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      NAMI-A and KP1019/1339, Two Iconic Ruthenium Anticancer Drug Candidates Face-to-Face: A Case Story in Medicinal Inorganic Chemistry

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          Abstract

          NAMI-A ((ImH)[ trans-RuCl 4(dmso-S)(Im)], Im = imidazole) and KP1019/1339 (KP1019 = (IndH)[ trans-RuCl 4(Ind) 2], Ind = indazole; KP1339 = Na[ trans-RuCl 4(Ind) 2]) are two structurally related ruthenium(III) coordination compounds that have attracted a lot of attention in the medicinal inorganic chemistry scientific community as promising anticancer drug candidates. This has led to a considerable amount of studies on their respective chemico-biological features and to the eventual admission of both to clinical trials. The encouraging pharmacological performances qualified KP1019 mainly as a cytotoxic agent for the treatment of platinum-resistant colorectal cancers, whereas the non-cytotoxic NAMI-A has gained the reputation of being a very effective antimetastatic drug. A critical and strictly comparative analysis of the studies conducted so far on NAMI-A and KP1019 allows us to define the state of the art of these experimental ruthenium drugs in terms of the respective pharmacological profiles and potential clinical applications, and to gain some insight into the inherent molecular mechanisms. Despite their evident structural relatedness, deeply distinct biological and pharmacological profiles do emerge. Overall, these two iconic ruthenium complexes form an exemplary and unique case in the field of medicinal inorganic chemistry.

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          Most cited references108

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          The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials.

          Cancer is rapidly becoming the top killer in the world. Most of the FDA approved anticancer drugs are organic molecules, while metallodrugs are very scarce. The advent of the first metal based therapeutic agent, cisplatin, launched a new era in the application of transition metal complexes for therapeutic design. Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anti-cancer agents that serve as alternatives to cisplatin and its derivertives. Ruthenium(iii) complexes have successfully been used in clinical research and their mechanisms of anticancer action have been reported in large volumes over the past few decades. Ruthenium(ii) complexes have also attracted significant attention as anticancer candidates; however, only a few of them have been reported comprehensively. In this review, we discuss the development of ruthenium(ii) complexes as anticancer candidates and biocatalysts, including arene ruthenium complexes, polypyridyl ruthenium complexes, and ruthenium nanomaterial complexes. This review focuses on the likely mechanisms of action of ruthenium(ii)-based anticancer drugs and the relationship between their chemical structures and biological properties. This review also highlights the catalytic activity and the photoinduced activation of ruthenium(ii) complexes, their targeted delivery, and their activity in nanomaterial systems.
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            From bench to bedside--preclinical and early clinical development of the anticancer agent indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A).

            Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A) is just the second ruthenium-based anticancer agent after NAMI-A which was developed to the stage of clinical trials. Important steps in the mode of action of KP1019 are thought to be the binding to the serum protein transferrin and the transport into the cell via the transferrin pathway. Additionally, the selective activation by reduction in the tumor might contribute to the low side effects observed in in vivo studies. Apoptosis is induced at non-toxic levels via the mitochondrial pathway. These features distinguish it from the established platinum anticancer drugs and suggest that different types of cancer might be treatable with this drug. Indeed, promising activity against certain types of tumors, which are not successfully treatable with cisplatin, and only a very low incidence of acquired resistance has been observed in in vitro and in vivo studies. Recently, a clinical phase I trial was finished in which none of the treated patients experienced serious side effects, while disease stabilization in five of six evaluable patients was achieved. In this review, the preclinical and early clinical development of KP1019 - from bench to bedside - is recapitulated.
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              KP1019, a new redox-active anticancer agent--preclinical development and results of a clinical phase I study in tumor patients.

              The promising drug candidate indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) is the second Ru-based anticancer agent to enter clinical trials. In this review, which is an update of a paper from 2006 (Hartinger et al., J. Inorg. Biochem. 2006, 100, 891-904), the experimental evidence for the proposed mode of action of this coordination compound is discussed, including transport into the cell via the transferrin cycle and activation by reduction. The results of the early clinical development of KP1019 are summarized in which five out of six evaluated patients experienced disease stabilization with no severe side effects.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                24 May 2019
                May 2019
                : 24
                : 10
                : 1995
                Affiliations
                [1 ]Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via L. Giorgieri 1, I-34127 Trieste, Italy
                [2 ]Department of Chemistry ‘Ugo Schiff’, University of Florence, Via della Lastruccia 3-13, I-50019 Sesto Fiorentino, Italy
                Author notes
                [* ]Correspondence: alessi@ 123456units.it (E.A.); luigi.messori@ 123456unifi.it (L.M.); Tel.: 040-5583961 (E.A.); Fax: 040-5583903 (E.A.)
                Author information
                https://orcid.org/0000-0002-4908-9400
                https://orcid.org/0000-0002-9490-8014
                Article
                molecules-24-01995
                10.3390/molecules24101995
                6571951
                31137659
                6c33f32f-13cd-4bf8-ad6e-f6d0af19088f
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 14 May 2019
                : 22 May 2019
                Categories
                Review

                anticancer,antimetastasis,uptake,protein binding,ruthenium,clinical study,biodistribution,activation,aquation

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