Illuminating cytochrome P450 binding: Ru(ii)-caged inhibitors of CYP17A1

Abstract

New Ru(II)-caged abiraterone complexes were synthesized that exhibit strong absorption in the visible region and release the steroidal CYP17A1 inhibitor abiraterone upon exposure to low energy visible light in buffer and prostate cancer cells. Photoinduced release results in abiraterone binding to its CYP17A1 target in an inhibitory mode.

A Red‐Light‐Activated Ruthenium‐Caged NAMPT Inhibitor Remains Phototoxic in Hypoxic Cancer Cells

“…Two sterically hindered ruthenium photocaging scaffolds were chosen based upon earlier work by the group of Turro and Kodanko: [Ru(tpy)(dmbpy)(L)] 2+ (tpy=2,2′;6′‐2′′‐terpyridine; dmbpy=6,6′‐dimethyl‐2,2′‐bipyridine) and [Ru(tpy)(biq)(L)] 2+ (biq=2,2′‐biquinoline). Both types of complexes have an absorption band that extends into the red region of the spectrum, and they photodissociate when the monodentate ligand (L) is a thioether or a pyridine moiety . These scaffolds were conjugated to 4‐[({[4‐(2‐methyl‐2‐propanyl)phenyl]sulfonyl}amino)methyl]‐ N ‐(3‐pyridinyl)benzamide (STF‐31), a known cytotoxic organic compound containing a pyridine moiety that can coordinate to ruthenium.…”

“…The almost identical EC 50 found for [ 1 ]Cl 2 in the dark and after light irradiation, and its high NAMPT inhibition in the dark, suggest that [ 1 ]Cl is thermally unstable: When followed for 48 hours at 37 °C in the dark in OptiMEM medium (Figure S8), [ 1 ] 2+ slowly decomposed to [Ru(tpy)(dmbpy)(OH 2 )] 2+ while [ 2 ] 2+ remained stable (Figure and Figure S9). This result is in contrast to Kodanko et al., who used [Ru(tpy)(dmbpy)] 2+ to cage a steroidal CYP17A1 inhibitor . According to our results, [Ru(tpy)(NN)(L)] 2+ complexes are only stable enough for PACT when NN=biq, while complexes with NN=dmbpy are more photoreactive and are also unstable in the dark …”

Breaking the barrier: an osmium photosensitizer with unprecedented hypoxic phototoxicity for real world photodynamic therapy

“…41 Similar PIs for PCT agents that release cytotoxic ligands and/or metal complexes have been reported. 27,29,50,56 These ndings inspired us to consider other ways of instilling hypoxic activity in Ru(II) complexes that are photostable and exploit photocatalytic pathways/mechanisms for cytotoxic effects. Our approach is to create metal complex PSs that combine powerful 1 O 2 sensitization, such that some activity can be maintained even in hypoxia, with the possibility of light-induced electron transfer reactions via triplet intraligand charge transfer ( 3 ILCT) excited states.…”

Cyclometalated Ruthenium(II) Complexes Derived from α-Oligothiophenes as Highly Selective Cytotoxic or Photocytotoxic Agents

“…1–4 More recently, RPCs are being explored as light-responsive agents for photobiological applications such as photodynamic therapy (PDT)/photoactivated cancer therapy (PACT) and photochemotherapy (PCT), 5–7 and as photocaging units for precise delivery of enzyme inhibitors. 8,9 Our RPC TLD1433 is currently in a clinical trial for treating bladder cancer with PDT (ClinicalTrials.gov Identifier: NCT03053635), which is the first example of a Ru(II)-based photosensitizer that has advanced to human studies.…”