Synthetic Approaches to the Fleximer Class of Nucleosides – A Historic Perspective

Ku, Therese; Seley‐Radtke, Katherine L.

doi:10.1002/9783527812103.ch8

Cited by 4 publications

(2 citation statements)

References 90 publications

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“…Table 7 provides a focused outline of key investigational agents and major takeaway points. To date, agents considered for clinical investigation in the context of COVID-19 include protease inhibitors (e.g., lopinavir, ritonavir);[ 501 505 509 540 541 542 543 544 545 546 ] nucleoside analogs (e.g., favipiravir, galidesivir, penciclovir, remdesivir, ribavirin);[ 515 547 ] 6′-fluorinated aristeromycin analogs;[ 548 549 ] acyclovir fleximer analogs;[ 550 551 ] interferon;[ 38 39 486 510 520 521 522 523 524 552 553 554 555 ] antimalarials;[ 231 486 487 488 489 490 491 492 493 494 495 496 497 498 556 ] neuraminidase inhibitors (e.g., peramivir, oseltamivir, zanamivir);[ 39 557 558 ] corticosteroids and immunomodulators;[ 15 39 291 480 481 482 483 484 485 ] antilice agent ivermectin;[ 559 560 ] as well as a highly heterogeneous group of other potential treatments. [ 528 529 530 531 561 562 563 564…”

Section: S Evere a Cute R mentioning

confidence: 99%

The 2019–2020 novel coronavirus (severe acute respiratory syndrome coronavirus 2) pandemic: A joint american college of academic international medicine-world academic council of emergency medicine multidisciplinary COVID-19 working group consensus paper

Stawicki

Jeanmonod

Miller

et al. 2020

J Global Infect Dis

330

356

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What started as a cluster of patients with a mysterious respiratory illness in Wuhan, China, in December 2019, was later determined to be coronavirus disease 2019 (COVID-19). The pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel Betacoronavirus , was subsequently isolated as the causative agent. SARS-CoV-2 is transmitted by respiratory droplets and fomites and presents clinically with fever, fatigue, myalgias, conjunctivitis, anosmia, dysgeusia, sore throat, nasal congestion, cough, dyspnea, nausea, vomiting, and/or diarrhea. In most critical cases, symptoms can escalate into acute respiratory distress syndrome accompanied by a runaway inflammatory cytokine response and multiorgan failure. As of this article's publication date, COVID-19 has spread to approximately 200 countries and territories, with over 4.3 million infections and more than 290,000 deaths as it has escalated into a global pandemic. Public health concerns mount as the situation evolves with an increasing number of infection hotspots around the globe. New information about the virus is emerging just as rapidly. This has led to the prompt development of clinical patient risk stratification tools to aid in determining the need for testing, isolation, monitoring, ventilator support, and disposition. COVID-19 spread is rapid, including imported cases in travelers, cases among close contacts of known infected individuals, and community-acquired cases without a readily identifiable source of infection. Critical shortages of personal protective equipment and ventilators are compounding the stress on overburdened healthcare systems. The continued challenges of social distancing, containment, isolation, and surge capacity in already stressed hospitals, clinics, and emergency departments have led to a swell in technologically-assisted care delivery strategies, such as telemedicine and web-based triage. As the race to develop an effective vaccine intensifies, several clinical trials of antivirals and immune modulators are underway, though no reliable COVID-19-specific therapeutics (inclusive of some potentially effective single and multi-drug regimens) have been identified as of yet. With many nations and regions declaring a state of emergency, unprecedented quarantine, social distancing, and border closing efforts are underway. Implementation of social and physical isolation measures has caused sudden and profound economic hardship, with marked decreases in global trade and local small business activity alike, and full ramifications likely yet to be felt. Current state-of-science, mitigation strategies, possible therapies, ethical considerations for healthcare workers and policymakers, as well as lessons learned for this evolving global threat and the eventual return to a “new normal” are discussed in this article.

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Section: S Evere a Cute R mentioning

confidence: 99%

The 2019–2020 novel coronavirus (severe acute respiratory syndrome coronavirus 2) pandemic: A joint american college of academic international medicine-world academic council of emergency medicine multidisciplinary COVID-19 working group consensus paper

Stawicki

Jeanmonod

Miller

et al. 2020

J Global Infect Dis

330

356

View full text Add to dashboard Cite

show abstract

“…Another structural modification which has proven effective was the development of the fleximers – nucleoside analogues wherein the purine base has been split into two separate heterocyclic fragments but remains connected by a single C-C bond ( Seley et al, 2002 ; Seley et al, 2005 ; Peters H. et al, 2015 ; Ku and Seley-Radtke, 2018 ). Thus, the fleximers exhibit additional conformational freedom in order to maximize structural interactions in the active site of the target enzyme while maintaining the structural similarity with a normal nucleoside substrate or inhibitor necessary for recognition by the enzyme ( Seley et al, 2005 ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of New 5′-Norcarbocyclic Aza/Deaza Purine Fleximers - Noncompetitive Inhibitors of E.coli Purine Nucleoside Phosphorylase

et al. 2022

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A new series of flexible 5′-norcarbocyclic aza/deaza-purine nucleoside analogs were synthesized from 6-oxybicyclo[3.1.0.]hex-2-ene and pyrazole-containing fleximer analogs of heterocyclic bases using the Trost procedure. The compounds were evaluated as potential inhibitors of E. coli purine nucleoside phosphorylase. Analog 1-3 were found to be noncompetitive inhibitors with inhibition constants of 14–24 mM. From the data obtained, it can be assumed that the new 5′-norcarbocyclic nucleoside analogs interact with the active site of the PNP like natural heterocyclic bases. But at the same time the presence of a cyclopentyl moiety with 2′ and 3′ hydroxyls is necessary for the inhibitory properties, since compounds 8–10, without those groups did not exhibit an inhibitory effect under the experimental conditions.

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Nucleoside Analogs with Fleximer Nucleobase

Chudinov

2020

Chem Heterocycl Comp

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This review article is devoted to the so-called fleximer nucleoside analogs, containing two or more planar moieties in the heterocyclic base, connected by a bond that permits rotation. Such analogs have been proposed as molecular probes for detecting enzyme-substrate interactions and studying the transcription and translation of nucleic acids, but subsequently have attracted the interest of researchers by their antiviral and antitumor activity. The methods used in the synthesis of such compounds, along with their structural features and also biological activity are considered in this review.

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Synthetic Approaches to the Fleximer Class of Nucleosides – A Historic Perspective

Cited by 4 publications

References 90 publications

The 2019–2020 novel coronavirus (severe acute respiratory syndrome coronavirus 2) pandemic: A joint american college of academic international medicine-world academic council of emergency medicine multidisciplinary COVID-19 working group consensus paper

The 2019–2020 novel coronavirus (severe acute respiratory syndrome coronavirus 2) pandemic: A joint american college of academic international medicine-world academic council of emergency medicine multidisciplinary COVID-19 working group consensus paper

Synthesis of New 5′-Norcarbocyclic Aza/Deaza Purine Fleximers - Noncompetitive Inhibitors of E.coli Purine Nucleoside Phosphorylase

Nucleoside Analogs with Fleximer Nucleobase

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