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The design of novel platinum(iv) complexes with mitochondria injury competence, besides the DNA damage mechanism, is a promising way to develop new platinum drugs. Herein, dihydro-2-quinolone (DHQLO) as a mitocan was incorporated into the platinum(iv) system for the first time to prepare a new series of DHQLO platinum(iv) compounds. Complex 1b could effectively inhibit the proliferation of tumor cells in vitro and in vivo. It accumulated at higher levels in both whole cells and DNA, and easily underwent intercellular reduction to release platinum(ii) and DHQLO moieties. The released platinum(ii) complex caused serious DNA damage by covalent conjunction with the DNA duplex, and remarkably increased the expression of the γ-H2AX protein. Moreover, 1b also caused serious mitochondria injury to induce mitochondrial membrane depolarization and increase ROS generation. Such actions upon DNA and mitochondria activate the p53 apoptotic pathway synergetically in tumor cells by upregulating the protein p53 and apoptotic proteins caspase9 and caspase3, which efficiently promoted the apoptotic death of tumor cells. Compound 1b with such synergic mechanism exhibited great potential in reversing cisplatin resistance and improving antitumor efficacies.

Cycloxygenases (COXs) and matrix metalloproteinases (MMPs) in the tumor microenvironment (TME) are tightly related to the progression of cancers. Here, naproxen as a potent inhibitor of both COX and MMP was combined with platinum(iv) to construct hybrids as antitumor agents. Compound 2 with comparable or even superior activities to that of cisplatin, oxaliplatin, and carboplatin, great potential for reversing drug resistance, and superior tumor targeting properties was screened out as a lead compound. Moreover, compound 2 possessed potent tumor growth inhibition capability in vivo, which was comparable to that of oxaliplatin, and displayed rather lower side effects than the platinum(ii) reference drugs. The naproxen platinum(iv) complex could easily undergo reduction and liberate the platinum(ii) complex and naproxen as well as exert a multifunctional antitumor mechanism: (i) the liberated platinum(ii) fragment would cause serious DNA injury; (ii) naproxen would inhibit COX-2 and decrease tumor-associated inflammation; and (iii) the naproxen platinum(iv) complex exhibited remarkable MMP-9 inhibition in tumor tissues. These antitumor functions can help reduce the growth and metastasis of malignancy.

A new aminonaphthalimide platinum(IV) complex was developed by incorporating aminonaphthalimide, a DNA intercalator, into the platinum(IV) system. This complex displayed potent antitumor activities against all tested tumor cell lines in vitro and showed great potential in overcoming drug resistance of cisplatin. Moreover, it remarkably inhibited the growth of CT26 xenografts in BALB/c mice without severe side effects in vivo. Then, the compound exhibited a dual DNA damage antitumor mechanism that it could interact with DNA in tetravalent form via the naphthalimide group to cause DNA lesion, and the further liberation of platinum(II) complex after reduction would induce remarkable secondary damage to DNA. Meanwhile, it caused cell apoptosis through an intrinsic apoptosis pathway by up-regulating the expression of caspase 3 and caspase 9., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Naphthalimide platinum(IV) antitumor complexes with potential dual DNA damage mechanism were designed, synthesized and evaluated for antitumor activities. The incorporation of DNA targeted naphthalimide group to the platinum(IV) system exerts much positive impacts on their antitumor efficacy. The mechanism research reveals that the title compounds could interact with dsDNA in platinum(IV) form via the naphthalimide group and cause DNA lesion. The further reduction would release platinum(II) complexes and naphthalimide acids which would induce remarkable secondary damage to DNA. Furthermore, the naphthalimide platinum(IV) compounds could combine with human serum albumin via electrostatic force, which are favourable for their storage and transport in blood. Moreover, the title compounds exhibit higher accumulation in tumor cells, and exert lower toxic and higher safe properties than oxaliplatin in vivo., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Glycosylated platinum(IV) complexes were synthesized as substrates for GLUTs and OCTs for the first time, and the cytotoxicity and detailed mechanism were determined in vitro and in vivo. Galactoside Pt(IV), glucoside Pt(IV), and mannoside Pt(IV) were highly cytotoxic and showed specific cancer-targeting properties in vitro and in vivo. Glycosylated platinum(IV) complexes 5, 6, 7, and 8 (IC 50 0.24-3.97 μM) had better antitumor activity of nearly 166-fold higher than the positive controls cisplatin (1a), oxaliplatin (3a), and satraplatin (5a). The presence of a hexadecanoic chain allowed binding with human serum albumin (HSA) for drug delivery, which not only enhanced the stability of the inert platinum(IV) prodrugs but also decreased their reduction by reductants present in human whole blood. Their preferential accumulation in cancer cells compared to noncancerous cells (293T and 3T3 cells) suggested that they were potentially safe for clinical therapeutic use.

A new series of glycosylated Pt(iv) complexes were designed, synthesized and evaluated for antitumor activities in vitro and in vivo. The incorporation of glycosyl groups to the Pt(iv) system has much influence on the antitumor abilities. Four lead compounds with activities comparable or even superior to cisplatin and oxaliplatin are screened out. These Pt(iv) complexes could be reduced to release Pt(ii) complexes and cause the death of tumour cells. The apoptosis-inducing properties of these compounds are similar to cisplatin. The accumulation of the glycosylated Pt(iv) complexes in cells and DNA is higher than cisplatin and oxaliplatin. The in vivo assay demonstrates that the tested compounds inhibit the growth of HepG2 tumors with low toxicity.