Influence of chemical structure and mechanism of hydrolysis on pharmacological activity and toxicological profile of approved platinum drugs

Abstract

The problems with platinum complexes are resistance and toxicity of anticancer therapy. The aim of current study is the comparison of the influence of chemical structure and mechanism of hydrolysis on pharmacological activity and toxicological profile of approved in platinum drugs: Cisplatin, Carboplatin, Oxaliplatin, Nedaplatin, Lobaplatin, Heptaplatin, Satraplatin. Hydrolysis of Carboplatin and Nedaplatin occurs by double step hydration, to obtain the same active products as with Cisplatin: diaqudiamine-platinum. The similarity in mechanisms of hydrolysis of Oxaliplatin, Lobaplatin Heptaplatin, and Satraplatin is that the first part of the hydrolysis corresponds to the ring-opening and addition of the first water molecule, and in the second step of reaction occur the loss of the ligand and the formation of the di-aquated product by the addition of a second water molecule. Cisplatin, Carboplatin, and Oxaliplatin are nephrotoxic. Cisplatin and Heptaplatin are nephrotoxic. The similar dose-limiting effects of Carboplatin, Oxaliplatin, Nedaplatin, Lobaplatin, and Satraplatin is myelosuppression.

Cisplatin Resistance in Cancer Therapy: Causes and Overcoming Strategies

“…Nedaplatin, a diammine‐glycolatoplatinum compound has 10 times greater solubility in water than CDDP. Like CDDP, it is hydrolyzed by double hydration to the same active metabolite [82,83] . This active CDDP derivative interacts with the nucleophilic groups of DNA, causing cell apoptosis but unfortunately it is cross resistance with CDDP.…”

“…It was approved by the Korean Food and Drug Administration for the treatment of gastric cancer in 1999. [83] It is a third-generation platinum-based drug that was used in phase I and II clinical trials against gastric, head and neck cancer cells. The combined regimen of Heptaplatin and 5-fluorouracil was reported as an effective therapy for individuals suffering from advanced stomach cancer.…”

Emerging Trends in Metal‐based Anticancer Agents: Drug Design to Clinical Trials and their Mechanism of Action

“…[20] Cisplatin and its successors such as carboplatin, oxaliplatin, lobaplatin, heptaplatin, and nedaplatin (Figure 2) are the most common and clinically accepted platinum complexes with effective anticancer activities. [28] The FDA approved cisplatin (Platinol®) in 1978 as a combination treatment for various tumors like testicular, ovarian, and bladder cancers. Carboplatin (Paraplatin®) was also approved by the FDA as a combination therapy for treating ovarian cancer.…”

“…They are most frequently used to treat malignancies of the head and neck, prostate, lung, breast, bladder, stomach, cervical, ovarian, and testicles [20] . Cisplatin and its successors such as carboplatin, oxaliplatin, lobaplatin, heptaplatin, and nedaplatin (Figure 2) are the most common and clinically accepted platinum complexes with effective anticancer activities [28] …”

Translocation Processes of Pt(II)-Based Drugs through Human Breast Cancer Cell Membrane: In Silico Experiments

“…According to the literature, the cddp undergoes the first hydrolysis upon entering a cell as a result of the low Cl – concentration in the cytoplasm (∼4–20 mM) compared to the extracellular medium (∼100 mM) forming the monoaqua derivative cis -[Pt­(NH 3 ) 2 (H 2 O)­Cl] 1+ (cdcla, see Figure ). ,, The diaqua metabolite cis -[Pt­(NH 3 ) 2 (H 2 O) 2 ] 2+ (see Figure ) is also generated to a notably lesser extent in the intracellular medium . When it comes to cancer cells, the aqua derivatives are deprotonated in the cytosol due to the high intracellular pH (pH > 7.4), forming the mono- and dihydroxo neutral complexes ( cis -[Pt­(NH 3 ) 2 Cl­(OH)] (cdclo) and cis -[Pt­(NH 3 ) 2 (OH) 2 ]) as shown in Figure . , …”