Acetate platinum(II) compound with 5,7-ditertbutyl-1,2,4-triazolo[1,5-<i>a</i>]pyrimidine that overcomes cisplatin resistance: structural characterization, <i>in vitro</i> cytotoxicity, and kinetic studies

<div><p>The reaction of silver acetate with <i>cis-</i>[PtI₂(dbtp)₂], where dbtp = 5,7-ditertbutyl-1,2,4-triazolo-[1,5-<i>a</i>]pyrimidine, yielded <i>cis</i>-[Pt(OOCCH₃)₂(dbtp)₂]·dmf (<b>1</b>). The complex has been analyzed by multinuclear magnetic resonance (¹H, ¹³C, ¹⁵N), IR, and Raman. The compound formed two rotamers in CDCl₃ and its spatial structures have been optimized using computational calculation. It was found that head-to-tail rotamer (<b>1a</b>) is more stable than its head-to-head counterpart (<b>1b</b>). <i>In vitro</i> antiproliferative activity against four tumor cell lines (A549, T47D, FaDu, and A2780cis) revealed in all cases significant cytotoxicity (IC₅₀ = 0.26–1.80 μM), possessing IC₅₀ values at least fivefold lower than cisplatin, carboplatin, and oxaliplatin (except A2780cis). The remarkable <i>in vitro</i> activity against T47D and A2780cis suggested the ability to overcome cisplatin resistance in these types of tumor cells. In addition, <i>in vitro</i> toxicity was evaluated against BALB/3T3 and has shown that the lipophilic platinum(II) complex (<b>1</b>) inhibits cell proliferation weaker than cisplatin and oxaliplatin. Additionally, <i>cis</i>-[Pt(OOCCH₃)₂(dbtp)₂]·dmf exhibited selective activity, in contrast to cisplatin or oxaliplatin.</p></div

Structures of synthesized isoprenoid phospholipids.

<p>Structures of synthesized isoprenoid phospholipids.</p

Antiproliferative activity of terpene-phospholipids against human cancer cell lines.

<p>Antiproliferative activity of terpene-phospholipids against human cancer cell lines.</p

Isoprenoid-phospholipid conjugates as potential therapeutic agents: Synthesis, characterization and antiproliferative studies

<div><p>The aim of this research was to extend application field of isoprenoid compounds by their introduction into phospholipid structure as the transport vehicle. The series of novel isoprenoid phospholipids were synthesized in high yields (24–97%), their structures were fully characterized and its anticancer activity was investigated <i>in vitro</i> towards several cell lines of different origin. Most of synthesized compounds showed a significantly higher antiproliferative effect on tested cell lines than free terpene acids. The most active phosphatidylcholine analogue, containing 2,3-dihydro-3-vinylfarnesoic acids instead of fatty acids in both <i>sn</i>-1 and <i>sn-</i>2 position, inhibits the proliferation of colon cancer cells at 13.6 μM.</p></div

Synthesis of acid (5).

<p>Reagents (i) CH₃C(OEt)₃, CH₃COOH, 138°C; (ii) KOH, EtOH.</p

Prepared acids used in the synthesis of terpene phospholipids.

<p>Prepared acids used in the synthesis of terpene phospholipids.</p

Resistance index (RI) values of terpene-phospholipids.

<p>Resistance index (RI) values of terpene-phospholipids.</p

Clopidogrel in a combined therapy with anticancer drugs—effect on tumor growth, metastasis, and treatment toxicity: Studies in animal models

<div><p>Clopidogrel, a thienopyridine derivative with antiplatelet activity, is widely prescribed for patients with cardiovascular diseases. In addition to antiplatelet activity, antiplatelet agents possess anticancer and antimetastatic properties. Contrary to this, results of some studies have suggested that the use of clopidogrel and other thienopyridines accelerates the progression of breast, colorectal, and prostate cancer. Therefore, in this study, we aimed to evaluate the efficacy of clopidogrel and various anticancer agents as a combined treatment using mouse models of breast, colorectal, and prostate cancer. Metastatic dissemination, selected parameters of platelet morphology and biochemistry, as well as angiogenesis were assessed. In addition, body weight, blood morphology, and biochemistry were evaluated to test toxicity of the studied compounds. According to the results, clopidogrel increased antitumor and/or antimetastatic activity of chemotherapeutics such as 5-fluorouracil, cyclophosphamide, and mitoxantrone, whereas it decreased the anticancer activity of doxorubicin, cisplatin, and tamoxifen. The mechanisms of such divergent activities may be based on the modulation of tumor vasculature <i>via</i> factors, such as transforming growth factor β1 released from platelets. Moreover, clopidogrel increased the toxicity of docetaxel and protected against mitoxantrone-induced toxicity, which may be due to the modulation of hepatic enzymes and protection of the vasculature, respectively. These results demonstrate that antiplatelet agents can be useful but also dangerous in anticancer treatment and therefore use of thienopyridines in patients undergoing chemotherapy should be carefully evaluated.</p></div

Dosing and treatment schedules used in experiments.

<p>Dosing and treatment schedules used in experiments.</p

Antiproliferative activity of isoprenoid-phospholipid conjugates against human leukemia MV4-11 cell line.

<p>Antiproliferative activity of isoprenoid-phospholipid conjugates against human leukemia MV4-11 cell line.</p