Synthesis of Antiproliferative <i>Cephalotaxus</i> Esters and Their Evaluation against Several Human Hematopoietic and Solid Tumor Cell Lines: Uncovering Differential Susceptibilities to Multidrug Resistance

Eckelbarger, Joseph D.; Wilmot, Jeremy T.; Epperson, Matthew T.; Thakur, Chandar S.; Shum, David; Antczak, Christophe; Tarassishin, Leonid; Djaballah, Hakim; Gin, David Y.

doi:10.1002/chem.200701998

Cited by 65 publications

(55 citation statements)

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“…40 Allylation of the dioxolanone using lithium hexamethyldisilazide (LiHMDS) as the base provided alkene 9, which was ringopened in a transesterification reaction to afford benzyl ester 10. 41 Intermediates 6, 10, and 14…”

Section: Resultsmentioning

confidence: 99%

Chemical Synthesis of Staphyloferrin B Affords Insight into the Molecular Structure, Iron Chelation, and Biological Activity of a Polycarboxylate Siderophore Deployed by the Human Pathogen Staphylococcus aureus

2015

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Staphyloferrin B (SB) is a citrate-based polycarboxylate siderophore produced and utilized by the human pathogen Staphylococcus aureus for acquiring iron when colonizing the vertebrate host. The first chemical synthesis of SB is reported, which enables further molecular and biological characterization and provides access to structural analogues of the siderophore. SB was prepared in twelve steps from commercially available starting materials with full control of the stereochemistry at the citric acid moiety achieved by using a citric acid synthon containing an alkene moiety. NMR spectroscopic studies confirmed that SB adopts a hemiaminal structure.Addition of synthetic SB to bacterial growth medium recovered the growth of the antibiotic resistant community isolate S. aureus USA300 JE2 cultured under conditions of iron limitation.Further, SB-dependent growth recovery required expression of the SB receptor SirA. Two structural analogues of SB, epiSB and SBimide, were also synthesized and employed to investigate how epimerization of the citric acid moiety or imide formation influence its function as a siderophore. Epimerization of the citric acid stereocenter perturbed the iron-binding properties and siderophore function of SB as evidenced by experimental and computational modeling studies. Although epiSB provided growth recovery to S. aureus USA300 JE2 cultured in irondeficient medium, the effect was attenuated relative to that of SB. Moreover, SB more effectively sequestered the Fe(III) bound to human holo-transferrin, an iron source of S. aureus, than epiSB. SBimide is an imide analogous to the imide forms of other citric acid siderophores that are often observed when these molecules are isolated from natural sources. Here, SBimide is shown to be unstable, converting to native SB at physiological pH. SB is considered to be a virulence factor of S. aureus, a pathogen that poses a particular threat to public health because of the number of drug-resistant strains emerging in hospital and community settings. Iron acquisition by S. aureus is important for its ability to colonize the human host and cause disease, and new chemical insights into the structure and function of SB will inform the search for new therapeutic strategies for combating S. aureus infections.3

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Section: Resultsmentioning

confidence: 99%

Chemical Synthesis of Staphyloferrin B Affords Insight into the Molecular Structure, Iron Chelation, and Biological Activity of a Polycarboxylate Siderophore Deployed by the Human Pathogen Staphylococcus aureus

2015

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“…Treatment of 5 with m-CPBA at 5 °C immediately provide unstable [2,3]-Meisenheimer rearrangement product 5a. 9 Cleavage of N-O bond appear to be a challenge due to the instability of 5a.…”

Section: Resultsmentioning

confidence: 99%

“…Several groups have reported enantioselective synthesis of the side-chains of HHT and HT. [1][2][3][4][5][6][7][8] We have also developed an efficient strategy to construct chiral tertiary alcohol via [2,3]-Meisenheimer rearrangement. Through this strategy, the (R)-20, side-chain acid of homoharringtonine, and (R)-30, side-chain acid of harringtonine, were enantioselectively prepared from L-aspartic acid and L-threonine respectively.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective synthesis of the side-chain acid of homoharringtonine and harringtonine from the same γ-butyrolactone intermediate

Sun¹,

Li²,

Shi³

et al. 2016

Arkivoc

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A versatile intermediate γ-butyrolactone 7 was prepared from L-alanine with 96% ee value, which could be used as a common intermediate for the preparation of the side-chain acid of homoharringtonine and harringtonine in 26.6% and 27% overall yield respectively. The key steps involved [2, 3]-Meisenheimer rearrangement, allylic bromination, and Barbier reaction. Some interesting experimental phenomena and effective solutions to these issues are reported herein.

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“…Yet, these synthetic endeavors are not reflected in the broad industrial manufacture of natural products. There is at least one total synthesis for each of the plant-derived natural products approved for therapeutic use in the last thirty years, presented in Table 1, with exemplary syntheses of (+)-artemisinin (Zhu and Cook, 2012), (+)-arglabin (Kalidindi et al, 2007), (−)-cannabidiol (Petrzilka et al, 1969), capsaicin (Kaga et al, 1989), (−)-colchicine (Lee et al, 1998), dronabinol ((−)-Δ 9 -trans-tetrahydrocannabinol (THC); (Trost and Dogra, 2007)), (+)-ingenol (as described in greater detail in the next paragraphs, ingenol is chemically converted to ingenol mebutate for therapeutic supply; (Liang et al, 2012)), masoprocol (meso-nordihydroguaiaretic acid; (Gezginci and Timmermann, 2001)), omacetaxine mepesuccinate ((−)-homoharringtonine; (Eckelbarger et al, 2008)), (−)-paclitaxel (Nicolaou et al, 1994), and (−)-solamargine (Wei et al, 2011a). Also found in this list is (−)-galanthamine, which is particularly notable because it is a rather complex plant-derived compound for which an entirely chemical industrial-scale production process exists (as described in detail in the next paragraphs).…”

Section: Organic Synthesismentioning

confidence: 99%

Discovery and resupply of pharmacologically active plant-derived natural products: A review

2015

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Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product- Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a "screening hit" through a "drug lead" to a "marketed drug" is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis.While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.

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Synthesis of Antiproliferative Cephalotaxus Esters and Their Evaluation against Several Human Hematopoietic and Solid Tumor Cell Lines: Uncovering Differential Susceptibilities to Multidrug Resistance

Cited by 65 publications

References 100 publications

Chemical Synthesis of Staphyloferrin B Affords Insight into the Molecular Structure, Iron Chelation, and Biological Activity of a Polycarboxylate Siderophore Deployed by the Human Pathogen Staphylococcus aureus

Chemical Synthesis of Staphyloferrin B Affords Insight into the Molecular Structure, Iron Chelation, and Biological Activity of a Polycarboxylate Siderophore Deployed by the Human Pathogen Staphylococcus aureus

Enantioselective synthesis of the side-chain acid of homoharringtonine and harringtonine from the same γ-butyrolactone intermediate

Discovery and resupply of pharmacologically active plant-derived natural products: A review

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