Ruthenium anti-cancer drugs explained

Ruthenium anti-cancer drugs are coordination complexes of ruthenium complexes that have anticancer properties. They promise to provide alternatives to platinum-based drugs for anticancer therapy.[1] [2] No ruthenium anti-cancer drug has been commercialized.

Since 1979, when Cisplatin entered clinical trials, there has been continuing interest in alternative metal-based drugs.[3] The leading ruthenium-based candidates are BOLD-100 and TLD-1433. Other ruthenium based therapeutics that have been tested clinically include NAMI-A and KP1019. The first ruthenium-based drug to enter clinical trials was NAMI-A. More ruthenium drugs are still under development. Ruthenium complexes as anticancer drugs were originally designed to mimic platinum drugs for targeting DNA, but emerging ruthenium compounds have shown a variety of mechanisms of actions, which include ROS generation, and as Endoplasmic reticulum stress agents.[4]

Properties of ruthenium complexes

Ruthenium has numerous properties that qualify it as an antineoplastic drug contender.[5] [6]

Oxidation states and geometry

Ruthenium complexes typically adopt oxidation states II and III[7] The geometry assumed by most ruthenium complexes is octahedral, which differs from the square planar molecular geometry typical for platinum(II). The presence of six ligands allows for tuning of the complexes' electronic and steric properties.[8] [9] Its partially filled 4d sub-shell allows it to form complexes that are useful for a wide variety of applications including catalysis, electronics, photochemistry, biosensors and anticancer drugs.[10] [11]

Ligand exchange rates

The rate of ligand exchange for ruthenium complexes is relatively slow in comparison with other transition metal complexes. The range of these exchange rates is around 10−2 to 10−4 s−1 which is on the scale of an average cell’s lifetime, giving the drug high kinetic stability and minimizing side reactions.[1] This allows the Ru complex to remain intact as it approaches the target as well as remain viable throughout its interaction with the cells. It is also possible through ligand variation to precisely tune the exchange kinetics, allowing a large degree of control over the complex’s stability.[12]

Activation

The theory of "activation by reduction" is based on the understanding that Ru(II) complexes are generally more reactive than Ru(III) complexes. As cancer cells are generally growing and multiplying much more rapidly than normal healthy cells, this creates an environment that is less oxygen-rich due to the raised metabolic rate. When this is paired with the tendency of cancerous cells to contain higher levels of glutathione and a lower pH, a chemically reducing environment is created.[1] This theoretically allows for ruthenium complexes to be administered as much less active, non-toxic Ru(III) compounds (as a prodrug), which can be activated solely at the site of the cancerous cells.[1] The reduction is thought to occur by mitochondrial proteins or microsomal single electron transfer proteins, though it may also occur by trans-membrane electron transport systems which reside outside the cell – implying that entry to the cancerous cells may not be required for the drug to be effective.[7] In theory it is also possible for the ruthenium compounds to be oxidized back to their inactive form if it leaves the cancerous environment. This phenomenon remains a theory, and has been primarily demonstrated in vitro.[5]

Although this theory is attractive, convenient, and grounded in fundamental ruthenium chemistry, this theory falls apart when investigated under in vivo. A direct contradiction of this theory was proven using XANES and BOLD-100. This study examined several tissues (tumor included) of SW480-bearing mice for 24 hours after administration of BOLD-100. This study showed that the Ru(III) oxidation state persists, and since BOLD-100 has significant biological effects within that 24-hour time point, this directly contradicts the "activation by reduction" mechanism.[13]

Biological transportation

The ruthenium complex BOLD-100 binds to serum albumin as established by X-ray crystallography. This adduct is proposed to facilitate uptake.[14] The levels of serum albumin in these cancerous cells are greatly increased, which may contribute to the lower toxicity associated to the ruthenium drugs in comparison to platinum.[12]

Prospective ruthenium anti-cancer drugs

BOLD-100

BOLD-100, or sodium trans-[tetrachlorobis (1H-indazole)ruthenate(III)], is the most clinically advanced ruthenium-based therapeutic. As of November 2021, BOLD-100 was being tested in a Phase 1b clinical trial in patients with advanced gastrointestinal cancers in combination with the chemotherapy regimen FOLFOX.

