Isolation and structure of pancratistatin

Pettit, George R.; Gaddamidi, Venkatswamy; Cragg, Gordon M.; Herald, Delbert L.; Sagawa, Yoneo

doi:10.1039/c39840001693

Cited by 127 publications

(73 citation statements)

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“…IR ν max /cm -1 : 2944, 2867, 1752, 1613, 1513, 1476, 1247; 1084, 1039, 934, 882, 828, 683. 1 4,17.9,55.2,58.9,66.4,72.1,72.8,101.9,108.3,112.2,113.5,113.7,129.1,130,135.1,147.6,147.9,159.1,202.5. Minor diastereoisomer: δ 12.3,17.9,55.2,59.7,64.8,71.5,72.9,101.8,108.4,112,113.4,113.7,129.2,130,134.8,147.5,147.8,159,202.4 [1,3]dioxol-5-yl)-2-(tert-butyldiphenyl-silanyloxy-methyl)-3-triisopropylsilanyloxypropionaldehyde (47) Colorless oil, 95% yield.…”

Section: General Procedures For Hydroboration Reaction Of 39 40 and 41mentioning

confidence: 99%

“…Galantamine (1), for example, is a specific, competitive and reversible acetyl cholinesterase inhibitor, being used in the clinical treatment of Alzheimer disease. 3 Pancratistatin (2), narciclasine (3), hippadine (4) and anhydrolycorinone (5) exhibit antiproliferative activity. 9,10 The highly sophisticated substitution pattern of the carbon skeleton of these alkaloids, associated with their relevant biological and pharmacological significance, induced the interest of synthetic organic chemists in establishing strategies aiming at their total syntheses, in both racemic and asymmetric versions.…”

Section: Introductionmentioning

confidence: 99%

“…IR ν max /cm -1 : 3070, 2956, 2930, 2890, 2857, 1727, 1475, 1239, 1112, 1099, 837, 702 -5.4, -5.3, -4.7, -4.6, 17.9, 18, 19.1, 25.6, 26.7, 59.8, 60.9, 70.6, 101.7, 102.8, 108.3, 111.4, 112.2, 127.6, 127.6, 127.7, 129.6, 129.7, 133, 133.1, 134.4, 135.5, 135.6, 147.5, 147.7, 202.7, 202.8 Colorless oil, 85% yield. IR ν max /cm -1 : 2944, 2867, 1752, 1613, 1513, 1476, 1247; 1084, 1039, 934, 882, 828, 683 4, 17.9, 55.2, 58.9, 66.4, 72.1, 72.8, 101.9, 108.3, 112.2, 113.5, 113.7, 129.1, 130, 135.1, 147.6, 147.9, 159.1, 202.5. Minor diastereoisomer: δ 12.3, 17.9, 55.2, 59.7, 64.8, 71.5, 72.9, 101.8, 108.4, 112, 113.4, 113.7, 129.2, 130, 134.8, 147.5, 147.8, 159, 202.4 Colorless oil, 95% yield.…”

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Studies toward the synthesis of Amaryllidaceae alkaloids from Morita-Baylis-Hillman adducts: a straightforward synthesis of functionalized dihydroisoquinolin-5(6H)-one core

