Discovery of Quinolinediones Exhibiting a Heat Shock Response and Angiogenesis Inhibition

Hargreaves, Robert H J; Whitesell, Luke; LaBarbera, Daniel V.; Jamil, Akmal; Chapuis, Jean Charles; Skibo, Edward B.

doi:10.1021/jm7014099

Cited by 18 publications

(14 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reactions with the isoquinoline-dione 3 and quinoline-dione 7 frameworks resulted in a mixture of regioisomers for analogues 19 and 21 , which were separated by silica gel column chromatography. 29 …”

Section: Resultsmentioning

confidence: 99%

Design, synthesis and biological evaluation of ezrin inhibitors targeting metastatic osteosarcoma

Paige

Kosturko

Bulut

et al. 2014

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

Respiratory failure due to pulmonary metastasis is the major cause of death for patients with osteosarcoma. However, the molecular basis for metastasis of osteosarcoma is poorly understood. Recently, ezrin, a member of the ERM family of proteins, has been associated with osteosarcoma metastasis to the lungs. The small molecule NSC 668394 was identified to bind to ezrin, inhibit in vitro and in vivo cell migration, invasion, and metastatic colony survival. Reported herein are the design and synthesis of analogues of NSC 668394, and subsequent functional ezrin inhibition studies. The binding affinity was characterized by surface plasmon resonance technique. Cell migration and invasion activity was determined by electrical cell impedance methodology. Optimization of a series of heterocyclic-dione analogues led to the discovery of compounds 21k and 21m as potential novel antimetastatic agents.

show abstract

Section: Resultsmentioning

confidence: 99%

Design, synthesis and biological evaluation of ezrin inhibitors targeting metastatic osteosarcoma

Paige

Kosturko

Bulut

et al. 2014

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…Work in this laboratory and elsewhere has shown COMPARE to be useful in drug discovery. 13,22,23 Recently, we reported the discovery of a quinolinedione-based antiangiogenesis agent using COMPARE. 23 Finally, we conclude that the analogues of 1 are not true mimics of wakayin.…”

Section: Discussionmentioning

confidence: 99%

“…13,22,23 Recently, we reported the discovery of a quinolinedione-based antiangiogenesis agent using COMPARE. 23 Finally, we conclude that the analogues of 1 are not true mimics of wakayin. The potential density maps shown in the graphical abstract reveals that the ring system of 1 is more electron-deficient than that of wakayin.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and in vitro evaluation of imidazole-based wakayin analogues

2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…53 The synthesis of QQs is well-precedented and there are several synthetic routes available to access the QQ motif. Typically, the quinone moiety is prepared through employment of the Teuber reaction, 174 whereby phenols or anilines are treated with Fremy's salt, 105,139,175 though other oxidants such as ceric(IV) ammonium nitrate, 176,177 (diacetoxyiodo)benzene, 178 or potassium dichromate 179 can also be used. Once the quinone ring is formed however, the installation of substituents on the quinone scaffold can be challenging and is often circumvented by the introduction of functional groups prior to quinone formation.…”

Section: Project Aims and Retrosynthetic Analysis Of Qqsmentioning

confidence: 99%

“…Here, the presence of chloride leaving groups would enable nucleophilic substitution reactions to take place, which would otherwise be sluggish and low-yielding. 177 To this end, it was envisaged that the QQ analogues VI-IX could be synthesised by the substitution of dichloro-QQs 92 and 56 by various alkyl-and aryl-amines (Scheme 3.2). For the purpose of this research, it was proposed that both the 6-(VI, VII) and 7-regioisomers (VIII, IX) would be prepared in the same synthetic step, though it should be noted that the 6-isomer (VI, VII) can be preferentially formed by the addition of a metal catalyst to the reaction mixture.…”

