Discovery of a Series of 3-Cinnoline Carboxamides as Orally Bioavailable, Highly Potent, and Selective ATM Inhibitors

Barlaam, Bernard; Cadogan, Elaine; Campbell, Andrew D.; Colclough, Nicola; Dishington, Allan; Durant, Stephen T.; Goldberg, Kristin; Hassall, Lorraine; Hughes, Gareth; MacFaul, Philip A.; McGuire, Thomas M.; Pass, Martin; Patel, Anil S.; Pearson, Stuart E.; Petersen, J.; Pike, Kurt G.; Robb, Graeme R.; Stratton, Natalie; Xin, Guohong; Zhai, Beibei

doi:10.1021/acsmedchemlett.8b00200

Cited by 26 publications

(17 citation statements)

References 15 publications

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“…One of them, which allows 4-halocinnolines to be obtained in high yields, is the Richter-type cyclization [52] of ortho -ethynylarenediazonium salts [53] and ortho -ethynylaryltriazenes [54,55,56]. The halogen atom at C4 position can be substituted with various nucleophilic reagents, i.e., water [53], alcoholates [57,58,59], sulfides [56,58,60] and amines [58,61,62,63,64]. The only mentioned example of a 4-azidocinnoline molecule was also obtained from the corresponding chlorocinnoline by nucleophilic substitution with sodium azide in ethanol [29].…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Properties of 6-Aryl-4-azidocinnolines and 6-Aryl-4-(1,2,3-1H-triazol-1-yl)cinnolines

et al. 2019

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An efficient approach towards the synthesis of 6-aryl-4-azidocinnolines was developed with the aim of exploring the photophysical properties of 6-aryl-4-azidocinnolines and their click reaction products with alkynes, 6-aryl-4-(1,2,3-1H-triazol-1-yl)cinnolines. The synthetic route is based on the Richter-type cyclization of 2-ethynyl-4-aryltriazenes with the formation of 4-bromo-6-arylcinnolines and nucleophilic substitution of a bromine atom with an azide functional group. The developed synthetic approach is tolerant to variations of functional groups on the aryl moiety. The resulting azidocinnolines were found to be reactive in both CuAAC with terminal alkynes and SPAAC with diazacyclononyne, yielding 4-triazolylcinnolines. It was found that 4-azido-6-arylcinnolines possess weak fluorescent properties, while conversion of the azido function into a triazole ring led to complete fluorescence quenching. The lack of fluorescence in triazoles could be explained by the non-planar structure of triazolylcinnolines and a possible photoinduced electron transfer (PET) mechanism. Among the series of 4-triazolylcinnoline derivatives a compound bearing hydroxyalkyl substituent at triazole ring was found to be cytotoxic to HeLa cells.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Properties of 6-Aryl-4-azidocinnolines and 6-Aryl-4-(1,2,3-1H-triazol-1-yl)cinnolines

et al. 2019

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“…In a recent study, they also explored 3-cinnoline carboxamide in place of 3quinoline carboxamide derivatives as an ATM kinase inhibitor to improve the ATM kinase selectivity. They identified compound A2, a very selective ATM inhibitor (ATM cell IC50 0.0028 μM) with favorable physicochemical and pharmacokinetic properties in their in vivo and in vitro studies (Figure 7) (90). Additionally, compound A2 in combination with irinotecan showed tumor regression in the SW620 colorectal tumor xenograft model, which showed superior inhibition in comparison with tumors treated with irinotecan alone (90).…”

Section: Quinoline Derivative's As Pikk Inhibitorsmentioning

confidence: 99%

Evolution of PIKK family kinase inhibitors A new age cancer therapeutics

Shaik

Kirubakaran

2020

Front Biosci

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Introduction 3. PIKK family of protein domain architecture 4. A brief introduction to PIKK family members 4.1. mTOR kinase: a master regulator 4.2. DNA-PK: A regulator of DNA DSBs repair by NHEJ mechanism 4.3. ATM kinase and ATR kinase: DNA damage sensing and response 4.4. hSMG1 kinase: a key regulator of non-sense mediated mRNA decay 5. Targeting PIKK kinases for cancer therapy 5.1. Conserved kinase domains in PIKKs 5.

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“…Compound 67 (Figure 35) was identified as a potent ATM inhibitor with excellent kinase selectivity and good physicochemical and pharmacokinetic properties. Monotherapy with ATM inhibitor 67 did not cause tumor regression in the SW620 colorectal tumor xenograft model, whereas combination with irinotecan resulted in significantly greater tumor growth inhibition in comparison to irinotecan alone [14,73]. The 1,3-dihydroimidazo[4,5- c ]cinnoline-2-one derivatives of general formula 68 (Figure 35) were patented as ATM modulators used to treat or prevent ATM mediated diseases, including cancer [74].…”

Section: Biological Activity Of Cinnoline Derivativesmentioning

confidence: 99%

“…Synthetic molecules bearing a cinnoline framework are extensively studied due to their various biological activities depending on the nature and position of their substituents. In addition, they are often designed as analogs of previously obtained quinoline or isoquinoline derivatives [11,12,13,14].…”

Section: Introductionmentioning

confidence: 99%

Cinnoline Scaffold—A Molecular Heart of Medicinal Chemistry?

Szumilak

Stańczak

2019

Molecules

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The cinnoline nucleus is a very important bicyclic heterocycle that is used as the structural subunit of many compounds with interesting pharmaceutical properties. Cinnoline derivatives exhibit broad spectrum of pharmacological activities such as antibacterial, antifungal, antimalarial, anti-inflammatory, analgesic, anxiolytic and antitumor activities. Some of them are under evaluation in clinical trials. In the present review, we have compiled studies focused on the biological properties of cinnoline derivatives conducted by many research groups worldwide between 2005 and 2019. Comprehensive and target oriented information clearly indicate that the development of cinnoline based molecules constitute a significant contribution to the identification of lead compounds with optimized pharmacodynamic and pharmacokinetic properties.

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Discovery of a Series of 3-Cinnoline Carboxamides as Orally Bioavailable, Highly Potent, and Selective ATM Inhibitors

Cited by 26 publications

References 15 publications

Synthesis and Properties of 6-Aryl-4-azidocinnolines and 6-Aryl-4-(1,2,3-1H-triazol-1-yl)cinnolines

Synthesis and Properties of 6-Aryl-4-azidocinnolines and 6-Aryl-4-(1,2,3-1H-triazol-1-yl)cinnolines

Evolution of PIKK family kinase inhibitors A new age cancer therapeutics

Cinnoline Scaffold—A Molecular Heart of Medicinal Chemistry?

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