Lopes¹,

Coelho²

2007

J. Braz. Chem. Soc.

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Descrevemos neste trabalho, os resultados de um estudo que teve como objetivo a síntese de esqueletos de carbono altamente funcionalizados de alcalóides de plantas da família das Amaryllidaceae. A partir de adutos de Morita-Baylis-Hillman, descrevemos a síntese total do núcleo diidroisoquinolin-5(6H)-ona funcionalizado, que é a parte inferior da estrutura de vários alcalóides dessa classe. Essa substância pode ser um intermediário útil e valioso para a síntese total dos alcalóides isolados de plantas da família Amaryllidaceae.We disclose herein our results concerning a study aiming at the synthesis of the highly substituted carbon skeleton of alkaloids isolated from plants of the Amaryllidaceae family. The total synthesis of the functionalized dihydroisoquinolin-5(6H)-one core, which is the bottom part of the structure of alkaloids isolated from this botanic family, is described, using MoritaBaylis-Hillman adducts as substrate. This compound should be a useful and valuable intermediate for the total synthesis of alkaloids isolated from Amaryllidaceae. Keywords: Morita-Baylis-Hillman adducts, Amaryllidaceae, dihydroisoquinolinones IntroductionPlants from the Amaryllidaceae family are spread all over the world and due to its pharmacological relevance some representatives of this botanic family are known by humans since antiquity. 1 Among the chemical constituents present in these plants, the alkaloids are the most important and, normally, they are responsible for the biological activities exhibited. As a matter of fact, the biological importance of the plants from this family led to an intense phytochemical research activity, which culminated with the isolation and chemical characterization of several structurally different classes of alkaloids. 2 Galanthamine (1), 3 pancratistatin (2), 4 narciclasine (3), 5 hippadine (4), 6 anhydrolycorinone (5), 6,7 and plicamine (6) 8 are examples that clearly show the structurally rich diversity of these alkaloids (Figure 1). Besides structural complexity, these alkaloids exhibit different biological activities. Galantamine (1), for example, is a specific, competitive and reversible acetyl cholinesterase inhibitor, being used in the clinical treatment of Alzheimer disease. 3 Pancratistatin (2), narciclasine (3), hippadine (4) and anhydrolycorinone (5) exhibit antiproliferative activity. 9,10 The highly sophisticated substitution pattern of the carbon skeleton of these alkaloids, associated with their relevant biological and pharmacological significance, induced the interest of synthetic organic chemists in establishing strategies aiming at their total syntheses, in both racemic and asymmetric versions. The results of these efforts can be easily measured by the countless reports available in the literature describing successful syntheses of several types of alkaloids isolated from Amaryllidaceae. 11 Particularly, the alkaloids which are structurally related to pantacristatin (2) were synthesized successfully by using the strategy of joining the two suitably substituted fragm...

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Section: General Procedures For Hydroboration Reaction Of 39 40 and 41mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Studies toward the synthesis of Amaryllidaceae alkaloids from Morita-Baylis-Hillman adducts: a straightforward synthesis of functionalized dihydroisoquinolin-5(6H)-one core

Lopes¹,

Coelho²

2007

J. Braz. Chem. Soc.

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“…17 Another plant-derived agent, pancratistatin, is also of interest as a potential candidate for preclinical development. 18 The research of Bob Pettit has received strong support over the years from the National Cancer Institute, and from 1989 to 2001 his significant contributions to anticancer drug discovery were recognized through NCI funding as an Outstanding Investigator. He has also received considerable support from private foundations and individuals who have been inspired by his unbounded enthusiasm and commitment to improving the lives of cancer patients and his outstanding record in achieving this all important goal.…”

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confidence: 99%

Special Issue in Honor of Professor George Robert Pettit

Powell

2008

J. Nat. Prod.

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It is an honor and a pleasure for us to serve as Guest Editors of this issue of the Journal of Natural Products dedicated to Professor George Robert (Bob) Pettit. We wish to express our sincere thanks to Bob's former students, postdoctoral fellows, visiting scientists, and his many colleagues from the former Cancer Research Institute at Arizona State University and institutions worldwide, for submitting such a diverse set of excellent manuscripts for this issue. Their generosity in terms of time and effort is greatly appreciated and provides well-deserved recognition of the many outstanding contributions that Bob has made to the field of natural products science and anticancer drug discovery over the past five decades.Bob Pettit was born on June 8, 1929, in Long Branch, New Jersey. He gained his B.S. in chemistry at Washington State University in 1952 and proceeded to Wayne State University, where he completed his M.S. in heterocyclic chemistry in 1954 and his Ph.D. in steroid chemistry in 1956, both under the direction of Professor Carl Djerassi. Bob remembers the Djerassi group of the mid-1950s as an exciting and diverse group of talented young scientists from many parts of the world, including Australia, India, Israel, New Zealand, and the United Kingdom, who proceeded to prominent positions in academia, government, and industry. These included Albert Bowers and John Zderic, who later became CEO and Vice President of Syntex, respectively. In 1956, Bob moved to Norwich Eaton Pharmaceuticals (now Proctor and Gamble) as Senior Research Chemist, and in 1957 he transferred 

