DOI: 10.1002/cmdc.200900224 The Relevance of Polar Surface Area (PSA) in Rationalizing Biological Properties of Several cis- Diamminemalonatoplatinum(II) Derivatives** Giulia Caron, [b] Giuseppe Ermondi, [b] Marzia B. Gariboldi, [c] Elena Monti, [c] Elisabetta Gabano, [a] Mauro Ravera, [a] and Domenico Osella* [a] Introduction For decades cis-diamminedichloroplatinum(II), or cisplatin (1) (Figure 1), has been among the top-selling anticancer drugs. The serendipitous discovery of its cytotoxic activity in 1961 by Rosenberg and co-workers [1] was followed by one of the most impressive synthetic efforts in research laboratories all over the world, aimed at finding alternatives to cisplatin in order to bypass its several side effects (mainly nausea, ototoxicity, and nephrotoxicity) and the development of drug resistance phe- nomena. However, besides cisplatin, only few other platinum complexes have been approved, worldwide or locally, for anti- cancer therapy, namely carboplatin, oxaliplatin, nedaplatin, lo- baplatin, and heptaplatin. [2] In the majority of the new Pt II de- rivatives, chlorides have been replaced by more stable chelat- ing ligands (very often dicarboxylates), resulting in complexes that have lower systemic toxicity, while retaining cytotoxic ac- tivity. A notable example of this strategy is carboplatin, which has significantly decreased side effects, but is as effective as cisplatin in the treatment of cancer and is widely employed in pediatric oncology. The role of the four ligands around the square planar Pt II core in determining the overall biochemical properties of plati- num complexes has been extensively explored, although the influence of the leaving groups has certainly been investigated in lesser detail than that of the carrier groups. [3, 4] The reactivity of the anionic ligands is an important feature of platinum com- pounds, because rapid substitution reactions with water or other biological molecules can lead to failure of the complex to reach its pharmacological target (mainly DNA), while exces- sive inertia will result in loss of biological activity. The struc- ture–activity relationship (SAR) summarized by Cleare and Hoe- schele several years ago [5, 6] identified chlorides in the cis con- figuration as having optimal lability when present with ammo- nia or organoamine ligands. Before dissociation, the structural characteristics of the leaving group play a role, along with those of the carrier groups, in determining water solubility, transport, and cellular uptake of the overall complexes. The use of dicarboxylates as leaving ligands introduces enormous possibilities of structural variation by modifying the carbon backbone. In particular, oxalic, glycolic, and malonic acids have been used to replace chloride ions in cisplatin analogues. Malonate has been used as a leaving group in “traditional” complexes, that is, in the already cited heptaplatin, approved in South Korea in 1999 as Sunpla. Moreover, malonate is widely used as a modifiable linker in drug targeting and deliv- ery strategies applied to platinum complexes, with the aim to obtain drugs with higher selectivity for malignant tissues. [7–10] The mechanism of action of cisplatin and its derivatives con- sists of four key steps: [11, 12] 1) cellular uptake, 2) activation by hydrolysis in the cytosol, 3) formation of DNA adducts in the nucleus, and 4) recognition of platinum–DNA adducts by damage-response proteins, followed by induction of apoptosis. A panel of six cis-diamminemalonatoplatinum(II) derivatives were designed and synthesized, and their physicochemical properties and in vitro biological activity were experimentally evaluated and studied in silico. All the complexes showed higher IC 50 values ( 20 mm) than those observed for cisplatin and its malonato analogue on three different human tumor cell lines, namely A2780 ovarian carcinoma, A549 lung carcino- ma, and MCF-7 breast carcinoma. In silico studies revealed that polar surface area (PSA) is the best descriptor to explain the poor biological activity observed for this series of new com- pounds, which in turn is likely due to poor cellular uptake. This finding is in line with general rules that assign a major role to PSA in characterizing the transport properties of drugs, in the actual case of antiproliferative metallopharmaceuticals. [a] Dr. E. Gabano, Prof. M. Ravera, Prof. D. Osella Dipartimento di Scienze dell’Ambiente e della Vita Università del Piemonte Orientale “Amedeo Avogadro” Viale T. Michel 11, 15100 Alessandria (Italy) Fax: (+ 39) 0131-360250 E-mail : domenico.osella@mfn.unipmn.it [b] Dr. G. Caron, Prof. G. Ermondi Dipartimento di Scienza e Tecnologia del Farmaco Università di Torino Via P. Giuria 9, 10125 Torino (Italy) [c] Dr. M. B. Gariboldi, Prof. E. Monti Dipartimento di Biologia Strutturale e Funzionale Università dell’Insubria Via A. da Giussano 10, 21052 Busto Arsizio (VA) (Italy) [**] Based on a lecture given at the 8th Workshop on Pharmaco-Bio-Metallics, October 24–26, 2008, Ravenna (Italy). Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cmdc.200900224. ChemMedChem 2009, 4, 1677 – 1685 # 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1677