PT 1

PT 1 is a selective activator of AMPK with EC50 value of 0.3 μM for AMPK α1β1γ1 [1].

AMP-activated protein kinase (AMPK) is serine/threonine protein kinase that involved in cellular energy homeostasis and acts as an energy sensor. AMPK is a heterotrimer and increases ATP generation [1].

PT 1 is a selective AMPK activator. PT1 activated human AMPK α
1394, AMPK α2398 and AMPK(α1β1γ1) with EC50 values of 8, 12 and 0.3 μM, respectively. PT1 exhibited maximum activity against AMPK(α1β1γ1) at concentration up to 5 μM. PT1 exhibited high selectivity for AMPK
α catalytic subunit. PT1 activated truncated AMPK α
1 subunit proteins including 313-335 aa with EC50 values of 8 μM, which was autoinhibitory domain. In HeLa cells without LKB1, PT1 induced AMPK and ACC phosphorylation, which were independent of LKB1. In human hepatoma HepG2 cells, PT1 dose-dependently reduced triacylglycerol and cholesterol content and induced AMPK and ACC phosphorylation [1]. In incubated mouse muscle, PT-1 increased γ1-containing AMPK activity and increased the AMPK-dependent phosphorylation of ULK1 on Ser555. However, in HEK293 cells expressing human γ1-, γ2- or γ3-AMPK, PT-1 activated them equally [2].

References:
[1].  Pang T, Zhang ZS, Gu M, et al. Small molecule antagonizes autoinhibition and activates AMP-activated protein kinase in cells. J Biol Chem, 2008, 283(23): 16051-16060.
[2].  Jensen TE, Ross FA, Kleinert M, et al. PT-1 selectively activates AMPK-γ1 complexes in mouse skeletal muscle, but activates all three γ subunit complexes in cultured human cells by inhibiting the respiratory chain. Biochem J, 2015, 467(3): 461-472.

An in vivo active 1,2,5-oxadiazole Pt(II) complex: A promising anticancer agent endowed with STAT3 inhibitory properties.[Pubmed:28324784]

Eur J Med Chem. 2017 May 5;131:196-206.

New Pt(II) complexes (Pt-1-3) bearing 1,2,5-oxadiazole ligands (1-3) were synthesized, characterized and evaluated for their ability to disrupt STAT3 dimerization. Ligand 3.HCl showed cytotoxic effects on HCT-116 cells (IC50 = 95.2 muM) and a selective ability to interact with STAT3 (IC50 = 8.2 muM) versus STAT1 (IC50 > 30 muM). Its corresponding platinum complex Pt-3 exhibited an increased cytotoxicity (IC50 = 18.4 muM) and a stronger interaction with STAT3 (IC50 = 1.4 muM), leading to inhibition of its signaling pathway. Pt-3 was also evaluated in cell-based assays for its action on p53 expression and on STAT3 phosphorylation. In syngeneic murine Lewis lung carcinoma (LLC) implanted in C57BL/6 mice, Pt-3 showed a higher antitumor activity with fewer side effects than cisplatin.

Pt nanoparticles immobilized in mesostructured silica: a non-leaching catalyst for 1-octene hydrosilylation.[Pubmed:28229136]

Chem Commun (Camb). 2017 Mar 7;53(20):2962-2965.

A catalyst containing small (ca. 2.5 nm) and crystalline Pt nanoparticles embedded into the walls of a mesostructured silica framework was found to be highly active in alkene hydrosilylation reaching TONs of ca. 10(5). More importantly, no Pt leaching was detected. This result is remarkable because Pt leaching is a recurrent problem in alkene hydrosilylation, which often prevents heterogeneous catalysts from being used industrially. This result is in contrast to the significant Pt leaching observed for other Pt/SiO2 catalysts.

Probing the Interactions of Cytotoxic [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)] and Its Pt(IV) Derivatives with Human Serum.[Pubmed:28206707]

ChemMedChem. 2017 Apr 6;12(7):510-519.

The discrepancy between the in vitro cytotoxic results and the in vivo performance of Pt56MeSS prompted us to look into its interactions and those of its Pt(IV) derivatives with human serum (HS), human serum albumin (HSA), lipoproteins, and serum-supplemented cell culture media. The Pt(II) complex, Pt56MeSS, binds noncovalently and reversibly to slow-tumbling proteins in HS and in cell culture media and interacts through the phenanthroline group with HSA, with a Kd value of approximately 1.5x10(-6) m. All Pt(IV) complexes were found to be stable toward reduction in HS, but those with axial carboxylate ligands, cct-[Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenantroline)(acetato)2 ](TFA)2 (Pt56MeSS(OAc)2 ) and cct-[Pt(1S,2S-DACH)(5,6-dimehtyl-1,10-phenantroline)(phenylbutyrato)2 ](TFA)2 (Pt56MeSS(PhB)2 ), were spontaneously reduced at pH 7 or higher in phosphate buffer, but not in Tris buffer (pH 8). HS also decreased the rate of reduction by ascorbate of the Pt(IV) complexes relative to the reduction rates in phosphate buffer, suggesting that for this compound class, phosphate buffer is not a good model for HS.

