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Review
. 2019 May 24;24(10):1995.
doi: 10.3390/molecules24101995.

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

Enzo Alessio  1 , Luigi Messori  2
Affiliations
Review

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

Enzo Alessio et al. Molecules. .

Abstract

NAMI-A ((ImH)[trans-RuCl4(dmso-S)(Im)], Im = imidazole) and KP1019/1339 (KP1019 = (IndH)[trans-RuCl4(Ind)2], Ind = indazole; KP1339 = Na[trans-RuCl4(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.

Keywords: activation; anticancer; antimetastasis; aquation; biodistribution; clinical study; protein binding; ruthenium; uptake.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic structures of NAMI-A ((ImH)[trans-RuCl4(dmso-S)(Im)], Im = imidazole), KP1019/KP1339 (KP1019 = (IndH)[trans-RuCl4(Ind)2], Ind = indazole; KP1339 = Na[trans-RuCl4(Ind)2]), and KP418 (imidazolium trans-bis-imidazoletetrachlororuthenate(III), (ImH)[trans-RuCl4(Im)2]). KP1019 is sometimes also called FFC14, or FFC14a, or FFC14A. The sodium salt of KP1019, besides KP1339, is also called KP-1339, or NKP1339, or—more recently—IT-139. Originally, the imidazole complex KP418 was called ICR.
Figure 2
Figure 2
Left: The adduct of NAMI-A with hen egg white lysozyme (HEWL). (top) Ru binding site close to Asp101. (bottom) Ru binding site close to Asp119. Reproduced from Ref. 59 by permission of The Royal Society of Chemistry. Top right: The adduct of NAMI-A with carbonic anhydrase (hCAII). Detail of the Ru center interactions with residues His 64. The oxygen atoms from water molecules are represented as red spheres. Reproduced from Ref. [60] with permission from Elsevier. Bottom right: Ribbon representation of the overall structure of the NAMI-A/HuHf (human ferritin) adduct. The side chain of His105 is shown as a ball and stick, while Ru and the water molecules completing the metal coordination sphere are shown as spheres. Reproduced from Ref. [61] by permission of The Royal Society of Chemistry.
Figure 3
Figure 3
Overall structure of serum albumin (HSA)–Myr–KP1339 (Myr = myristate, domain I, blue; domain II, green; domain III, red). The two bound metal centers are labeled Ru1 and Ru2. The seven fatty acids (FA) bound to HSA are labeled as FA1 to 7 (aliphatic chain, gray spheres; carboxylate oxygens, red spheres). Reproduced from Ref. [65] (ACS AuthorChoice).
Figure 4
Figure 4
A proposed model depicting the mode of action of KP1019. Reproduced from Ref. [113].
See this image and copyright information in PMC

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