Antineoplastic Agents. 527. Synthesis of 7-Deoxynarcistatin, 7-Deoxy-<i>trans</i>-dihydronarcistatin, and <i>trans</i>-Dihydronarcistatin 1

Pettit, George R.; Melody, Noeleen

doi:10.1021/np0304518

Cited by 46 publications

(42 citation statements)

References 20 publications

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“…The ionic hydrogenation (CF 3 CO 2 H, Et 3 SiH) of a Δ8(9)-D-homosteroid is known to proceed stereospecifically to give a D-homosteroid with the trans-antitrans configuration 14. Such sterically hindered olefins have been hydrogenated at low temperature in dichloromethane with trifluoroacetic acid as a proton donor and triethylsilane as a hydride donor 15.…”

Section: Resultsmentioning

confidence: 99%

“…The scale-up preparation of trans -dihydronarciclasines 1a and 1c utilizing the preceeding hydrogenation improvements increased the availability of both cancer cell growth inhibitors for conversion to the respective phosphate prodrugs9 and further preclinical development.…”

Section: Resultsmentioning

confidence: 99%

“…In concert with the increased requirements for both precursors, it became important to uncover a selective hydrogenation reaction for conversion of the obvious precursors narciclasine ( 2a ) and 7-deoxy-narciclasine ( 2c ) readily available from certain Narcissus (Amaryllidaceae) species3a,9 to the required dihydro-derivatives. That approach appeared to be of more immediate practicality than multistep total syntheses 8c,10…”

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Antineoplastic Agents. 454. Synthesis of the Strong Cancer Cell Growth Inhibitors trans-Dihydronarciclasine and 7-Deoxy-trans-dihydronarciclasine

et al. 2009

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To further pursue the antineoplastic leads offered by our isolation of trans-dihydronarciclasine (1a) and 7-deoxy-trans-dihydronarciclasine (1c) from two medicinal plant species of the Amaryllidaceae family, a practical palladium-catalyzed hydrogenation procedure was developed for synthesis of these isocarbostyrils from narciclasine (2a) and 7-deoxynarciclasine (2c).From a 1982 collection (bulbs) of the Chinese medicinal plant Zephyranthes candida (Amaryllidaceae) 1b we isolated the strong (ED 50 0.0032 μg/mL) P388 lymphocytic leukemia cell growth inhibitor trans-dihydronarciclasine (1a). The structure was established by detailed spectroscopic analyses of its peracetate derivative (1b) 1b and confirmed by comparison with the minor product from catalytic hydrogenation of narciclasine (2a). 2 Hydrogenation afforded as the major product the expected cis-dihydronarciclasine (3a) accompanied by the trans isomer (1a) and iso-narciclasine (4a). Subsequently, trans-dihydronarciclasine (1a) was found to exhibit strong cancer cell growth inhibition (mean panel GI 50 12.6 nM) against the U.S. National Cancer Institute (NCI) panel of cancer cell lines3a,b whereas its cis isomer (3a) 3c was only very weakly active (mean panel GI 50 3800 nM). Importantly, the trans isomer (1a) gave an active Compare correlation coefficient of 0.92 in respect to (+)-pancratistatin (5). 3a The trans isomer (1a) also showed strong activity against a range of RNA viruses while the synthetic cis isomer (3a) was completely inactive. 4 Because of the close structural and biological relationship of trans-dihydronarciclasine (1a) to (+)-pancratistatin (5), already in preclinical development, it became necessary to increase the availability of trans isomer 1a and the closely related 7-deoxy-trans-dihydronarciclasine (1c), by synthesis. The latter was isolated from Hymenocallis sp. (P388 ED 50 0.02 μg/mL) and gave an active Compare correlation coefficient of 0.89 in respect to (+)-pancratistatin (5). 3 Those structural and biological relationships of 1a and 1c to (+)-pancratistatin (5) are of special importance owing to its well known 5 in vitro and in vivo anticancer activity augmented by the rapidly increasing knowledge of the very promising activation of the mitochondrial route to cancer cell apoptosis.6a Importantly, pancratistatin has been shown to induce apoptosis routinely in various cancer cell lines at sub-micromolar concentrations while being nontoxic to normal human fibroblasts and endothelial cells at the same drug concentrations.6b,c As anticipated, narciclasine (2a) has recently been found to induce the mitochondrial and/or caspase-8/caspase-10 death receptor pathway in human MCF-7 breast as well as PC-3 prostate cancer cell lines. 5 Presumably, the strong cancer cell growth inhibitors 1a and 1c will also display related mechanisms of action selectively targeting cancer cells. The need to begin more detailed preclinical development of 1a and 1c led to our syntheses of the potentially useful phosphate prodrugs trans-dihydronarcis...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Antineoplastic Agents. 454. Synthesis of the Strong Cancer Cell Growth Inhibitors trans-Dihydronarciclasine and 7-Deoxy-trans-dihydronarciclasine

