Metallo prodrugs that take advantage of the inherent acidity surrounding cancer cells have yet to be developed. We report a new class of pH-activated metallo prodrugs (pHAMPs) that are activated by light- and pH-triggered ligand dissociation. These ruthenium complexes take advantage of a key characteristic of cancer cells and hypoxic solid tumors (acidity) that can be exploited to lessen the side effects of chemotherapy. Five ruthenium complexes of the type [(N,N)Ru(PL)] were synthesized, fully characterized, and tested for cytotoxicity in cell culture (1: N,N = 2,2'-bipyridine (bipy) and PL, the photolabile ligand, = 6,6'-dihydroxybipyridine (6,6'-dhbp); 2: N,N = 1,10-phenanthroline (phen) and PL = 6,6'-dhbp; 3: N,N = 2,3-dihydro-[1,4]dioxino[2,3-f][1,10]phenanthroline (dop) and PL = 6,6'-dhbp; 4: N,N = bipy and PL = 4,4'-dimethyl-6,6'-dihydroxybipyridine (dmdhbp); 5: N,N = 1,10-phenanthroline (phen) and PL = 4,4'-dihydroxybipyridine (4,4'-dhbp). The thermodynamic acidity of these complexes was measured in terms of two pK values for conversion from the acidic form (X) to the basic form (X) by removal of two protons. Single-crystal X-ray diffraction data is discussed for 2, 2, 3, 4, and 5. All complexes except 5 showed measurable photodissociation with blue light (λ = 450 nm). For complexes 1-4 and their deprotonated analogues (1-4), the protonated form (at pH 5) consistently gave faster rates of photodissociation and larger quantum yields for the photoproduct, [(N,N)Ru(HO)]. This shows that low pH can lead to greater rates of photodissociation. Cytotoxicity studies with 1-5 showed that complex 3 is the most cytotoxic complex of this series with IC values as low as 4 μM (with blue light) versus two breast cancer cell lines. Complex 3 is also selectively cytotoxic, with sevenfold higher toxicity toward cancerous versus normal breast cells. Phototoxicity indices with 3 were as high as 120, which shows that dark toxicity is avoided. The key difference between complex 3 and the other complexes tested appears to be higher uptake of the complex as measured by inductively coupled plasma mass spectrometry, and a more hydrophobic complex as compared to 1, which may enhance uptake. These complexes demonstrate proof of concept for dual activation by both low pH and blue light, thus establishing that a pHAMP approach can be used for selective targeting of cancer cells.

Methyl groups are ubiquitous in biologically active molecules. Thus, new tactics to introduce this alkyl fragment into polyfunctional structures are of significant interest. With this goal in mind, a direct method for the Markovnikov hydromethylation of alkenes is reported. This method exploits the degenerate metathesis reaction between the titanium methylidene unveiled from Cp2Ti(μ‐Cl)(μ‐CH2)AlMe2 (Tebbe's reagent) and unactivated alkenes. Protonolysis of the resulting titanacyclobutanes in situ effects hydromethylation in a chemo‐, regio‐, and site‐selective manner. The broad utility of this method is demonstrated across a series of mono‐ and di‐substituted alkenes containing pendant alcohols, ethers, amides, carbamates, and basic amines.

A new polyene cyclization strategy exploiting β-ionyl derivatives was developed. Photoinduced deconjugation of the extended π-system within these chromophores unveils a contrathermodynamic polyene that engages in a Heck bicyclization to afford [4.4.1]-propellanes. This cascade improves upon the limited regioselectivity achieved using existing biomimetic tactics and tolerates both electron-rich and electron-deficient (hetero)­aryl groups. The utility of this approach was demonstrated with the diverted total synthesis of taxodione and salviasperanol, two isomeric abietane diterpenes that were previously inaccessible along the same synthetic pathway.

A photoinduced isomerization reaction enables stereocontrolled access to a range of fused 5–8–5 ring systems.