Abstract #4529: In vivo antitumor activity of platinum(II) complexes with thiosemicarbazones derived from 2-formyl and 2-acetyl pyridine and containing ring incorporated at N(4)- positio Free

Introduction: Thiosemicarbazones are among the most potent inhibitors of ribonucleotide reductase (RR) activity and possess a wide range of biological activity depending on the parent aldehyde or ketone heterocyclic thiosemicarbazones (TSCs) have aroused considerable interest in chemistry and biology due to their antibacterial, antimalarial, antineoplastic and antiviral activities and represent an important series of compounds because of potentially beneficial biological activity. In this study we report the toxicity and antitumor activity of new platinum (II) complexes: the thiosemicarbazones of 2-formyl and 2-acetyl pyridine, containing azepane ring incorporated at N(4) position, HL¹ (1) and HL² (2) with platinum (II) afforded the complexes, [Pt(L¹)Cl] (3) and [Pt(L²)Cl] (4). Materials and Methods: On stock solutions of the compounds 1-4 were prepared immediately before use. They were suspended in corn oil following initial dissolution in 10% DMSO. BDA/2 mice were used for toxicity studies. Lymphocytic leukemia P388 bearing BDF1 mice were used to determine the antitumor effect. The tumor was maintained in ascetic form by injection of 10⁶ cells at 7-day intervals in to the peritoneal cavity of DBA/2 mice. The antitumor activity of the compounds was assessed from the oncostatic parameter T/C %, according to the protocol of NCI. Treatments were given as a single LD10 dose on day 1. Results and Discussion: The LD10 therapeutic dose was 40, 37, 57, 53 and 76 mg/Kg for compounds 1 - 4. The ligand 1 and 2 display some antitumor activity, while the compounds 3 and 4 show reduction of the toxicity, and very high increase of survival time of the drug-treated leukemia bearing mice. The ligand 2 is achieving a T/C value of 118 % and the platinum (II) complex 4 of 417 %. The ligand 1 is achieving a T/C value of 147 % and the platinum (II) complex 3 of 298 %. Also, five of the six mice were cured and were considered as long-term survivors. The long-term survivors are defined as mice alive 90 days after tumor inoculation. Conclusions: The replacement of a methyl group at position C(7) (HL²) by a C(7)H group (HL¹) in the 2-pyridyl position, causes marked differences on the biological results, a significant increase of survival time of the drug-treated leukemia bearing mice, T/C 147 % and 118 % for HL¹ and HL² respectively. Probably, the platinum (II) complexes, 3 and 4 may interact better with DNA and/or proteins than the other compounds. In conclusion, these experiments show that the activity of the metal complexes 3 and 4, is different compared with the activity of the ligands alone and probably represent independent cytotoxic entities.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4529.