based on the natural gradient of the concentration of ascorbic acid in the human body, which is higher inside than outside the cell, rather than on an exogenous chemical or physical agent [6]. Accordingly, the prodrug becomes reactive by only forming cisplatin within the intracellular medium. Int. J. Mol. Sci. 2020, 21, 4741; doi:10.3390/ijms21134741 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 4741 2 of 11 Int. J. Mol. Sci. 2020, 25, x FOR PEER REVIEW 2 of 11 OH H3N Cl H3N Cl OH Pt H N Cl Pt Cl 3 H3N Pt H3N Cl OH H3N Cl cisplatin oxoplatin O -x O x- O activation asplatin side effectsx- attack Extracellular Intracellular activation dual effects * 43 Figure 1. Chemical structures of the parent Pt(II)-based drug (cisplatin) and the Pt(IV) prodrugs 44 Figure(oxoplatin 1. Chemical and asplatin). structures Schematic of the representation parent Pt(II)-bas of theed mechanism drug (cisplatin) by which and a metallodrugthe Pt(IV) prodrugs damages 45 (oxoplatinDNA. Cisplatin and asplatin). (shown in Schematic green) is very representa reactive,tion and of the the final mechanism step of the by reaction whichproduces a metallodrug a large 46 damagesdistortion DNA. in the Cisplatin double (shown helix structure in green) of is the very DNA. reactive, However, and the it final also reactsstep of withthe reaction the biomolecules produces 47 apresent large indistortion the extracellular in the media.double Thesehelix non-specificstructure of interactions the DNA. areHowever, the source it ofalso the reacts main side-ewithff ectsthe 48 biomoleculesof this drug (X present marked in inthe purple). extrace Oxoplatinllular media. (shown These in non-specific red) is less reactive interactions andenters are the the source cell directly of the 49 mainwithout side-effects any other of reactions. this drug It is(X activatedmarked in thepurple intracellular). Oxoplatin medium (shown by ascorbicin red) is acid, less which reactive reduces and 50 entersthe Pt(IV) the centerscell directly to Pt(II), without leading any to theother in situ reactions. generation It is of activated cisplatin. in In asplatinthe intracellular (shown as medium red–orange by 51 ascorbicballs), one acid, of thewhich axial reducesOH ligands the Pt(IV) is replaced centers byto Pt(I aspirin.I), leading It is also to activatedthe in situ to generation cisplatin inside of cisplatin. the cell − 52 Inby asplatin the action (shown of ascorbic as red–orange acid. The balls), free form one of of aspirin the axial (orange −OH ball)ligands produces is replaced a dual-potency by aspirin. anti-tumor It is also 53 activatedeffect (denoted to cisplatin as an asterisk).inside the cell by the action of ascorbic acid. The free form of aspirin (orange 54 ball) produces a dual-potency anti-tumor effect (denoted as an asterisk). Inspired by Sadler’s work [7], two different groups proposed the injection of a bifunctional 55 prodrugInspired by covering by Sadler’s the Pt(IV) work center[7], two with different an active gr ratheroups proposed than a passive the injection ligand, e.g., of a aspirin. bifunctional In this 56 prodrugsynthetic by strategy, covering aspirin the Pt(IV) replaces center one with of the an axial activeOH rather ligands, than leading a passive to asplatin,ligand, e.g., also aspirin. called platin-A In this − 57 synthetic(Figure1)[ strategy,8,9]. The aspirin subsequent replaces release one of of the cisplatin axial −OH upon ligands, reduction leading leads to asplatin, to the highly also called reactive platin- Pt(II) 58 Aagent (Figure and 1) the [8,9]. free formThe subsequent of the bioactive release ligand. of cisplatin The former upon attacks reduction the DNA leads ofthe to malignantthe highlycell reactive while 59 Pt(II)the latter agent reduces and the the free mechanism form of the of cancerbioactive growth ligand. and The/or helps former to mitigateattacks the the DNA side-e offfects the ofmalignant the drug. 60 cellBecause while they the latter contain reduces two active the mechanism moieties (metallic of cancer center growth+ bioactive and/or helps ligand), to mitigate asplatin-like the side-effects molecules 61 ofcan the be drug. designed Because to produce they contain a dual-potency two active emoietiffect.es We (metallic used computational center + bioactive methods ligand), to predict asplatin- the 62 likeeffects molecules of replacing can be aspirin designed with to other produce bioactive a dual-p ligands.otency This effect. work We is used therefore computational a further step methods towards to 63 predictdesigning the enhancedeffects of bifunctionalreplacing aspirin prodrugs. with other bioactive ligands. This work is therefore a further 64 step towards designing enhanced bifunctional prodrugs. 2. Results 65 2. ResultsWith the aim of proposing molecules applicable to the treatment of cancer rather than conducting 66 a gedankenexperiment,With the aim of proposing we adapted molecules the computational applicable strategy to the of treatment Ponte et al. of [10 cancer] to screen rather the latestthan 67 conductingFood and Drug a gedankenexperiment, Administration (FDA)-approved we adapted oncology the computational drug set (AOD9) strategy published of Ponte by et the al. National [10] to 68 screenCancer the Institute, latest partFood of theand US Drug National Administrati Instituteson of (FDA)-approved Health (NIH). This oncology set contains drug the set most (AOD9) recent 69 published147 approved by the anti-cancer National drugs Cancer [11 ].Institute, We imposed part of only the one US prerequisite:National Institutes the presence of Health of one (NIH). carboxylic This 70 setgroup contains in the the structure most recent that 147 ensures approved a link anti-can to the Ptcer coordination drugs [11]. We sphere imposed via aonly simple one prerequisite: esterification 71 the presence of one carboxylic group in the structure that ensures a link to the Pt coordination sphere Int. J. Mol. Sci. 2020, 25, x FOR PEER REVIEW 3 of 11 72 via a simple esterification reaction [12]. This systematic selection yielded five drugs: melphalan, 73 bendamustine, chlorambucil, aminolevulinic acid and tretinoin (retinoic acid). Figure 2 shows the 74 structures of these drugs as deposited in the PubChem database [13,14]. 75 The successful design of asplatin suggests an effective synthetic strategy for coordinating a 76 bioactive ligand to oxoplatin by forming a carboxylate bridge at one of the hydroxyl groups. This is, 77 however, not a trivial task because an efficient prodrug has to fulfil two prerequisites: (1) the Pt(IV)– 78 ligand bond must be sufficiently stable so as not to dissociate prior to reaching the cancerous tissues; 79 and (2) there must be an efficient activation pathway in the intracellular media of the malignant cells 80 [12]. These two crucially important points have been assessed in a recent theoretical contribution by 81 Ponte, Russo and Sicilia [10], who used density functional theory (DFT) calculations to simulate the 82 mechanism for the reduction of asplatin.