STEROIDAL PLATINUM COMPLEXES

1. STEROIDAL PLATINUM COMPLEXES MIROSLAV KVASNICA DEPARTMENT OF MEDICINAL STEROIDS INSTITUTE OF ORGANIC CHEMISTRY AND BIOCHEMISTRY ACADEMY OF SCIENCES OF THE CZECH REPUBLIC

2. WHY PLATINUM ???

3. 1. Diversity of possible complexes cisplatin carboplatin oxaliplatin satraplatin iproplatin

4. 2. Using of platinum complexes • treatment of solid malignacies (small cell lung cancer, ovarian and testicular cancer, epidermoid carcinomas of the head and neck, cancer of breast, uterus, and cervix) Advantages of cisplatin • Exhibits a wide spectrum of antitumour activity against drug-resistant as well as drug sensitive tumours • Shows activity against slow-growing tumour as well as rapidly-growing tumours • Shows no strain or species specificity • Exhibits activity against viral-induced and chemical-inducedtumours • Affects both solid and disseminated tumours

5. 3. Mechanism of action inside the cell: PtII(NH3)2Cl2 + H2O→ [PtII(NH3)2Cl(H2O)]+ + Cl- [PtII(NH3)2Cl(H2O)]+ + H2O→ [PtII(NH3)2(H2O)2]2+ Pil, P., Lippard, S. J. In Encyclopedia of Cancer, J. R. Bertino, Ed. Academic Press: San Diego, CA, 1997, Vol. 1, pp. 392-410.

6. 4. Drawbacks of cisplatin • toxicity (nephrotoxicity, neurotoxicity, nausea and vomitting, ototoxicity, alopecia, electrolyte disturbance, dermatitis) • drug resistance * limit the formation of lethal platinum-DNA adducts * enable and enhance DNA repair (NER) * enable cells to tolerate platinum-DNA damage once it occurs * enhance intracellular detoxification such as the glutathione

7. WHY STEROID ???

8. 1. Diversity of possible structure estrone cholesterol cholic acid testosterone

9. 2. Afinity to cell receptors androgen receptor estrogen receptor

10. Reagents as possible ligands 1) Diamine complexes 2) Dicarboxylic complexes R = H, NH2, Br 3) Other reagents

11. Published complexes

12. Synthesis of steroidal amino acid complexes (i) Boc-L-Met, DCC/benzene; (ii) TFA/CH2Cl2; (iii) K2[PtCl4]/DMF, H2O; (iv) (Boc)2-L-His, DCC/benzene. Kvasnica M., Budesinsky M., Swaczynova J., Pouzar V., Kohout L.: Bioorg. Med. Chem. 16 (2008) 3704–3713

13. Kvasnica M., Budesinsky M., Swaczynova J., Pouzar V., Kohout L.: Bioorg. Med. Chem. 16 (2008) 3704–3713

14. TCS50 (μmol/L) values for complexes 1c-7c and 1f-4f obtained from the Calcein AM assays with the tested cancer and normal cell lines; means ± SD obtained from three independent experiments performed in triplicate. CEM – T-lymphoblastic leukaemia A549 – human lung adenocarcinoma MCF7 – human breast adenocarcinoma BJ – human fibroblast RPMI 8226 – human myeloma Kvasnica M., Budesinsky M., Swaczynova J., Pouzar V., Kohout L.: Bioorg. Med. Chem. 16 (2008) 3704–3713

15. Synthesis of steroidal diamino complexes (i) Br(CH2)xBr, NaOH/THF, H2O; (ii) 2-(aminomethyl) or 2-(aminoethyl)pyridine/EtOH; (iii) K2[PtCl4]/DMF, H2O.

16. BJ – human fibroblast CEM – T-lymphoblastic leukaemia U2OS – human osteosarcoma MCF7, BT474, BT549, MDA-MB - human breast adenocarcinoma

17. Synthesis of steroidal dicarboxylato complexes I R1, R2, R3 = OH – cholic; R1, R2 = OH, R3 = H – chenodeoxycholic; R1, R3 = OH, R2 = H – deoxycholic; R1 = OH, R2, R3 = H – lithocholic; R1, R2, R3 = H – cholanic (i) TSTU, TEA/DMF; (ii) diethyl aminomalonate/DMF;(iii) a) Ba(OH)2/EtOH,H2O b)[(NH3)2Pt(H2O)2]SO4/EtOH, H2O

18. Synthesis of platinum reagents for dicarboxylato complexes • K2[PtCl4] + 4 KI → K2[PtI4] + 4 KCl • K2[PtI4] + 2 NH3 → (NH3)2PtI2 + 2 KI • (NH3)2PtI2 + Ag2SO4 → [(NH3)2Pt(H2O)2]SO4 + AgI  • [(NH3)2Pt(H2O)2]SO4 + BaX → (NH3)2PtX + BaSO4  Synthesis of cisplatin Source: wikipedia

19. Synthesis of steroidal dicarboxylato complexes II 1) Knoevenagel condensation

21. 2) Substitution of tosylates

22. Platinum in steroidal skeleton

23. Thank you for your attention.