Development of novel platinum cytostatic drugs

Introduction

Cancer diseases belong to leading causes of death worldwide. In the Czech Republic, death of cancer counted 27% of total deaths (2006) and it even exceeded the number of deaths associated with cardiovascular disease.

At present, many malignant diseases in advanced stages can be treated therapeutically. However, most tumors can be treated only with palliative chemotherapy. Several factors which significantly reduce the response to drug therapy and worse prognosis contribute to this fact. It is mainly the damage of function of kidneys and liver (owing to the high toxicity of chemotherapeutics), higher age, or mechanisms of secondary resistance.

Malignancy can be defined as the result of locally unregulated tissue growth of autonomous nature, which leads to the development of atypical structures. The rapid growth of tumor cells often leads to permanent damage of the person. In principle, the cellular metabolism of healthy cells and cancer cells is identical; all therapeutic approaches that may affect tumor cells can also damage healthy cells. The success of chemotherapy can be expected for such tumor cells, the metabolism of which is different from that of healthy cells. Tumors have a different shape and different functions from normal tissue. Tumors are generally divided into benign that grow slowly, are separated from normal tissue and do not form metastases (secondary tumors) and malignant that grow rapidly, metastasize and grow into the surrounding tissue.

The treatment of cancer is based on administration of cytostatic drugs inhibiting the growth of tumor cells and their combination with other therapeutic procedures, such as surgical removal of the tumor, radiation therapy, and immunotherapy. Cytotoxic agents have been introduced into clinical practice in the 40’s and 50’s of the 20th century, but research and development in this area continues. New antitumor drugs are being developed to achieve a high affinity to the tumor and relatively low toxicity to other tissues. Research and development is focused mainly on complexes suitable for oral administration because of the simple application and less stress to the patient. Currently, the development of platinum compounds is directed to new derivatives of Pt(II) and Pt(IV) complexes of the fourth generation.


Research activities and interests

Preparation of (R-amidino) PtClx compounds as potential platinum chemotherapeutics

The aim is to find the optimal way to prepare platinum complexes with R amidine. Due to the structural similarity with picoplatin, cytostatic effect of these complexes is presumed. Experimental conditions are adjusted to obtain the desired complex in the highest yield and purity. High-performance liquid chromatography with UV/VIS spectroscopy, LC/MS, XRD powder diffraction, NMR, IR, and other analytical methods are used for the analytical determination.


Preparation of DACHPtY type compounds as precursors for platinum chemotherapeutics

The work is oriented to the preparation of platinum complexes with 1R,2R diaminecyclohexane ligand (DACH). Compounds of this type are used as the starting materials in the production of cytotoxic drugs such as oxaliplatin or complex AP5346. The disadvantage of the currently used starting materials (DACHPtCl2 and DACHPtI2) is their very low solubility in water of not more than 0.3 grams, which complicates the performance of the reaction in water or means technological problem in terms of equipment utilization. The work is therefore focused on the preparation of DACHPtY complexes with variable withdrawing ligands to ensure higher solubility in water. The starting material in the preparation of these compounds is the commercially available DACHPtCl2, which gives the desired platinum complex by reacting with silver salts.


Preparation of picoplatin analogues

This work is focused on the area of preparation of original platinum complexes with potential cytostatic activity, especially on the preparation of picoplatin analogues (PikoPtCl2) and platinum compounds with 1R, 2R-diaminecyclohexane ligand (DACH), analogues of nowadays clinically used oxaliplatin. The aim is to prepare such analogues, which would show identical or higher cytostatic activity and lower side effects related primarily to their low solubility in water and the resulting poor ability to resorb after application to the patient. For the characterization and identification of the products we employ various analytical methods (DAD HPLC, LC-MS, AAS, XRF, elemental analysis, XRD and FTIR).