Total synthesis of streptonigrin

Basha, Fatima Z.; Hibino, Satoshi; Kim, Deukjoon; Pye, Walter E.; Wu, Tai Teh; Weinreb, Steven M.

doi:10.1021/ja00531a054

Cited by 45 publications

(16 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A summary of our streptonigrin formal synthesis illustrates the convergent modular strategy: quinoline-5,8-dione 39 has been prepared in ten linear steps in an overall yield of 22% from inexpensive ethyl glyoxalate. 18 − 21 …”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of the Antitumor Antibiotic (±)-Streptonigrin: First- and Second-Generation Routes for de Novo Pyridine Formation Using Ring-Closing Metathesis

et al. 2013

View full text Add to dashboard Cite

The total synthesis of (±)-streptonigrin, a potent tetracyclic aminoquinoline-5,8-dione antitumor antibiotic that reached phase II clinical trials in the 1970s, is described. Two routes to construct a key pentasubstituted pyridine fragment are depicted, both relying on ring-closing metathesis but differing in the substitution and complexity of the precursor to cyclization. Both routes are short and high yielding, with the second-generation approach ultimately furnishing (±)-streptonigrin in 14 linear steps and 11% overall yield from inexpensive ethyl glyoxalate. This synthesis will allow for the design and creation of druglike late-stage natural product analogues to address pharmacological limitations. Furthermore, assessment of a number of chiral ligands in a challenging asymmetric Suzuki–Miyaura cross-coupling reaction has enabled enantioenriched (up to 42% ee) synthetic streptonigrin intermediates to be prepared for the first time.

show abstract

Section: Resultsmentioning

confidence: 99%

Total Synthesis of the Antitumor Antibiotic (±)-Streptonigrin: First- and Second-Generation Routes for de Novo Pyridine Formation Using Ring-Closing Metathesis

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Aerward, several synthetic chemists have developed different methods for the total synthesis of this unique alkaloid (124). [103][104][105] Moreover, the piperidine alkaloids, albonoursin (126) and its N-methyl derivative (127) together with the siderophore norcardamine (128) were also recovered from the same Micromonospora strain fermentation broth. Both streptonigrin (124) and its analogue (125) were able to induce apoptosis in the human neuroblastoma SH-SY5Y cells through p53-dependent mechanism.…”

Section: Macrolidesmentioning

confidence: 95%

“…83 Fortimicin A (100) exhibited broadspectrum potent antibacterial effects against Gram-positive and negative bacteria both in vitro (MIC 0.02-10 mg mL À1 ) and in vivo, while fortimicin B and C (101, 102) were less active. 84 From the same Micromonospora strain, antibiotic SF-1854 was isolated as a byproduct and characterized as 1, N-formylfortimicin A (103). It showed 8-16 times weaker activity than fortimicin A (100).…”

Section: Macrolidesmentioning

confidence: 99%

The genus Micromonospora as a model microorganism for bioactive natural product discovery

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Having established a retrosynthetic plan for the synthesis of 6-and 7-amino-substituted QQs (VI-IX), 8-hydroxyquinoline (93) and 8-hydroxyquinaldine (58) were first oxidised with sodium chlorate to afford dichloroquinones 92 and 56, respectively (Scheme 3.3). 65,181 After recrystallisation from ethanol, QQs 92 and 56 were then treated with a variety of amines to give the 6-and 7-isomers (94)(95)(96)(97)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111) in good combined yields and in an approximately 1:1 ratio. 65 Derivatives prepared included those designed to probe the effect of bulky amines (i.e.…”

Section: The Synthesis 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

Total synthesis of streptonigrin

Cited by 45 publications

References 1 publication

Total Synthesis of the Antitumor Antibiotic (±)-Streptonigrin: First- and Second-Generation Routes for de Novo Pyridine Formation Using Ring-Closing Metathesis

Total Synthesis of the Antitumor Antibiotic (±)-Streptonigrin: First- and Second-Generation Routes for de Novo Pyridine Formation Using Ring-Closing Metathesis

The genus Micromonospora as a model microorganism for bioactive natural product discovery

The Synthesis and Evaluation of Heterocycles as Anti-Tuberculosis Agents

Contact Info

Product

Resources

About