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“…Pancratia littoralis). 9 Furthermore, the amount of pancratistatin (1) contained in B. magna would suggest a defensive strategy and potential new plant source of isocarbostyril 1 as amaryllidaceous species have not been recorded among the plants selected by this grasshopper as preferred foods. 7,8 Interestingly, the southern grasshopper mouse, Onychomy tossidus, views B. magna as quite palatable.…”

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Antineoplastic Agents. 553. The Texas Grasshopper Brachystola magna

et al. 2005

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Bioassay (P388 lymphocytic leukemia cell line and human cancer cell lines) -guided separation of an extract prepared from the previously chemically uninvestigated Texas grasshopper Brachystola magna led to isolation of the cancer cell growth inhibitory pancratistatin (1), narciclasine (2) and ungeremine (3). Pancratistatin (1) was first isolated from the bulbs of Hymenocallis littoralis (a.k.a. Pancratium littorale Jacq) and the original crystal structure was deduced by X-ray analysis of a monomethyl ether derivative. In the present study a crystal of pancratistatin (1) was isolated from an extract of B. magna, which led to the X-ray crystal structure of this anticancer drug. Since isoquinoline derivatives 1-3 are previously known only as constituents of amaryllidaceous plants, some of the interesting implications of their rediscovery in the grasshopper B. magna that does not appear to utilize amaryllis family plants were discussed.In 1965-66 we began the first exploratory survey of terrestrial arthropods as potential sources of new and structurally unique anticancer drugs and by 1968 had uncovered a number of promising leads. 2 Over the relatively short four year period when resources were available, we isolated, e.g. antineoplastic constituents from butterfly wings, 3a an Asian beetle, 3b and a wasp. 3c Recently, this relatively unexplored area 4 for discovering medically useful new drugs has begun to be revisited on a much larger scale. 5 One of the insect leads we began to pursue in 1967 was the lubber grasshopper 6 Brachystola magna collected in Texas, but this foraging generalist ranger moved north to Minnesota and west to Arizona. 7 Most grasshoppers are usually polyphagous and pursue plants from a broad variety of taxa. However, B magna will even consume other insects including grasshoppers alive or dead. 7,8 In this regard, it's believed that insects vary their diet to obtain, e.g. plant constituents important for their own chemical defense. 7 When 2-propanol extracts of B. magna were found to provide a 40% increase in life span (at 200 mg/Kg) against the U.S. National Cancer Institute murine P388 lymphocytic leukemia, we gave increased attention to the lead. By 1970 a combination of negative events occurred, of which the most serious was the untimely passing of our entomologist colleague, D. G. Ford. This coincided with, for practical purposes, the disappearance of B. Magna from the southwest along with the necessary financial resources. Because the extract from the initial collection (less than 1 kg) of B. magna amounted to only 11 g, isolation of the antineoplastic constituent had to await the development of improved bioassays (especially with cancer cell lines), isolation and instrumental techniques. The rather surprising solution to this research objective now follows:The original Texas collection of Brachystola magna provided a 2-propanol extract that upon solvent partitioning between 9:1→1:1 CH 3 OH-H 2 O and hexane→CH 2 CL 2 and the H 2 O * To whom correspondence should be addressed. Te...

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Isolation and structure of pancratistatin

Cited by 127 publications

References 0 publications

Studies toward the synthesis of Amaryllidaceae alkaloids from Morita-Baylis-Hillman adducts: a straightforward synthesis of functionalized dihydroisoquinolin-5(6H)-one core

Studies toward the synthesis of Amaryllidaceae alkaloids from Morita-Baylis-Hillman adducts: a straightforward synthesis of functionalized dihydroisoquinolin-5(6H)-one core

Special Issue in Honor of Professor George Robert Pettit

Antineoplastic Agents. 553. The Texas Grasshopper Brachystola magna

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