Exposure of Pt(5 5 3) and Rh(1 1 1) to atomic and molecular oxygen: do defects enhance subsurface oxygen formation?[Pubmed:28323632]

J Phys Condens Matter. 2017 Apr 26;29(16):164002.

Subsurface oxygen is known to form in transition metals, and is thought to be an important aspect of their ability to catalyze chemical reactions. The formation of subsurface oxygen is not, however, equivalent across all catalytically relevant metals. As a result, it is difficult to predict the stability and ease of the formation of subsurface oxygen in metals, as well as how the absorbed oxygen affects the chemical and physical properties of the metal. In comparing how a stepped platinum surface, Pt(5 5 3), responds to exposure to gas-phase oxygen atoms under ultra-high vacuum conditions to planar Rh(1 1 1), we are able to determine what role, if any, steps have on the capacity of a metal for subsurface oxygen formation. Despite the presence of regular defects, we found that only surface-bound oxygen formed on Pt(5 5 3). Alternatively, on the Rh(1 1 1) surface, oxygen readily absorbed into the selvedge of the metal. These results suggest that defects alone are insufficient for the formation of subsurface oxygen, and the ability of the metal to absorb oxygen is the primary factor in the formation and stabilization of subsurface oxygen.

PT-1 selectively activates AMPK-gamma1 complexes in mouse skeletal muscle, but activates all three gamma subunit complexes in cultured human cells by inhibiting the respiratory chain.[Pubmed:25695398]

Biochem J. 2015 May 1;467(3):461-72.

AMP-activated protein kinase (AMPK) occurs as heterotrimeric complexes in which a catalytic subunit (alpha1/alpha2) is bound to one of two beta subunits (beta1/beta2) and one of three gamma subunits (gamma1/gamma2/gamma3). The ability to selectively activate specific isoforms would be a useful research tool and a promising strategy to combat diseases such as cancer and Type 2 diabetes. We report that the AMPK activator PT-1 selectively increased the activity of gamma1- but not gamma3-containing complexes in incubated mouse muscle. PT-1 increased the AMPK-dependent phosphorylation of the autophagy-regulating kinase ULK1 (unc-51-like autophagy-activating kinase 1) on Ser555, but not proposed AMPK-gamma3 substrates such as Ser231 on TBC1 (tre-2/USP6, BUB2, cdc16) domain family, member 1 (TBC1D1) or Ser212 on acetyl-CoA carboxylase subunit 2 (ACC2), nor did it stimulate glucose transport. Surprisingly, however, in human embryonic kidney (HEK) 293 cells expressing human gamma1, gamma2 or gamma3, PT-1 activated all three complexes equally. We were unable to reproduce previous findings suggesting that PT-1 activates AMPK by direct binding between the kinase and auto-inhibitory domains (AIDs) of the alpha subunit. We show instead that PT-1 activates AMPK indirectly by inhibiting the respiratory chain and increasing cellular AMP:ATP and/or ADP:ATP ratios. Consistent with this mechanism, PT-1 failed to activate AMPK in HEK293 cells expressing an AMP-insensitive R299G mutant of AMPK-gamma1. We propose that the failure of PT-1 to activate gamma3-containing complexes in muscle is not an intrinsic feature of such complexes, but is because PT-1 does not increase cellular AMP:ATP ratios in the specific subcellular compartment(s) in which gamma3 complexes are located.

Turning enzymes ON with small molecules.[Pubmed:20154666]

Nat Chem Biol. 2010 Mar;6(3):179-188.

Drug discovery and chemical genetic efforts typically focus on the identification and design of inhibitors or loss-of-function probes as a means to perturb enzyme function. These tools are effective in determining the physiological consequence of ablating the activity of a specific enzyme. Remarkably, nearly a dozen examples of non-natural small molecules that activate enzyme catalysis have been identified within the past decade. In aggregate, these studies delineate four unique activation mechanisms that the small molecules exploit. These complementary gain-of-function probes offer a way to address the sufficiency of an enzyme to drive a particular cellular phenotype, and they also provide new opportunities for drug discovery. This review covers the identification and characterization of these unique small-molecule activators.