Caging the uncageable: using metal complex release for photochemical control over irreversible inhibition

Huisman, Matthew; White, Jessica K.; Lewalski, Veronica G.; Podgorski, Izabela; Turró, Claudia; Kodanko, Jeremy J.

doi:10.1039/c6cc07083c

Cited by 43 publications

(58 citation statements)

References 24 publications

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“…Taken together with data from previously synthesized metal–inhibitor conjugates (Figure 5), 34 our results collectively confirm that the position and nature of the metal center strongly influence potency and selectivity of CTSL inhibition. A comparison of conjugates 7 and 9 , which contain the same parent inhibitor structure but different metal fragments, Re(phen)(CO) 3 and Ru(tpy)(Me 2 bpy), respectively, indicates that the Re(I) group is much better tolerated than the more bulky Ru(II) fragment in the CTSL active site.…”

Section: Resultssupporting

confidence: 87%

“…A solution of (2 S ,3 S )-3-((( S )-1-(dimethylamino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)oxirane-2-carboxylic acid ( 6 ; 34 477 mg, 1.56 mmol) and p -nitrophenol (217 mg, 1.56 mmol) in EtOAc (4.5 mL) was maintained at 0 °C for 5 min under a nitrogen atmosphere. A solution of DCC (331 mg, 1.60 mmol) in EtOAc (4.5 mL) was added dropwise over a period of 30 min.…”

Section: Methodsmentioning

confidence: 99%

“…In a sealable tube, a solution of 1 34 (191 mg, 0.470 mmol) and CHCl 3 /MeOH (4.5/18 mL) was maintained at room temperature and argon was bubbled through the solution for 20 min. Re(1,10-phenanthroline)(CO) 3 (OTf) 36 (210 mg, 0.350 mmol) was added to the mixture, and the tube containing the mixture was sealed under an inert atmosphere, wrapped in aluminum foil, and heated to 60 °C for 16 h. The solvent was removed in vacuo without external heating, resulting in a yellow solid.…”

Section: Methodsmentioning

confidence: 99%

“…34 Cathepsin S inhibition data were collected using CTSS (4 nM), Z -Val-Val-Arg-AMC (10 μ M), 1 , 2 , 7 , and 8 (1–20 μ M) in 50 mM phosphate buffer, pH 6.5, <1% DMSO, 2.5 mM EDTA, and DTT 8 mM at 25 °C. Cathepsin B inhibition data were collected using CTSB (4 nM), Z -Arg-Arg-AMC (10 μ M), 1 , 2 , 7 , and 8 (1 nM to 100 μ M) in 0.4 M acetate buffer, pH 5.5, <1% DMSO, 5 mM EDTA, 0.01% Triton X-100, and DTT 10 mM at 25 °C.…”

Section: Methodsmentioning

confidence: 99%

“…Progress curve data were analyzed using the program Dynafit 39 to obtain k inact and K i values using a literature method. 34 …”

Section: Methodsmentioning

confidence: 99%

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Affinity-Enhanced Luminescent Re(I)- and Ru(II)-Based Inhibitors of the Cysteine Protease Cathepsin L

et al. 2018

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Two new Re(I)- and Ru(II)-based inhibitors were synthesized with the formulas [Re(phen)(CO)3(1)](OTf) (7; phen = 1,10-phenanthroline, OTf = trifluoromethanesulfonate) and [Ru(bpy)2(2)](Cl)2 (8; bpy = 2,2′-bipyridine), where 1 and 2 are the analogues of CLIK-148, an epoxysuccinyl-based cysteine cathepsin L inhibitor (CTSL). Compounds 7 and 8 were characterized using various spectroscopic techniques and elemental analysis; 7 and 8 both show exceptionally long excited state lifetimes. Re(I)-based complex 7 inhibits CTSL in the low nanomolar range, affording a greater than 16-fold enhancement of potency relative to the free inhibitor 1 with a second-order rate constant of 211000 ± 42000 M−1 s−1. Irreversible ligation of 7 to papain, a model of CTSL, was analyzed with mass spectroscopy, and the major peak shown at 24283 au corresponds to that of papain-1-Re(CO)3(phen). Compound 7 was well tolerated by DU-145 prostate cancer cells, with toxicity evident only at high concentrations. Treatment of DU-145 cells with 7 followed by imaging via confocal microscopy showed substantial intracellular fluorescence that can be blocked by the known CTSL inhibitor CLIK-148, consistent with the ability of 7 to label CTSL in living cells. Overall this study reveals that a Re(I) complex can be attached to an enzyme inhibitor and enhance potency and selectivity for a medicinally important target, while at the same time allowing new avenues for tracking and quantification due to long excited state lifetimes and non-native element composition.

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Section: Resultssupporting

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Progress curve data were analyzed using the program Dynafit 39 to obtain k inact and K i values using a literature method. 34 …”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Affinity-Enhanced Luminescent Re(I)- and Ru(II)-Based Inhibitors of the Cysteine Protease Cathepsin L

et al. 2018

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Roles of Pericellular Proteases in Tumor Angiogenesis: Therapeutic Implications

Kraniak

Mattingly

Sloane

2018

Extracellular Targeting of Cell Signaling in Cancer

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Red‐Light‐Controlled Release of Drug–Ru Complex Conjugates from Metallopolymer Micelles for Phototherapy in Hypoxic Tumor Environments

Sun

Yan

Thiramanas

et al. 2018

Adv Funct Materials

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Traditional photodynamic phototherapy is not efficient for anticancer treatment because solid tumors have a hypoxic microenvironment. The development of photoactivated chemotherapy based on photoresponsive polymers that can be activated by light in the "therapeutic window" would enable new approaches for basic research and allow for anticancer phototherapy in hypoxic conditions. This work synthesizes a novel Ru-containing block copolymer for photoactivated chemotherapy in hypoxic tumor environment. The polymer has a hydrophilic poly(ethylene glycol) block and a hydrophobic Ru-containing block, which contains red-light-cleavable (650-680 nm) drug-Ru complex conjugates. The block copolymer self-assembles into micelles, which can be efficiently taken up by cancer cells. Red light induces release of the drug-Ru complex conjugates from the micelles and this process is oxygen independent. The released conjugates inhibit tumor cell growth even in hypoxic tumor environment. Furthermore, the Ru-containing polymer for photoactivated chemotherapy in a tumor-bearing mouse model is applied. Photoactivated chemotherapy of the polymer micelles demonstrates efficient tumor growth inhibition. In addition, the polymer micelles do not cause any toxic side effects to mice during the treatment, demonstrating good biocompatibility of the system to the blood and healthy tissues. The novel red-light-responsive Ru-containing polymer provides a new platform for phototherapy against hypoxic tumors.

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Caging the uncageable: using metal complex release for photochemical control over irreversible inhibition

Cited by 43 publications

References 24 publications

Affinity-Enhanced Luminescent Re(I)- and Ru(II)-Based Inhibitors of the Cysteine Protease Cathepsin L

Affinity-Enhanced Luminescent Re(I)- and Ru(II)-Based Inhibitors of the Cysteine Protease Cathepsin L

Roles of Pericellular Proteases in Tumor Angiogenesis: Therapeutic Implications

Red‐Light‐Controlled Release of Drug–Ru Complex Conjugates from Metallopolymer Micelles for Phototherapy in Hypoxic Tumor Environments

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