et al. 2009

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“…As part of our search for novel and bioactive compounds, we isolated three new Amaryllidaceae alkaloids, 5,6-dehydrodihydrolycorine (1), 6b-acetoxycrinamine (2), and (þ)-8-O-acetylhomolycorine a-N-oxide (3), together with eleven known analogs from bulbs of Lycoris radiata, a Chinese folk medicine famous for the treatment of poliomyelitis [15]. The new structures were elucidated by means of spectroscopic methods, and the known compounds were identified as 6-hydroxycrinamine (4) [16], homolycorine (5) [17], dihydrolycorine (6) [18], lycorine (7) [18], 7-oxodihydrolycorine (8) [19], (þ)-hippeastrine (9) [20], 2a-hydroxy-6-O-methoxyloduline (10) [21], galanthamine (11) [22], 7-deoxynarciclasine (12) [23], pancratinine C (13) [24], and 5,6-dihydrobicolorine (14) [25]. In addition, compounds 1 -3 were evaluated for their cytotoxic activities against five human cancer cell lines.…”

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Amaryllidaceae Alkaloids from Lycoris radiata

Feng

Wang

et al. 2011

Helvetica Chimica Acta

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A phytochemical investigation on bulbs of Lycoris radiata resulted in the isolation of three new Amaryllidaceae alkaloids, named 5,6-dehydrodihydrolycorine (1), 6b-acetoxycrinamine (2), and (þ)-8-O-acetylhomolycorine a-N-oxide (3), together with eleven known alkaloids, 4 -14. The structures of the new alkaloids were established by means of spectroscopic methods, and the known compounds were identified by comparison of their data with those in the literature. Compound 2 showed cytotoxicity against HL-60, A-549, and MCF-7 cells, with IC 50 values of 8.1, 24.3, and 15.0 mm, respectively.Introduction. -Amaryllidaceae alkaloids have for a long time attracted great interest of synthetic organic chemists because of their several biological activities and their potential diversity in pharmacology [1 -9]. So far, more than 100 alkaloids have been isolated from Amaryllidaceae plants [10], which exhibited diverse bioacitivities, such as antiviral, insect antifeedant, antineoplastic, and acetylcholinesterase inhibitory activities [10 -14]. As part of our search for novel and bioactive compounds, we isolated three new Amaryllidaceae alkaloids, 5,6-dehydrodihydrolycorine (1), 6b-acetoxycrinamine (2), and (þ)-8-O-acetylhomolycorine a-N-oxide (3), together with eleven known analogs from bulbs of Lycoris radiata, a Chinese folk medicine famous for the treatment of poliomyelitis [15]. The new structures were elucidated by means of spectroscopic methods, and the known compounds were identified as 6-hydroxycrinamine ( , and 5,6-dihydrobicolorine (14) [25]. In addition, compounds 1 -3 were evaluated for their cytotoxic activities against five human cancer cell lines.

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“…Unsurprisingly, the limited availability of these isocarbostyrils, as well as their interesting frameworks, have made these attractive and relevant targets for organic synthesis, and many successful strategies for the construction of 1, 2, and 3 have been described. [4] In contrast, the syntheses of the natural products trans-dihydronarciclasine (4) [5] and trans-dihydrolycoricidine (5) [6] have not been explored as extensively even though they demonstrate potent cytotoxicities. [7] To date, three syntheses of (+)-5 have been reported in the literature [8] and a third report describes the synthesis of the nonnatural enantiomer (À)-5.…”

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confidence: 99%