Structure-activity Relationships in Functionalized Platinum-acridine Anticancer Agents
| Author | : Leigh Ann Graham |
| Publisher | : |
| Total Pages | : 146 |
| Release | : 2012 |
| Genre | : |
| ISBN | : |
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Since Rosenberg's serendipitous discovery of the cytotoxic properties of cisdiamminedichlor(id)oplatinum(II), better known as cisplatin, the development of new platinum-based chemotherapies with improved activity and reduced toxicity has become a pressing goal. Many second- and third-generation derivatives of cisplatin have been successful in decreasing toxicity, enhancing delivery, and showing a broader spectrum of antitumor activity. Recently, a dual platinating/intercalating DNA-targeted agent, [PtCl(en)(N-[acridin-9-ylamino)ethyl]-N-methylpropionamidine] dinitrate (25), has been reported that shows high activity in NCI-H460 non-small-cell-lung cancer (NSCLC) both in vitro and in vivo, but has proven to have high systemic toxicity (nephrotoxicity). In order to reduce the toxicity of this agent, two new methodologies were developed to reduce unwanted platinum interactions with sulfur-containing biomolecules such as glutathione. The first method was aimed at changing the chlor(id)o leaving group of the prototype (25) to a monodentate carboxylate. Although carboxylates in general, and monocarboxylates in particular, are more labile leaving groups than chloride, bulky groups incorporated in this leaving group may be successful in blocking the axial positions in associative substitution reactions. The ultimate goal of generating an analogue of 25 with monodentate carboxylates was not reached due to the tautomerization and N, N-chelation of the acridine chromophore, resulting in the formation of two new complexes that contain seven-membered N, N-chelates that were synthesized and studied for biological activity (28 and 29). These chelates do not undergo ligand substitution reactions with biological nucleophiles, such as nucleobase nitrogen and cysteine sulfur, and do not intercalate into DNA. This was demonstrated in model systems using NMR and UV-visible spectroscopies. Despite their inertness, in colorimetric cell proliferation assays complexes 28 and 29 do maintain micromolar activity in NCI-H460 lung cancer cells. The results are discussed in the context of potential DNA-mediated and DNA-independent cell kill mechanisms and the potential use of the chelates as prodrugs. The second project involved the synthesis of platinum-acridine prodrugs with hydrolysable carboxylic acid ester groups that would lead to the formation of N-O chelate complexes under physiological conditions. The synthesis of these complexes was achieved through the addition of the acridine ligand across the metal-activated triple bond of a nitrile that contained a cleavable ester group. The most active ester-modified derivatives and the unmodified parent compounds showed up to 6-fold higher activity in ovarian cancer (OVCAR-3) and breast cancer (MCF-7, MDA-MB-23) cell lines than cisplatin. An even more pronounced inhibition of cell proliferation at nanomolar concentrations was observed in pancreatic (PANC-1) and non-small cell lung cancer cells (NSCLC, NCI-H460) of 80- and 150-fold, respectively. Most importantly, introduction of the ester groups did not adversely affect the cytotoxic properties of the hybrids, which form the same DNA adducts as the parent compounds. In-line high-performance liquid chromatography-electrospray mass spectrometry (LC-MS) was used to demonstrate that the ester moieties in the newly synthesized compounds undergo platinum-mediated hydrolysis in a chloride concentration-dependent manner to form a chelated carboxylate form of the agent. This new ester-cleavage mechanism under physiological conditions could potentially provide a new opportunity for tumor-targeted therapy of platinumacridines through the self-immolative release of this family of cytotoxic agents.
