Poly(ADP-ribose) Polymerase in Neurodegeneration: Radiosynthesis and Radioligand Binding in ARC-SWE tg Mice

Alluri, Santosh Reddy; Riss, Patrick J.

doi:10.1021/acschemneuro.8b00053

Cited by 13 publications

(12 citation statements)

References 33 publications

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“…Meanwhile, over-activated PARP-1 will increase its interaction with transcription regulators such as nuclear receptors, sirtuins, and other metabolic transcription factors. Further, it will also lead to the impairment of mitochondrial function that seems to be an early and critically important event in the pathogenesis of AD 9 , 11 . Although the role of PARP-1 in human AD is not fully elucidated and many mechanisms are under investigations, accumulating evidences suggest that PARP-1 inhibitors are viable to neuroprotection and PARP-1 has emerged as a potential therapeutic target for AD 12 , 13 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors

Gao

Wang

Cui

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 ± 1.25 nM) and MDA-MB-436 cancer cell (11.62 ± 2.15 μM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer’s disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 ± 0.91 μM) which was stronger than neostigmine (12.01 ± 0.45 μM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer’s disease.

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Section: Introductionmentioning

confidence: 99%

Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors

Gao

Wang

Cui

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…A further application of an Uhle's ketone derivative was the synthesis and radiosynthesis of [ 3 H]rucaparib (125) (Scheme 24). 22 Rucaparib (123) is a selective poly(ADPribose)polymerase (PARP) inhibitor; in particular, it is a PARP-1 inhibitor that is used as an anticancer agent. 45 It is approved in the United States and in Europe as a third-line treatment for BRCA-mutated ovarian cancer.…”

Section: Short Review Synthesismentioning

confidence: 99%

“…In 2018, Cao and co-workers 15 reported the synthesis of racemic 4-amino-Uhle's ketone derivatives 25 and 26 (Scheme 4) using methodology previously developed by the Bernardi group 16 three years earlier. This approach consisted of a Brønsted acid catalyzed domino Friedel-Crafts/Henry reaction between commercially available indole-4-carbaldehyde (22) and nitroethylene. The tricyclic alcohol 23 was obtained in 66% yield, using (±)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate as the phosphoric acid (PA).…”

Section: Short Review Synthesismentioning

confidence: 99%

“…In fact, when this synthetic procedure was employed for the preparation of N-pivaloyl-7-fluoro-Uhle's ketone 59, the regioselectivity of the cyclization, C4 versus C2 position, was very low and only 9% of the desired product 59 was obtained (Scheme 9). 22 Scheme 9 2018 Alluri and Riss 22 synthesis of N-pivaloyl-7-fluoro-Uhle's ketone 59 from 7-fluoroindole…”

Section: Short Review Synthesismentioning

confidence: 99%

“…Scheme22 2005 Spadoni and co-workers18 synthesis of a conformationally restricted melatonin analogue from Uhle's ketone 35…”

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Synthesis and Reactivity of Uhle’s Ketone and Its Derivatives

Bartoccini¹,

Piersanti²

2020

Synthesis

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Uhle’s ketone and its derivatives are highly versatile intermediates for the synthesis of a variety of 3,4-fused tricyclic indole frameworks, i.e. indole alkaloids of the ergot family, that are found in various bioactive natural products and pharmaceuticals. Therefore, the development of a convenient preparative method for this structural motif as well as its opportune/useful derivatization have been the subject of longstanding interest in the fields of synthetic organic chemistry and medicinal chemistry. Herein, we summarize recent and less recent methods for the preparation of Uhle’s ketone and its derivatives as well as its main reactivity towards the synthesis of bioactive substances. Regarding the preparation, it can be roughly classified into two categories: (a) using 4-unfunctionalized and 4-functionalized indole derivatives as starting materials to construct a fused six-member ring, and (b) constructing the indole ring through intramolecular cycloaddition. Principally, the reactivity of the cyclic Uhle’s ketone shown here is derived from the classical electrophilicity of the carbonyl carbon or the acidity of the α-hydrogen and, though less intensively investigated, chemical reactions that induce ring expansion to form novel ring skeletons.1 Introduction2 Synthesis2.1 Disconnection A: Cyclization Reaction of the Opportune 3,4-Disubstituted Indole2.2 Disconnection B: Intramolecular Friedel–Crafts Cyclization2.3 Disconnection B: Intramolecular Cyclization via Metal–Halogen Exchange2.4 Disconnection C: Intramolecular Diels–Alder Furan Cycloaddition2.5 Disconnection D: Intramolecular Dearomatizing [3 + 2] Annulation3 Reactivity3.1 Use of Uhle’s Ketone for Lysergic Acid3.2 Use of Uhle’s Ketone for Rearranged Clavines3.3 Use of Uhle’s Ketone for Medicinal Chemistry4 Conclusion and Outlook

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Synthesis of a Pinacol Boronate Precursor for [¹⁸F]Rucaparib Radiosynthesis

Seo,

Park,

Cheon

2023

Asian J Org Chem

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A novel synthetic approach toward pinacol boronate used as a precursor in the recent radiosynthesis of [18F]rucaparib is described in this study. The Heck reaction of an ortho‐iodoaniline derivative bearing a chloride group at the meta‐position with acrylonitrile produced the desired (E)‐2‐aminocinnamonitrile derivative. The subsequent cyanide‐catalyzed imino‐Stetter reaction of aldimine derived from the obtained 2‐aminocinnamonitrile and aldehyde afforded the required trisubstituted indole‐3‐acetonitrile. The reduction of the nitrile group with cobalt boride followed by the construction of an azepinone scaffold generated indoloazepinone bearing a chloride substituent at the C6‐position of the indole scaffold. The Suzuki–Miyaura borylation of the chloride substituent produced pinacol boronate previously used in the synthesis of [18F]rucaparib. Detailed outcomes of different approaches using different 2‐aminocinnamonitriles were discussed as well.

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Poly(ADP-ribose) Polymerase in Neurodegeneration: Radiosynthesis and Radioligand Binding in ARC-SWE tg Mice

Cited by 13 publications

References 33 publications

Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors

Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors

Synthesis and Reactivity of Uhle’s Ketone and Its Derivatives

Synthesis of a Pinacol Boronate Precursor for [¹⁸F]Rucaparib Radiosynthesis

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Poly(ADP-ribose) Polymerase in Neurodegeneration: Radiosynthesis and Radioligand Binding in ARC-SWE tg Mice

Cited by 13 publications

References 33 publications

Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors

Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors

Synthesis and Reactivity of Uhle’s Ketone and Its Derivatives

Synthesis of a Pinacol Boronate Precursor for [18F]Rucaparib Radiosynthesis

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Synthesis of a Pinacol Boronate Precursor for [¹⁸F]Rucaparib Radiosynthesis