NAMI

Notes and References

  1. 10.1007/s00280-010-1293-1 . Ruthenium-based chemotherapeutics: Are they ready for prime time? . 2010 . Antonarakis . Emmanuel S. . Emadi . Ashkan . Cancer Chemotherapy and Pharmacology . 66 . 1–9 . 20213076 . 1 . 4020437.
  2. 10.1016/j.jinorgbio.2011.09.030 . Approaching tumour therapy beyond platinum drugs . 2012 . Bergamo . A. . Gaiddon . C. . Schellens . J.H.M. . Beijnen . J.H. . Sava . G. . Journal of Inorganic Biochemistry . 106 . 90–9 . 22112845 . 1.
  3. 10.1016/S0162-0134(00)80045-8 . Reduction and Subsequent Binding of Ruthenium Ions Catalyzed by Subcellular Components . 1980 . Clarke . M.J. . Bitler . S. . Rennert . D. . Buchbinder . M. . Kelman . A.D. . Journal of Inorganic Biochemistry . 12 . 79–87 . 7373292 . 1.
  4. Mjos. Katja Dralle. Orvig. Chris. 2014-04-23. Metallodrugs in Medicinal Inorganic Chemistry. Chemical Reviews. en. 114. 8. 4540–4563. 10.1021/cr400460s. 24456146. 0009-2665. free.
  5. 10.1039/C0DT01816C . Ruthenium anticancer compounds: Myths and realities of the emerging metal-based drugs . 2011 . Bergamo . Alberta . Sava . Gianni . Dalton Transactions . 40 . 31 . 7817–23 . 21629963.
  6. 10.2174/138955709790361566 . New Platinum and Ruthenium Complexes - the Latest Class of Potential Chemotherapeutic Drugs - a Review of Recent Developments in the Field . 2009 . Amin . Amr . Buratovich . Michael . Mini-Reviews in Medicinal Chemistry . 9 . 13 . 1489–503 . 20205631.
  7. Page . Simon . 1 January 2012 . Ruthenium compounds as anticancer agents . . . 49 . 1 . 26–29 .
  8. 10.1016/j.jorganchem.2010.11.009 . Organometallic ruthenium-based antitumor compounds with novel modes of action . 2011 . Ang . Wee Han . Casini . Angela . Angela Casini . Sava . Gianni . Dyson . Paul J. . Journal of Organometallic Chemistry . 696 . 5 . 989–98.
  9. Gopal YN, Jayaraju D, Kondapi AK . Inhibition of topoisomerase II catalytic activity by two ruthenium compounds: a ligand-dependent mode of action . Biochemistry . 38 . 14 . 4382–8 . April 1999 . 10194357 . 10.1021/bi981990s .
  10. Kostova I . Ruthenium complexes as anticancer agents . Current Medicinal Chemistry . 13 . 9 . 1085–107 . 2006 . 16611086 . 10.2174/092986706776360941 .
  11. Antonarakis ES, Emadi A . Ruthenium-based chemotherapeutics: are they ready for prime time? . Cancer Chemotherapy and Pharmacology . 66 . 1 . 1–9 . May 2010 . 20213076 . 4020437 . 10.1007/s00280-010-1293-1 .
  12. Book: 10.1016/S0898-8838(09)00201-3 . 21258628 . 3024542 . Controlling platinum, ruthenium, and osmium reactivity for anticancer drug design . Advances in Inorganic Chemistry . 2009 . Bruijnincx . Pieter C.A. . Sadler . Peter J. . 9780123750334 . 61 . 1–62.
  13. Blazevic . Amir . Hummer . Alfred A. . Heffeter . Petra . Berger . Walter . Filipits . Martin . Cibin . Giannantonio . Keppler . Bernhard K. . Rompel . Annette . Electronic State of Sodium trans-[Tetrachloridobis(1H-indazole)ruthenate(III)] (NKP-1339) in Tumor, Liver and Kidney Tissue of a SW480-bearing Mouse . Scientific Reports . 23 January 2017 . 7 . 1 . 40966 . 10.1038/srep40966. 28112202 . 5256101 . 2017NatSR...740966B .
  14. Bijelic . Aleksandar . Theiner . Sarah . Keppler . Bernhard K. . Rompel . Annette . X-ray Structure Analysis of Indazolium trans- [Tetrachlorobis(1 H -indazole)ruthenate(III)] (KP1019) Bound to Human Serum Albumin Reveals Two Ruthenium Binding Sites and Provides Insights into the Drug Binding Mechanism . Journal of Medicinal Chemistry . 23 June 2016 . 59 . 12 . 5894–5903 . 10.1021/acs.jmedchem.6b00600. 27196130 . 4921950 .