Antineoplastic Agents. 553. The Texas Grasshopper Brachystola magna

Abstract

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...

Total Syntheses of Pancratistatin. A Review

“…16 Also, frozen extracts of the Texas grasshopper Brachystola magna from 1967, which were only analyzed recently, were found to have 0.041% pancratistatin. 17 The structure of pancratistatin was determined by NMR spectral analysis and confirmed by the determination of an X-ray crystal structure of pancratistatin monomethyl ether. 13 The X-ray structure of the natural product itself was obtained later.…”

“…13 The X-ray structure of the natural product itself was obtained later. 17 Similarly to narciclasine/7-deoxynarciclasine pair, pancratistatin was found to have its naturally occurring 7-deoxy congener, isolated by Ghosal and coworkers in 1989 from Haemanthus Kalbreyeri . 15 …”

A Survey of Phytotoxic Microbial and Plant Metabolites as Potential Natural Products for Pest Management

“…For 21,22-dihydrocytochalasin B, the 24-h IC 50 and MIC values were 154 and 48 mg/l, respectively, while sphaeropsidin A had 24-h IC 50 and MIC values of 14 and 35 mg/l, respectively ( Table 6). Ungeremine has been isolated from the extracts of a variety of plant species, including Ungernia minor [36], Crinum americanum [37], C. asiaticum [38], Zephyranthes flava [39], and Pancratium maritimum [20], and also found in the lubber grasshopper Brachystola magna, most likely from the direct or indirect (e.g., consumption of other grasshoppers) ingestion of plant material [40]. Previous research evaluating the toxicity of ungeremine against ten different bacterial isolates (both Gram-positive and Gram-negative) including S. aureus identified the MIC value to be between 25 -50 mg/l [41].…”

Chemotherapeutic Effects of Bioassay-Guided Extracts of the American Cockroach,Periplaneta americana

“…Similar reports of arthropod extracts as anticancer agents emerged regarding the Asian rhinocerous beetle, Allomyrina dichotomus, 24 the North American yellow jacket wasp, Vespula pensylvanica, 25 and much later, the Texas lubber grasshopper, Brachystola magna. 26 We have been interested in potential chemotherapeutic properties of the American cockroach, Periplaneta americana, a species widely disseminated in China and throughout major cosmopolitan areas of the world. P americana has been extensively studied for its uncommon ability to resist environmental threats, which has contributed to its evolutionary presence for more than 300 million years.…”