Structure−Activity Relationships of Ring C-Secotaxoids. 1. Acylative Modifications

Appendino, Giovanni; Bettoni, Piergiorgio; Noncovich, Alain; Sterner, Olov; Fontana, Gabriele; Bombardelli, Ezio; Pera, Paula; Bernacki, Ralph J.

doi:10.1021/np0303456

Cited by 9 publications

(3 citation statements)

References 19 publications

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“…The acylative modification of IDN 5390, which resulted in compounds 50 a – d and 51 , was also investigated (Figure 14), though none of the newly synthesized compounds exhibited an increase in potency 77…”

Section: Taxane Resistance Associated With Multidrug Transportersmentioning

confidence: 99%

Paclitaxel And Docetaxel Resistance: Molecular Mechanisms and Development of New Generation Taxanes

et al. 2007

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Taxanes represent one of the most promising classes of anticancer agents. Unfortunately, their clinical success has been limited by the insurgence of cellular resistance, mainly mediated by the expression of the MDR phenotype or by microtubule alterations. However, the remarkable relevance of paclitaxel and docetaxel in clinical oncology stimulated intensive efforts in the last decade to identify new derivatives endowed with improved activities towards resistant tumor cells, resulting in a huge number of novel natural and synthetic taxanes. Among them, several structurally different derivatives were found to exhibit a promising behavior against the MDR phenotype in terms of either MDR inhibiting properties, or enhanced cytotoxicity compared to parental drugs, or both. On the other hand, only in more recent years have the first taxanes retaining activity against resistant cancer cells bearing alterations of the tubulin/microtubule system emerged. This review describes the main molecular mechanisms of resistance to paclitaxel and docetaxel identified so far, focusing on the advances achieved in the development of new taxanes potentially useful for the treatment of resistant tumors.

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Section: Taxane Resistance Associated With Multidrug Transportersmentioning

confidence: 99%

Paclitaxel And Docetaxel Resistance: Molecular Mechanisms and Development of New Generation Taxanes

et al. 2007

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“…Six analogues of IDN 5390 (Scheme 1) were synthesized using the β-Lactam Synthon Method ,21 through Ojima-Holton coupling21–24 of modified C-seco-10-deacetylbaccatins 6a–c with β-lactams 1 and 2 . Attempts to replace the C2 benzoyl moiety of a C-seco-baccatin with a substituted benzoyl group failed 25. Accordingly, it was necessary to modify the C2 position of 10-deacetylbaccatin (10-DAB) before the cleavage of the C-ring.…”

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confidence: 99%

Novel C-seco-taxoids possessing high potency against paclitaxel-resistant cancer cell lines overexpressing class III β-tubulin

Pepe

Sun

Zanardi

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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Novel C-seco-taxoids were synthesized from 10-deacetylbaccatin III and their potencies evaluated against drug-sensitive and drug-resistant cancer cell lines. The drug-resistant cell lines include ovarian cancer cell lines resistant to cisplatin, topotecan, adriamycin and paclitaxel overexpressing class III β-tubulin, A2780TC1 and A2780TC3. The last two cell lines were selected through chronic exposure of A2780wt to paclitaxel and Pgp blocker cyclosporine. All novel C-seco-taxoids exhibited remarkable potency against A2780TC1 and A2780TC3 cell lines, and no cross resistance to cisplatinand topotecan-resistant cell lines, A2780CIS and A2780TOP. Four of those C-seco-taxoids exhibit much higher activities than IDN5390 against paclitaxel-resistant cell lines, A2780ADR, A2780TC1 and A2780TC3. SB-CST-10202 possesses the best all-round high potencies across different drugresistant cell lines. Molecular modeling studies, including molecular dynamics simulations, on the drug-protein complexes of class I and III β-tubulins were performed to identify possible cause of the remarkable potency of these C-seco-taxoids against paclitaxel-resistant cell lines overexpressing class III β-tubulin.Paclitaxel and docetaxel represent two of the most important chemotherapeutic drugs currently used for the treatment of ovarian cancer, breast cancer, melanoma, non-small cell lung cancer and Kaposi's sarcoma. Upon prolonged exposure to antitumor agents, cancer cells develop mechanisms of drug-resistance, thus becoming progressively less sensitive to the effect of drugs. Higher doses are then required to achieve the same efficacy with consequent increase in systemic toxicity to normal tissues.A great effort has been devoted to overcome these limitations, by studying in detail the mechanisms of drug-resistance and by identifying novel and highly specific anticancer drugs. Nevertheless, an increasingly prominent mechanism of drug resistance, which has not been successfully addressed yet, is related to the overexpression of specific tubulin isotypes. 1-4 Tubulin dimers, derived from different β isotypes have different behaviors in vitro in regard *E-mail: iojima@notes.cc.sunysb.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The equilibrium between growing and shortening of microtubule ends is defined as dynamic instability. 9 The effect of paclitaxel on the dynamic instability of microtubules depends on its concentration levels. At sub-stoichiometric levels, paclitaxel is able to suppress shortening rates, but it does not affect growing rate of polymer mass. At stoichiometric levels with r...

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“…For example, ortataxel (B4) is a promising orally administered taxoid now in Phase II clinical trials [26]. SAR studies of ring C-secotaxoids were recently published [27].…”

Section: Anticancer and Antitumor Compoundsmentioning

confidence: 99%

Plant-derived natural product research aimed at new drug discovery

et al. 2008

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Many important bioactive compounds have been discovered from natural sources using bioactivity-directed fractionation and isolation (BDFl) [Balunas MJ, Kinghorn AD (2005) Drug discovery from medicinal plants. Life Sci 78:431-441]. Continuing discovery has also been facilitated by the recent development of new bioassay methods. These bioactive compounds are mostly plant secondary metabolites, and many naturally occurring pure compounds have become medicines, dietary supplements, and other useful commercial products. Active lead compounds can also be further modified to enhance the biological profiles and developed as clinical trial candidates. In this review, the authors will summarize research on many different useful compounds isolated or developed from plants with emphasis placed on those recently discovered by the authors' laboratories as antitumor and anti-HIV clinical trial candidates.

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Structure−Activity Relationships of Ring C-Secotaxoids. 1. Acylative Modifications

Cited by 9 publications

References 19 publications

Paclitaxel And Docetaxel Resistance: Molecular Mechanisms and Development of New Generation Taxanes

Paclitaxel And Docetaxel Resistance: Molecular Mechanisms and Development of New Generation Taxanes

Novel C-seco-taxoids possessing high potency against paclitaxel-resistant cancer cell lines overexpressing class III β-tubulin

Plant-derived natural product research aimed at new drug discovery

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