Section: Project Aims and Retrosynthetic Analysis Of Qqsmentioning

confidence: 99%

The Synthesis and Evaluation of Heterocycles as Anti-Tuberculosis Agents

Santoso¹

View full text Add to dashboard Cite

<p>Tuberculosis (TB) is the leading cause of death from a single infectious agent, Mycobacterium tuberculosis (Mtb), worldwide. Currently, the efficacy of TB treatment regimens has declined due to the rise in antibacterial resistance and the shortage of new TB drugs. Thus, much effort has been spent in anti-tuberculosis drug development and in identifying new therapeutic targets against Mtb. One such target is NADH dehydrogenase-II (NDH-II), an essential enzyme in the mycobacterial electron transport chain that is not present in mammalian cells. In this thesis, four classes of heterocyclic compounds that have the potential to target NDH-II and their evaluation as anti-tubercular agents, are described. An overview of TB drug development and NDH-II as a promising target for TB drugs are described in Chapter 1. In Chapters 2 and 3, the potential of anti-tubercular drugs based on the quinolinequinone (QQ) scaffold is described. QQs have previously shown promise as TB drugs by activating NDH-II to overproduce harmful reactive oxygen species leading to bacterial cell death. Chapter 2 describes the total synthesis of the QQ natural products ascidiathiazone A and ascidiathiazone B, and derivatives thereof, using a synthetic route that allows for high divergency and the efficient synthesis of the natural products and their intermediates. To this end, the first total synthesis of ascidiathiazone B is reported, as is the identification of ascidiathiazone A as a promising anti-tuberculosis drug with an MIC of 1.6 μM against Mtb. Insight into the ability of a representative quinone, 7-chloro-6-chloroethylamino-2-methyl-QQ, to increase NDH-II activity is also described. In Chapter 3, the syntheses of thirty-two simplified QQs with different functional groups at the 6- and 7-positions of the QQ scaffold are described. These compounds were screened against Mtb, with the lead compound from this library, 7-chloro-6-propargylamino-QQ, exhibiting an MIC of 8 μM against Mtb. Structure-activity data revealed diminished biological activity for QQs bearing tertiary amines, as compared to those with secondary amines, suggesting that the presence of a hydrogen bond donor at the 6- and 7-positions of QQs may play a critical role in antimycobacterial activity. In Chapter 4, the synthesis and anti-mycobacterial activity of chromonyl-pyrimidines is presented. Chromonyl-pyrimidines have a structural resemblance to quinolinyl pyrimidines, a class of known NDH-II inhibitors and anti-TB agents. Chromones have shown promise as TB drugs, though they have not yet been reported to bind NDH-II. Despite this, chromonyl-pyrimidines contain a ketone functionality that may be able to bind the quinone binding site. For the first eleven-member library of chromonyl pyrimidines synthesised, all but two of the compounds exhibited inhibitory activity against Mtb, however, the growth inhibition was modest (MIC = 36-684 M). Accordingly, a second generation of chromonyl pyrimidines was synthesised, which included six compounds with improved potency against Mtb – all with an MIC value of 12.5 μM. The activity of these chromonyl pyrimidines was attributed to the presence of aromatic rings both on the pyrimidine and the chromone scaffolds, though changes to the electronic properties of the aryl groups, i.e. the incorporations of electron-withdrawing and electron-donating groups, did not affect inhibitory activity. Finally, in Chapter 5, a library of phthalazinones and pyrimidinyl-phthalazinones with anti-tubercular activity is described. While phthalazinones have not yet been extensively explored as anti-mycobacterial agents, the phthalazinone scaffold has the potential to act as an uncoupler. Uncouplers are typically weak acids or bases that act on the electron transport chain by dissipating the proton motive force and ultimately preventing the generation of ATP. In Mtb, this uncoupling process is detrimental and leads to cell death. Phthalazinones are weakly basic and, due to their bicyclic ketone-bearing motif, has the potential to bind NDH-II at the proposed Q-site. Accordingly, a series of phthalazinones was synthesised to investigate their anti-tubercular activity and uncoupling activity. From the library of phthalazinones, N-tert-butyl- and nitro-substituted phthalazinones elicited high inhibitory activity, both with an MIC value of 3 μM. Of particular note among the pyrimidinyl-phthalazinones was the 4-fluorophenyl-pyrimidinyl-N-heptyl phthalazinone, which showed high potency against Mtb with an MIC of 1.6 μM. Further biological studies showed that some phthalazinones increased the rate of NADH oxidation in mycobacteria, which could be a result of uncoupling activity, while a number of pyrimidinyl-phthalazinones decreased NADH oxidation rates. These mechanistic results indicated that the two classes of compounds may have different modes of inhibition.</p>

show abstract

Discovery of Quinolinediones Exhibiting a Heat Shock Response and Angiogenesis Inhibition

Cited by 18 publications

References 29 publications

Design, synthesis and biological evaluation of ezrin inhibitors targeting metastatic osteosarcoma

Design, synthesis and biological evaluation of ezrin inhibitors targeting metastatic osteosarcoma

Synthesis and in vitro evaluation of imidazole-based wakayin analogues

The Synthesis and Evaluation of Heterocycles as Anti-Tuberculosis Agents

Contact Info

Product

Resources

About