Fused-azepinones: Emerging scaffolds of medicinal importance

Akunuri, Ravikumar; Vadakattu, Manasa; Bujji, Sushmitha; Veerareddy, Vaishnavi; Madhavi, Y.V.; Nanduri, Srinivas

doi:10.1016/j.ejmech.2021.113445

Cited by 17 publications

(7 citation statements)

References 124 publications

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“…Compound 5 , dibromotryptamine, has been previously shown to be cytotoxic in a colon cancer model but no specific intracellular mechanism of action has been published . Compound 6 , ( Z )-debromohymenialdisine, has previously been shown to inhibit several kinase classes, but has not to our knowledge been assessed biochemically for PKA inhibition …”

Section: Resultsmentioning

confidence: 99%

“…40 Compound 6, (Z)-debromohymenialdisine, has previously been shown to inhibit several kinase classes, but has not to our knowledge been assessed biochemically for PKA inhibition. 41 Screening Leads Demonstrate Equal Inhibitory Potency against Both J-PKAcα and wt-PKA Kinases. After reproducing the observed inhibition in the screening assay and elucidating the chemical structure of active agents isolated from natural products samples, we next tested these compounds for inhibition of holoenzyme complexes of both the J-PKAcα chimeric fusion enzyme and the wt-PKAcα enzyme.…”

Section: Compounds 1−4)mentioning

confidence: 99%

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Biochemical Discovery, Intracellular Evaluation, and Crystallographic Characterization of Synthetic and Natural Product Adenosine 3′,5′-Cyclic Monophosphate-Dependent Protein Kinase A (PKA) Inhibitors

Wilson

Fiesco

et al. 2023

ACS Pharmacol. Transl. Sci.

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The recent demonstration that adenosine 3′,5′-cyclic monophosphate (cAMP)-dependent protein kinase A (PKA) plays an oncogenic role in a number of important cancers has led to a renaissance in drug development interest targeting this kinase. We therefore have established a suite of biochemical, cell-based, and structural biology assays for identifying and evaluating new pharmacophores for PKA inhibition. This discovery process started with a 384-well high-throughput screen of more than 200,000 substances, including fractionated natural product extracts. Identified active compounds were further prioritized in biochemical, biophysical, and cell-based assays. Priority lead compounds were assessed in detail to fully characterize several previously unrecognized PKA pharmacophores including the generation of new X-ray crystallography structures demonstrating unique interactions between PKA and bound inhibitor molecules.

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Section: Resultsmentioning

confidence: 99%

Section: Compounds 1−4)mentioning

confidence: 99%

Biochemical Discovery, Intracellular Evaluation, and Crystallographic Characterization of Synthetic and Natural Product Adenosine 3′,5′-Cyclic Monophosphate-Dependent Protein Kinase A (PKA) Inhibitors

Wilson

Fiesco

et al. 2023

ACS Pharmacol. Transl. Sci.

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“…Indolobenzazepines and indoloquinolines are fused heterocyclic scaffolds, which have gained a considerable interest in the field of medicinal chemistry. − Indolo[3,2- d ]benzazepines or paullones (backbone A in Chart ), first synthesized in 1992, were discovered as potential inhibitors of cyclin-dependent kinases (Cdks) ,, with antiproliferative activity similar to that of flavopiridol, the first Cdk-inhibitor that reached clinical trials as an anticancer drug. Later, other possible targets have been identified, namely, sirtuins, , GSK3β, ,,, and mitochondrial malate dehydrogenase .…”

Section: Introductionmentioning

confidence: 99%

“…24−26 Furthermore, some of the indolo [3,2-c]quinolines are effective and selective KRAS-mutated oncogene G-quadruplex stabilizers causing cancer cell apoptosis. 27 Indolo [3,2-d]benzazepines are non-planar heterocyclic systems due to the sp 3 -hybridized methylene carbon atom in the seven-membered azepine ring, whereas the indolo [3,2-c]quinolines are planar, making them effective DNA intercalators and/or topo I/II inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile

et al. 2022

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A series of latonduine and indoloquinoline derivatives HL 1 – HL 8 and their copper(II) complexes ( 1–8 ) were synthesized and comprehensively characterized. The structures of five compounds ( HL 6 , [CuCl(L 1 )(DMF)]·DMF , [CuCl(L 2 )(CH 3 OH)] , [CuCl(L 3 )]·0.5H 2 O , and [CuCl 2 (H 2 L 5 )]Cl·2DMF ) were elucidated by single crystal X-ray diffraction. The copper(II) complexes revealed low micro- to sub-micromolar IC 50 values with promising selectivity toward human colon adenocarcinoma multidrug-resistant Colo320 cancer cells as compared to the doxorubicin-sensitive Colo205 cell line. The lead compounds HL 4 and 4 as well as HL 8 and 8 induced apoptosis efficiently in Colo320 cells. In addition, the copper(II) complexes had higher affinity to DNA than their metal-free ligands. HL 8 showed selective inhibition for the PIM-1 enzyme, while 8 revealed strong inhibition of five other enzymes, i.e., SGK-1, PKA, CaMK-1, GSK3β, and MSK1, from a panel of 50 kinases. Furthermore, molecular modeling of the ligands and complexes showed a good fit to the binding pockets of these targets.

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“…[7] Azepinones correspond to a vital class of seven-member heterocycles that exists in many naturally occurring organic compounds, [8] bioactive molecules, [9] medicinally relevant compounds [10] and natural products. [11] Many alkaloids contain azepinone nuclei as the core structure units (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Metal‐Catalyzed Approaches for the Construction of Azepinones

et al. 2022

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The azepinone scaffolds are an important framework of pharmaceutically interesting compounds and many bioactive natural products. This review mainly focused on the metalcatalyzed approaches towards the synthesis of azepinones . Mainly it covers cycloisomerization and metal carbenoid insertion. It also involves transformations through cycloaddition reactions, metathesis reactions, microwave reactions and direct CÀ H/CÀ C/CÀ N activation reactions. The applications, substrate scope, limitations and plausible mechanisms of these transformations have also been discussed.

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Fused-azepinones: Emerging scaffolds of medicinal importance

Cited by 17 publications

References 124 publications

Biochemical Discovery, Intracellular Evaluation, and Crystallographic Characterization of Synthetic and Natural Product Adenosine 3′,5′-Cyclic Monophosphate-Dependent Protein Kinase A (PKA) Inhibitors

Biochemical Discovery, Intracellular Evaluation, and Crystallographic Characterization of Synthetic and Natural Product Adenosine 3′,5′-Cyclic Monophosphate-Dependent Protein Kinase A (PKA) Inhibitors

Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile

Metal‐Catalyzed Approaches for the Construction of Azepinones

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