Design, synthesis and biological activity of β-carboline-based type-5 phosphodiesterase inhibitors

Maw, Graham N.; Allerton, Charlotte; Gbekor, Eugene; Million, William A.

doi:10.1016/s0960-894x(03)00159-8

Cited by 49 publications

(28 citation statements)

References 10 publications

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“…Indeed, these pyrrolidine moieties substituted by various aromatic groups (e.g., pyridine, benzyl, imidazole) were able to bring IC 50 to very low nanomolar or sub-nanomolar values (IC 50 = 0.8−2.0 nM for 77a, 77b, 78a, and 78b). 103,105 ■ GLUTAMATE RECEPTORS BINDERS (NMDA, MGLUR)…”

Section: ■ Phosphodiesterase Type 5 (Pde5) Inhibitorsmentioning

confidence: 99%

“…Overall, among the R,R enantiomers tested, only a few showed IC 50 values similar to those mentioned above. ,,, Other studies focused exclusively on 3,4-methylenedioxyphenyl analogues. Interestingly, the tolerance for N -substitution was lesser in this context, and small, aliphatic moieties were found more promising for anti-PDE5 activity than aromatic or extended groups (e.g., IC 50 = 16 nM for 76 vs. 5 nM for 8 ). ,, In addition, the introduction of polar groups, such as OH or NH 2 , was detrimental, compared to hydrophobic equivalents . Finally, 6-(3,4-methylenedioxyphenyl) compounds bearing ( R )-pyrrolidine-type substituents at the amido position of the piperazinedione ring were developed as the most potent β-carboline-based PDE5 inhibitors to date.…”

Section: Phosphodiesterase Type 5 (Pde5) Inhibitorsmentioning

confidence: 99%

“…Finally, 6-(3,4-methylenedioxyphenyl) compounds bearing ( R )-pyrrolidine-type substituents at the amido position of the piperazinedione ring were developed as the most potent β-carboline-based PDE5 inhibitors to date. Indeed, these pyrrolidine moieties substituted by various aromatic groups (e.g., pyridine, benzyl, imidazole) were able to bring IC 50 to very low nanomolar or sub-nanomolar values (IC 50 = 0.8–2.0 nM for 77a , 77b , 78a , and 78b ). , …”

Section: Phosphodiesterase Type 5 (Pde5) Inhibitorsmentioning

confidence: 99%

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β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer’s Disease Therapy

et al. 2021

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The natural β-carboline alkaloids display similarities with neurotransmitters that can be favorably exploited to design bioactive and bioavailable drugs for Alzheimer's disease (AD) therapy. Several AD targets are currently and intensively being investigated, divided in different hypotheses: mainly the cholinergic, the amyloid β (Aβ), and the Tau hypotheses. To date, only symptomatic treatments are available involving acetylcholinesterase and NMDA inhibitors. On the basis of plethoric single-target structure−activity relationship studies, the β-carboline scaffold was identified as a powerful tool for fostering activity and molecular interactions with a wide range of AD-related targets. This knowledge can undoubtedly be used to design multitarget-directed ligands, a highly relevant strategy preferred in the context of multifactorial pathology with intricate etiology such as AD. In this review, we first individually discuss the AD targets of the β-carbolines, and then we focus on the multitarget strategies dedicated to the deliberate design of new efficient scaffolds.

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Section: ■ Phosphodiesterase Type 5 (Pde5) Inhibitorsmentioning

confidence: 99%

Section: Phosphodiesterase Type 5 (Pde5) Inhibitorsmentioning

confidence: 99%

Section: Phosphodiesterase Type 5 (Pde5) Inhibitorsmentioning

confidence: 99%

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β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer’s Disease Therapy

et al. 2021

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“…Maw et al. reported a library synthesis of piperazine fused β‐carbolines . D ‐tryptophan methyl ester hydrochloride was condensed with piperonal in the presence of TFA to afford a Pictet‐Spengler cyclized product β‐carboline methyl carboxylate 305 (Scheme ).…”

Section: β‐Carboline Fused Heterocycles Synthesized Via Post‐pictet‐smentioning

confidence: 99%

Post‐Pictet‐Spengler Cyclization (PPSC): A Strategy to Synthesize Polycyclic β‐Carboline‐Derived Natural Products and Biologically Active N‐Heterocycles

Singh

Kumar

Patil³

et al. 2020

Adv Synth Catal

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Pictet-Spengler reaction is a typical condensation reaction of β-arylethylamine or Tryptamine with an aldehyde or ketone followed by ring closure to generate tetrahydroisoquinoline (THIQ) and Tetrahydro-β-carboline (THβC), respectively. Both these key skeletons represent huge range of structurally diverse naturally occurring isoquinoline and indole alkaloids. Nature has synthesized structurally complex Reserpine, Ajmalicine as well as other related alkaloids using various biosynthetic pathways via Pictet-Spengler reaction followed by post-Pictet-Spengler cyclization (PPSC) stratergy. This biosynthetic process is the short and reliable method to access diverse range of polycyclic heterocycles. Over the period of last sixty years, several researchers have synthesized complex alkaloids without highlighting the synthetic utility of the post-Pictet-Spengler cyclization strategy. We summarized the synthesis of numerous natural products and related natural product inspired heterocyclic scaffolds which follow the PPSC strategy to demonstrate its usefulness for the construction of diverse compound collection.

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“…β ‐Carbolines isolated from Peganum harmala and Eurycoma longifolia act as topoisomerase and cyclin dependent kinase inhibitors . The parent compound Harmine inhibited breast cancer resistant protein as revealed by cell line studies.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Human Anticancer Cell Line Studies on Coumarin‐β‐carboline Hybrids as Possible Antimitotic Agents

Samundeeswari

Kulkarni

Joshi³

et al. 2016

ChemistrySelect

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A series of coumarin tetrahydro‐β‐carboline hybrids 3 have been synthesized by the Pictet‐Spengler reaction. Stoichiometrically controlled DDQ oxidation has led to dihydro 4 and β‐carboline 5. In vitro anticancer activity against 60 cell lines has revealed the potency of 3 f, 4 a and 5 c. In silico studies indicate the binding properties of 5 c with Kinesin spindle protein (KSP) and tubulin protein. Gel electrophoresis studies revealed that compound 3 f partially cleaved the CT‐DNA, whereas the ring C aromatized compound 5 c completely cleaved the CT‐DNA. Structures of the newly synthesized compounds are confirmed by spectroscopic and X‐ray studies.

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Design, synthesis and biological activity of β-carboline-based type-5 phosphodiesterase inhibitors

Cited by 49 publications

References 10 publications

β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer’s Disease Therapy

β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer’s Disease Therapy

Post‐Pictet‐Spengler Cyclization (PPSC): A Strategy to Synthesize Polycyclic β‐Carboline‐Derived Natural Products and Biologically Active N‐Heterocycles

Synthesis and Human Anticancer Cell Line Studies on Coumarin‐β‐carboline Hybrids as Possible Antimitotic Agents

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