Naproxen platinum(IV) hybrids inhibiting cycloxygenases, matrix metalloproteinases and causing DNA damage: Synthesis and biological evaluation as antitumor agents in vitro and in vivo

Cycloxygenases (COXs) and matrix metalloproteinases (MMPs) in tumor microenvironment (TME) are tightly related to the progression of cancers. Naproxen as potent inhibitor for both COX and MMP was conjuncted with platinum(IV) to construct hybrids as antitumor agents. Compound 2 with comparable or even superior activities to cisplatin, oxaliplatin and carboplatin, great potential in reversing drug resistance, and superior tumor targeting properties was screened out as a lead compound. Moreover, compound 2 possessed potent tumor growth inhibition in vivo which was comparable to oxaliplatin, and displayed rather lower side effects than the platinum(II) reference drugs. Naproxen platinum(IV) complex could easily undergo reduction and liberate platinum(II) complex and naproxen, and 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; (iii) Naproxen platinum(IV) complex exhibited remarkable MMP-9 inhibition in tumor tissues. These antitumor functions reduced the growth and metastasis of malignancy.