👤 Supuran CT

Contemporary analyses of cell metabolism have called out three metabolites: ATP, NADH, and acetyl-CoA, as sentinel molecules whose accumulation represent much of the purpose of the catabolic arms of metabolism and then drive many anabolic pathways. Such analyses largely leave out how and why ATP, NADH, and acetyl-CoA (Figure 1 ) at the molecular level play such central roles. Yet, without those insights into why cells accumulate them and how the enabling properties of these key metabolites power much of cell metabolism, the underlying molecular logic remains mysterious. Four other metabolites, S-adenosylmethionine, carbamoyl phosphate, UDP-glucose, and Δ2-isopentenyl-PP play similar roles in using group transfer chemistry to drive otherwise unfavorable biosynthetic equilibria. This review provides the underlying chemical logic to remind how these seven key molecules function as mobile packets of cellular currencies for phosphoryl transfers (ATP), acyl transfers (acetyl-CoA, carbamoyl-P), methyl transfers (SAM), prenyl transfers (IPP), glucosyl transfers (UDP-glucose), and electron and ADP-ribosyl transfers (NAD(P)H/NAD(P)+) to drive metabolic transformations in and across most primary pathways. The eighth key metabolite is molecular oxygen (O2), thermodynamically activated for reduction by one electron path, leaving it kinetically stable to the vast majority of organic cellular metabolites. Show less

We present a new class of phosphorescent cyclometalated iridium(III) polypyridine poly(ethylene glycol) (PEG) complexes [Ir(N(⁾C)2(bpy-CONH-PEG)](PF6) (bpy-CONH-PEG = 4-(N-(2-(ω-methoxypoly-(1-oxapropyl))ethyl)aminocarbonyl)-4'-methyl-2,2'-bipyridine, number average molecular weight (Mn) = 5272.23, weight average molecular weight (Mw) = 5317.38, polydispersity index (PDI) = 1.009; HN(⁾C = 2-phenylpyridine, Hppy (1a), 2-((1,1'-biphenyl)-4-yl)pyridine, Hpppy (2a), 2-phenylquinoline, Hpq (3a), 2-phenylbenzothiazole, Hbt (4a), 2-(1-naphthyl)benzothiazole, Hbsn (5a)). The photophysical, photochemical, and biological properties of these complexes have been compared with those of their PEG-free counterparts [Ir(N(⁾C)2(bpy-CONH-Et)](PF6) (bpy-CONH-Et = 4-(N-ethylaminocarbonyl)-4'-methyl-2,2'-bipyridine; HN(⁾C = Hppy (1b), Hpppy (2b), Hpq (3b), Hbt (4b), Hbsn (5b)). Upon irradiation, all the complexes exhibited intense and long-lived green to orange-red emission under ambient conditions. The emission was phosphorescence in nature and can be quenched by O2 with the generation of singlet oxygen ((1)O2). The quantum yields for (1)O2 production of the complexes in aerated DMSO (0.24-0.83) were found to be dependent on the excited-state lifetimes of the complexes, which can be altered using different cyclometalating ligands (N(⁾C). Cell-based assays indicated that the PEG complexes were noncytotoxic in the dark (IC50 > 300 μM); however, most of them became significantly cytotoxic upon irradiation (IC50 = 3.4 - 23.2 μM). Laser-scanning confocal microscopy images revealed localization of complex 3a in the mitochondrial region of HeLa cells and the induction of rapid necrotic cell death upon light activation. Additionally, the lack of dark toxicity and potential application of the PEG complexes as a visualizing reagent have been demonstrated using zebrafish (Danio rerio) as an animal model. Show less

Cationic ruthenium(II) pentamethylcyclopentadienyl benzenesulfonamide sandwich complexes have been synthesized and screened for enzymatic inhibition of the physiologically dominant carbonic anhydrase (CA) isozymes: human CA I and II, mitochondrial isozymes VA and VB, and the cancer-associated isozyme IX. The complexes demonstrated weaker binding to CAs compared with typical aromatic sulfonamides, inhibiting the enzyme at high nanomolar concentrations. An in vitro cytotoxic evaluation of the complexes was also undertaken against a range of tumorigenic cell lines and a healthy human cell line. Complexes inhibited the growth of cancerous cells at low micromolar concentrations while expressing lower levels of toxicity towards the normal human cell line. Factors influencing the synthesis, cytotoxicity, and enzyme affinity for this series of organometallic complexes are discussed. Show less