3 research outputs found
Structural–Spectrochemical Correlations of Variable Dimensionality Crystalline Metal–Organic Framework Materials in Hydrothermal Reactivity Patterns of Binary–Ternary Systems of Pb(II) with (a)Cyclic (Poly)carboxylate and Aromatic Chelator Ligands
Efforts
to comprehend the structural–spectrochemical correlations of
crystalline metal–organic framework materials of PbÂ(II) with
(a)Âcyclic and aromatic chelators linked to photoluminescent applications
led to the hydrothermal pH-specific synthesis of crystalline materials
[PbÂ{H<sub>2</sub>BTC}Â(phen)Â(H<sub>2</sub>O)]<sub><i>n</i></sub>·2<i>n</i>H<sub>2</sub>OÂ(<b>1</b>), [Pb<sub>2</sub>{CBTC}]<sub><i>n</i></sub>(<b>2</b>), [Pb<sub>4</sub>(phen)<sub>8</sub>{CBTC}<sub>2</sub>(H<sub>2</sub>O)<sub>4</sub>]<sub>3</sub>·70.3H<sub>2</sub>OÂ(<b>3</b>), and [PbÂ{HCTA}Â(H<sub>2</sub>O)<sub>2</sub>]<sub><i>n</i></sub>·<i>n</i>H<sub>2</sub>OÂ(<b>4</b>). X-ray studies showed that <b>1</b>–<b>4</b> exhibit unique architectures linked
to 2D–3D coordination polymers formulated by Z-type units composed
of Pb<sub>2</sub>O<sub>2</sub> cores, unusually high number of lattice–water
molecules, and π–π and H-bond interactions. The
contribution of the nature–structure properties of the aliphatic-(a)Âcyclic
organic (poly)Âcarboxylic/aromatic chelators-ligands to binary-ternary
PbÂ(II) reactivity weaves into the assembly of supramolecular networks,
thereby providing clear structural–spectroscopic inter-relationships
exemplifying the observed photoluminescent activity in a distinct
MOF-linked fashion
Structural–Spectrochemical Correlations of Variable Dimensionality Crystalline Metal–Organic Framework Materials in Hydrothermal Reactivity Patterns of Binary–Ternary Systems of Pb(II) with (a)Cyclic (Poly)carboxylate and Aromatic Chelator Ligands
Efforts
to comprehend the structural–spectrochemical correlations of
crystalline metal–organic framework materials of PbÂ(II) with
(a)Âcyclic and aromatic chelators linked to photoluminescent applications
led to the hydrothermal pH-specific synthesis of crystalline materials
[PbÂ{H<sub>2</sub>BTC}Â(phen)Â(H<sub>2</sub>O)]<sub><i>n</i></sub>·2<i>n</i>H<sub>2</sub>OÂ(<b>1</b>), [Pb<sub>2</sub>{CBTC}]<sub><i>n</i></sub>(<b>2</b>), [Pb<sub>4</sub>(phen)<sub>8</sub>{CBTC}<sub>2</sub>(H<sub>2</sub>O)<sub>4</sub>]<sub>3</sub>·70.3H<sub>2</sub>OÂ(<b>3</b>), and [PbÂ{HCTA}Â(H<sub>2</sub>O)<sub>2</sub>]<sub><i>n</i></sub>·<i>n</i>H<sub>2</sub>OÂ(<b>4</b>). X-ray studies showed that <b>1</b>–<b>4</b> exhibit unique architectures linked
to 2D–3D coordination polymers formulated by Z-type units composed
of Pb<sub>2</sub>O<sub>2</sub> cores, unusually high number of lattice–water
molecules, and π–π and H-bond interactions. The
contribution of the nature–structure properties of the aliphatic-(a)Âcyclic
organic (poly)Âcarboxylic/aromatic chelators-ligands to binary-ternary
PbÂ(II) reactivity weaves into the assembly of supramolecular networks,
thereby providing clear structural–spectroscopic inter-relationships
exemplifying the observed photoluminescent activity in a distinct
MOF-linked fashion
Data_Sheet_1_A quest for the stereo-electronic requirements for selective agonism for the neurotrophin receptors TrkA and TrkB in 17-spirocyclic-dehydroepiandrosterone derivatives.docx
IntroductionThe neurotrophin system plays a pivotal role in the development, morphology, and survival of the nervous system, and its dysregulation has been manifested in numerous neurodegenerative and neuroinflammatory diseases. Neurotrophins NGF and BDNF are major growth factors that prevent neuronal death and synaptic loss through binding with high affinity to their specific tropomyosin-related kinase receptors namely, TrkA and TrkB, respectively. The poor pharmacokinetic properties prohibit the use of neurotrophins as therapeutic agents. Our group has previously synthesized BNN27, a prototype small molecule based on dehydroepiandrosterone, mimicking NGF through the activation of the TrkA receptor.MethodsTo obtain a better understanding of the stereo-electronic requirements for selective activation of TrkA and TrkB receptors, 27 new dehydroepiandrosterone derivatives bearing a C17-spiro-dihydropyran or cyclobutyl moiety were synthesized. The new compounds were evaluated for their ability (a) to selectively activate the TrkA receptor and its downstream signaling kinases Akt and Erk1/2 in PC12 cells, protecting these cells from serum deprivation-induced cell death, and (b) to induce phosphorylation of TrkB and to promote cell survival under serum deprivation conditions in NIH3T3 cells stable transfected with the TrkB receptor and primary cortical astrocytes. In addition the metabolic stability and CYP-mediated reaction was assessed.ResultsAmong the novel derivatives, six were able to selectively protect PC12 cells through interaction with the TrkA receptor and five more to selectively protect TrkB-expressing cells via interaction with the TrkB receptor. In particular, compound ENT-A025 strongly induces TrkA and Erk1/2 phosphorylation, comparable to NGF, and can protect PC12 cells against serum deprivation-induced cell death. Furthermore, ENT-A065, ENT-A066, ENT-A068, ENT-A069, and ENT-A070 showed promising pro-survival effects in the PC12 cell line. Concerning TrkB agonists, ENT-A009 and ENT-A055 were able to induce phosphorylation of TrkB and reduce cell death levels in NIH3T3-TrkB cells. In addition, ENT-A076, ENT-A087, and ENT-A088 possessed antiapoptotic activity in NIH-3T3-TrkB cells exclusively mediated through the TrkB receptor. The metabolic stability and CYP-mediated reaction phenotyping of the potent analogs did not reveal any major liabilities.DiscussionWe have identified small molecule selective agonists of TrkA and TrkB receptors as promising lead neurotrophin mimetics for the development of potential therapeutics against neurodegenerative conditions.</p