An antiinflammatory cum immunomodulatory piperidinylbenzopyranone from dysoxylum binectariferum : isolation, structure and total synthesis

Naik, Ramachandra G.; Kattige, S. L.; Bhat, Sujata V.; Alreja, B. D.; Souza, N. J. De; Rupp, R. H.

doi:10.1016/s0040-4020(01)90352-7

Cited by 151 publications

(72 citation statements)

References 9 publications

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“…They are believed to possess properties capable of potential protection against carcinogenesis [57] and have long been known to interact with various kinases at the ATP-binding site [58]. Flavone acetic acid, genistein, and quercetin, whose structures are presented in Fig. The isolation from the stem bark of Dysoxylum binectariferum and the total synthesis of a compound [60] previously described as rohitukine [61,62], enabled the synthesis of flavopiridol and its analogues [38], summarised in Fig. (6).…”

Section: Flavonoidsmentioning

confidence: 99%

Inhibitors of Cyclin-Dependent Kinases as Anti-Cancer Therapeutics

Fischer

Lane²

2000

CMC

141

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Initiation, progression, and completion of the cell cycle are regulated by various cyclin-dependent kinases (CDKs), which are thus critical for cell growth. Tumour development is closely associated with genetic alteration and deregulation of CDKs and their regulators, suggesting that inhibitors of CDKs may be useful anticancer therapeutics. Indeed, early results suggest that transformed and normal cells differ in their requirement for e.g. cyclin/CDK2 and that it may be possible to develop novel antineoplastic agents devoid of the general host toxicity observed with conventional cystostatic drugs. Numerous active-site inhibitors of CDKs have been studied; the main limitation with these ATP antagonists is kinase specificity for CDKs. However, screening of compound collections, as well as rational design based on enzyme-ligand complex crystal structures, are now yielding pre-clinical candidates, particularly certain purine and flavonoid analogues, with impressive potency and selectivity. Natural CDK inhibitors (CKIs), e.g. the tumour suppressor gene products p16 INK4 , p21 WAF1 , and p27 KIP1 , form the starting point for the design of mechanism-based CDK inhibitors. A number of these small proteins have been dissected and inhibitory lead peptides amenable to peptidomimetic development have been identified. Conversion of these peptides into pharmaceutically useful molecules is greatly aided by the recent elucidation of CKI/CDK crystal and solution structures. Additional interaction sites on CDKs being exploited for the purposes of inhibitor design include: phosphorylation/dephosphorylation sites, macromolecular substrate binding site, CKS regulatory subunit binding sites, cyclin-binding site, cellular localisation domain, and destruction box. Finally, progress has recently been made in the application of antisense technology in order to target CDK activity.

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Section: Flavonoidsmentioning

confidence: 99%

Inhibitors of Cyclin-Dependent Kinases as Anti-Cancer Therapeutics

Fischer

Lane²

2000

CMC

141

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“…3 Therefore, one possible therapeutic strategy would be to directly modulate CDK activity to prevent cell cycle progression. To this end, the small molecular CDK inhibitor flavopiridol, a flavanoid derived from the plant Dysoxylum binectariferum, 5 has demonstrated activity against all CDKs tested to date and at concentrations 1000 times lower than are required to inhibit protein kinase A or the EGFR tyrosine kinase. 6 In general, flavopiridol treatment in vitro has produced growth inhibition or growth arrest by different mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Flavopiridol Induces Mitochondrial-Mediated Apoptosis in Murine Glioma GL261 Cells via Release of Cytochrome c and Apoptosis Inducing Factor

Newcomb

Tamasdan²,

Entzminger³

et al. 2003

Cell Cycle

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Glioblastoma (GBM) remains one of the most challenging solid cancers to treat due to its highly proliferative, angiogenic and invasive nature. The small molecule CDK inhibitor, flavopiridol, has demonstrated antitumor activity in human xenograft models and is currently in clinical trials showing efficacy in patients with advanced disease. We have developed an experimental animal model using the murine glioma GL261 cells as a novel in vivo system to screen potential therapeutic agents for GBM. Results of in vitro testing demonstrate that flavopiridol has several relevant clinical characteristics such as its ability to:

