Systematically altering the lipophilicity of rhenium(<scp>i</scp>) tricarbonyl anticancer agents to tune the rate at which they induce cell death

Konkankit, Chilaluck C.; Vaughn, Brett A.; Huang, Zhouyang; Boros, Eszter; Wilson, Justin J.

doi:10.1039/d0dt01097a

Cited by 31 publications

(24 citation statements)

References 45 publications

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“…The calculated log P values for these carboxylic acids are −0.54, −0.28, 0.33, and 0.79 for formic, acetic, propanoic, and butyric acids, respectively, reflecting the magnitudes of increases in lipophilicity expected for the complexes. Cellular uptake is often correlated to lipophilicity, − and metal complexes bearing lipophilic groups have leveraged this property to enhance their therapeutic potentials. − We postulated that the use of these ligands could allow us to investigate this relationship for these Ru-based MCU inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Carboxylate-Capped Analogues of Ru265 Are MCU Inhibitor Prodrugs

et al. 2022

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The mitochondrial calcium uniporter (MCU) is a transmembrane protein that resides on the inner membrane of the mitochondria and mediates calcium uptake into this organelle. Given the critical role of mitochondrial calcium trafficking in cellular function, inhibitors of this channel have arisen as tools for studying the biological relevance of this process and as potential therapeutic agents. In this study, four new analogues of the previously reported Ru-based MCU inhibitor [ClRu(NH 3 ) 4 (μ-N)Ru(NH 3 ) 4 Cl]Cl 3 (Ru265) are reported. These compounds, which bear axial carboxylate ligands, are of the general formula [(RCO 2 )Ru(NH 3 ) 4 (μ-N)Ru(NH 3 ) 4 (O 2 CR)]X 3 , where X = NO 3 − or CF 3 SO 3 − and R = H (1), CH 3 (2), CH 2 CH 3 (3), and (CH 2 ) 2 CH 3 (4). These complexes were fully characterized by IR spectroscopy, NMR spectroscopy, and elemental analysis. X-ray crystal structures of 1 and 3 were obtained, revealing the expected presence of both the linear Ru(μ-N)Ru core and axial formate and propionate ligands. The axial carboxylate ligands of complexes 1− 4 are displaced by water in buffered aqueous solution to give the aquated compound Ru265′. The kinetics of these processes were measured by 1 H NMR spectroscopy, revealing half-lives that span 5.9−9.9 h at 37 °C. Complex 1 with axial formate ligands underwent aquation approximately twice as fast as the other compounds. In vitro cytotoxicity and mitochondrial membrane potential measurements carried out in HeLa and HEK293T cells demonstrated that none of these four complexes negatively affects cell viability or mitochondrial function. The abilities of 1−4 to inhibit mitochondrial calcium uptake in permeabilized HEK293T cells were assessed and compared to that of Ru265. Fresh solutions of 1−4 are approximately 2-fold less potent than Ru265 with IC 50 values in the range of 14.7−19.1 nM. Preincubating 1−4 in aqueous buffers for longer time periods to allow for the aquation reactions to proceed increases their potency of mitochondrial uptake inhibition to match that of Ru265. This result indicates that 1− 4 are aquation-activated prodrugs of Ru265′. Finally, 1−4 were shown to inhibit mitochondrial calcium uptake in intact, nonpermeabilized cells, revealing their value as tools and potential therapeutic agents for mitochondrial calcium-related disorders.

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Section: Resultsmentioning

confidence: 99%

Carboxylate-Capped Analogues of Ru265 Are MCU Inhibitor Prodrugs

et al. 2022

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“…The drug must be endowed with the appropriate lipophilicity to cross the cell membrane; an overly lipophilic compound would accumulate in the membrane . Lipinski’s rule of five also strongly advices drug log P values not to exceed 5 …”

Section: Resultsmentioning

confidence: 99%

Pt(IV) Prodrugs with Non-Steroidal Anti-inflammatory Drugs in the Axial Position

et al. 2022

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We report herein the design, synthesis, and biological investigation of a series of novel Pt(IV) prodrugs with non-steroidal anti-inflammatory drugs naproxen, diclofenac, and flurbiprofen, as well as these with stearic acid in the axial position. Six Pt(IV) prodrugs 5–10 were designed, which showed superior antiproliferative activity compared to cisplatin as well as an ability to overcome tumor cell line resistance to cisplatin. By tuning the drug lipophilicity via variation of the axial ligands, the most potent Pt(IV) prodrug 7 was obtained, with an enhanced cellular accumulation of up to 153-fold that of cisplatin and nanomolar cytotoxicity both in 2D and 3D cell cultures. Pt2+ species were detected at different depths of MCF-7 spheroids after incubation with Pt(IV) prodrugs using a Pt-coated carbon nanoelectrode. Cisplatin accumulation in vivo in the murine mammary EMT6 tumor tissue of BALB/c mice after Pt(IV) prodrug injection was proved electrochemically as well. The drug tolerance study on BALB/c mice showed good tolerance of 7 in doses up to 8 mg/kg.

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“…Compounds having more lipophilicity can produce in vitro anticancer activities within a much shorter time. 33 …”

Section: Rhenium( I ) Complexesmentioning

confidence: 99%

“…Compounds having more lipophilicity can produce in vitro anticancer activities within a much shorter time. 33 Re(I) tricarbonyl NNN and NSO complexes A tricarbonyl complex bearing a piperidinyl sulphonamide group (Re15) with the formula [Re(CO) 3 (N(SO 2 pip)dpa)] + and ligand (N(SO 2 pip)dpa) was synthesized and reported by Subasinghe et al These compounds were tested against a human breast cancer cell line (MCF-7). The IC 50 of the ligand was 139 mM and the IC 50 of complex Re15 was 360 mM.…”

Section: Organometallic Rhenium(i) Imine Complexesmentioning

confidence: 99%

“… 31 They are biologically active and have the potential to be utilized as targeted drugs in cancer therapy. 32 Consequently, these complexes are emerging as promising anticancer agents, which can be a viable alternative to platinum-based anticancer drugs 33 for application in medicinal chemistry. 34 Re exhibits variable oxidation states (−3, −1, +1, +2, +3, +4, +5, +6, and +7), and thereby delivers noteworthy and unique properties 35 in the realm of transition metals.…”

Section: Introductionmentioning

confidence: 99%

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Target-specific mononuclear and binuclear rhenium(i) tricarbonyl complexes as upcoming anticancer drugs

Vaibhavi

Kar

et al. 2022

RSC Adv.

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Systematically altering the lipophilicity of rhenium(i) tricarbonyl anticancer agents to tune the rate at which they induce cell death

Abstract: Increasing the lipophilicity of rhenium-based anticancer agents increases the rate at which they induce their biological effects.

Cited by 31 publications

References 45 publications

Carboxylate-Capped Analogues of Ru265 Are MCU Inhibitor Prodrugs

Carboxylate-Capped Analogues of Ru265 Are MCU Inhibitor Prodrugs

Pt(IV) Prodrugs with Non-Steroidal Anti-inflammatory Drugs in the Axial Position

Target-specific mononuclear and binuclear rhenium(i) tricarbonyl complexes as upcoming anticancer drugs

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