Antineoplastic Agents. 573. Isolation and Structure of Papilistatin from the Papilionid Butterfly Byasa polyeuctes termessa

Abstract

Bioassay-guided separation of an extract of the wings from a Taiwan butterfly, Byasa polyeuctes termessa, allowed isolation of a new cancer cell growth inhibitor designated papilistatin (1a). The structure was determined by analysis of 1D and 2D NMR spectra and by HRMS. Against a panel of six human and the murine P388 leukemia cancer cell lines, papilistatin exhibited cancer cell growth inhibition with GI 50 s of 0.093-3.5 μg/mL. Papilistatin was also found to have antibacterial activity.Insects are now believed to number some four to six million species, 2 with butterflies and moths (order Lepidoptera) comprising over 100,000 species. 3 Such an enormous reservoir of as yet unexplored compounds that could include biologically active structures is most compelling. Recent examples that provide some insight into the scope of this potential reservoir include the pheromones of the giant white butterfly Idea leuconoe , 4a spiroacetals from a parasitoid wasp (order Hymenoptera),4b the defensive spray of a walkingstick insect (order Phasmatodea),4c and the anticancer drug pancratistatin from a grasshopper (order Saltatoria). 4d The medically important toxins of certain Brazilian centipede (class Chilopoda) venoms present another dimension.5 Investigation of other Arthropoda classes such as the arachnids, comprising nearly 40,000 species, are leading to discoveries of new and potentially useful constituents.6 Illustrative are the p53-MDM2/MDMX inhibitor, derived from a toxin of an Asian scorpion,6a and the sulfated nucleoside constituents of a spider venom.6bIn 1965-66, we began to pioneer the first systematic investigation of arthropods for antineoplastic components and summarized the initial promising results in 1968. 3 Our most recent advance in that area was the isolation from a Texas grasshopper of pancratistatin, 4d a preclinical anticancer drug that had in the meantime been isolated by us from an African plant. Another class Insecta metabolite investigation that was delayed until recently pertains to the papilionid butterfly Byasa polyeuctes termessa (Atrophaneura polyeuctes termessus Fruhstorfer), which was collected in Taiwan in 1967. We now report the isolation and structure of a new cancer cell growth inhibitor from the butterfly, designated papilistatin (1a).To our knowledge, no prior chemical studies of B. polyeuctes have been reported, nor of the genus, except that one member, Byasa alcinous (Atrophaneura alcinous Klug), was investigated for papilochromes 7 and butyric acids 8 with negative results. In addition, it was reported that B. alcinous is attracted to Aristolochia debilis , 9 one of many Aristolochiaceae † Dedicated to the memory of Professor Georgy B. Elyakov , a pioneering expert in the chemistry of naturally occurring substances, especially from marine organisms.

First total synthesis of Papilistatin

“…The melting points were determined with an X-4 binocular microscope melting-point apparatus (Beijing Tech Instruments Co, Beijing, China) and were uncorrected. 1 H NMR spectra were obtained by using a Bruker AV 400 spectrometer. Chemical shifts (d) were given in parts per million (ppm) and were measured downfield from internal tetramethylsilane.…”

“…The mixture was warm to 40 • C and stirred for 6 h. The mixture was rotary evaporated to remove dioxane and methanol, and the resulting mixture was cooled to 0 • C and acidified with 2 mol L -1 hydrochloric acid to afford 0.62 g (85%) of papilistatin as a yellow solid. mp > 300 • C; 1…”

“…1) was isolated in 2010 by Pettit from a Taiwan butterfly, and was found to have anticancer and antibacterial activity. 1 Against a panel of six human and the murine P388 leukemia cancer cell lines, papilistatin exhibited cancer cell growth inhibition with GI 50 's of 0.093-3.5 mg mL -1 . We have been continuously studying the synthesis and biological activities of phenanthroindolizidine alkaloids.…”

Insects: an underrepresented resource for the discovery of biologically active natural products

“…A novel small molecule, designated papilistatin ( 113 , Fig. 19 ), was isolated from the wings of Byasa polyeuctes termessa , a Taiwan butterfly (Papilionidae) 161 . Papilistatin showed strong cytotoxicity against colon and pancreatic cancer cells and selective Gram-positive antibacterial activity.…”

The Biotechnological Potential of Secondary Metabolites from Marine Bacteria

“…Most of the isolated antimicrobial metabolites are capable of rapidly killing a wide range of microbes. Large-sized antimicrobial proteins (>100 amino acids) are often lytic proteins that bind nutrients [68,70] or destroy specific cell patterns [71][72][73], causing DNA degradation [73,74] and inhibiting intracellular synthesis of peptidoglycan [75][76][77] and specific proteins by disrupting the structure or function of microbial cell membranes [7,54,78,79] (Figure 3). In recent years, two accessible databases have been created for storing and querying information on almost two hundred antibacterial peptides-BACTIBASE [80] and BAGEL [81,82].…”