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“…Flavopiridol (L86-8275), a synthetic flavone derivative that was initially isolated from the stem bark of the Indian tree Dysoxylum binectariferum (1,2), is a potent growth inhibitor of diverse human tumor cell lines and induces apoptosis in hematopoietic cell lines derived from acute myelogenous leukemia (AML), B-cell and T-cell lymphomas, and multiple myeloma (3 -5). Flavopiridol-induced apoptosis results at least in part from inhibition of multiple serine/threonine cyclindependent kinases (2).…”

mentioning

confidence: 99%

Phase I and Pharmacokinetic Study of Flavopiridol followed by 1-β-d-Arabinofuranosylcytosine and Mitoxantrone in Relapsed and Refractory Adult Acute Leukemias

Karp

Passaniti

Gojo

et al. 2005

Clinical Cancer Research

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Purpose: The serine/threonine kinase inhibitor flavopiridol targets multiple cyclin-dependent kinases, induces checkpoint arrest, and interrupts transcriptional elongation.We designed a phase I clinical trial using a timed sequential therapy approach where flavopiridol was given for the dual purpose of initial cytoreduction and enhancing cell cycle progression of the remaining leukemia cell cohort followed by cycle-dependent drugs 1-h-D-arabinofuranosylcytosine (ara-C) and mitoxantrone. Experimental Design: Flavopiridol was given by1-hour infusion daily for 3 days beginning day1 followed by 2 g/m 2 /72 h ara-C beginning day 6 and 40 mg/m 2 mitoxantrone beginning day 9. In vivo correlates included pharmacokinetics, modulation of blast cycle regulators, and serum and marrow supernatant vascular endothelial growth factor levels. Results: Of 34 adults receiving induction therapy, 16 (47%) evinced direct leukemia cytotoxicity with z50 % drop in peripheral blast counts and tumor lysis in 9 (26 %). Four (12 %) died during therapy (two fungal infections and two sudden death). Dose-limiting toxicity occurred at 60 mg/m 2 /d with profound neutropenia >40 days duration, and maximal tolerated dose was 50 mg/m 2 /d. Overall response rate was 31% in 26 acute myelogenous leukemia and 12.5% in acute lymphoblastic leukemia. Pharmacokinetics showed that a linear two-compartment model with first-order elimination provided the best fit of the observed concentration versus time data. Flavopiridol down-regulated one or more target proteins in marrow blasts in vivo.Vascular endothelial growth factor was detected in sera and marrow supernatant pretreatment, and sera obtained on day 3 inhibited bovine aortic endothelial cell proliferation by a mean of 32% (range, 10-80%). Conclusions: Our data suggest that flavopiridol is cytotoxic to leukemic cells and, when followed by ara-C and mitoxantrone, exerts biological and clinical effects in patients with relapsed and refractory acute leukemias. These findings warrant continuing development of flavopiridol at 50 mg/m 2 /d Â 3 days in combination with cytotoxic and biological agents for acute leukemias.

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An antiinflammatory cum immunomodulatory piperidinylbenzopyranone from dysoxylum binectariferum : isolation, structure and total synthesis

Cited by 151 publications

References 9 publications

Inhibitors of Cyclin-Dependent Kinases as Anti-Cancer Therapeutics

Inhibitors of Cyclin-Dependent Kinases as Anti-Cancer Therapeutics

Flavopiridol Induces Mitochondrial-Mediated Apoptosis in Murine Glioma GL261 Cells via Release of Cytochrome c and Apoptosis Inducing Factor

Phase I and Pharmacokinetic Study of Flavopiridol followed by 1-β-d-Arabinofuranosylcytosine and Mitoxantrone in Relapsed and Refractory Adult Acute Leukemias

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