Phenanthroindolizidine Alkaloids as Cytotoxic Substances in a Danaid Butterfly, Ideopsis similis, against Human Cancer Cells

Abstract

We previously reported the presence of cytotoxic substances in extracts of the Danaid butterfly, Ideopsis similis. In the present study, we isolated cytotoxic substances against a human gastric cancer cell line, TMK-1, in I. similis pupae, with an activity similar to that of the adult butterfly. The basic fraction, prepared from a methanol extract, accounted for 83% of the cytotoxic activity. Two major cytotoxic substances were purified by HPLC, and one was determined to be a new phenanthroindolizidine alkaloid, trans-(+)-3,14alpha-dihydroxy-6,7-dimethoxyphenanthroindolizidine (1), and the other a known compound, trans-(+)-3,14alpha-dihydroxy-4,6,7-trimethoxyphenanthroindolizidine (2). The IC(50) values for TMK-1 cells were 0.5 ng/mL and 0.7 ng/mL, respectively. These two compounds showed similar cytotoxic potential with four other cancer cell lines including cervical, lung, and colon carcinomas and leukemia. Quantitative analyses indicated the presence of each of the two phenanthroindolizidine alkaloids at levels of 11-74 microg in each larva, pupa, or adult of I. similis. However, 1 was not detected in the leaves of Tylophora tanakae, a host plant for larvae of I. similis, and the level of 2 (2 microg per gram of leaves) was far less than that in the larvae. Since the leaves of T. tanakae are known to contain various phenanthroindolizidines, compounds 1 and 2 are presumably metabolically converted from such alkaloids in larvae of I. similis.

Anti-Inflammatory Mechanisms of Phenanthroindolizidine Alkaloids

“…Thus far, all effective phenanthroindolizidine alkaloids reported for anticarcinoma activity are angular molecules (Rao and Venkatachalam, 2000;Staerk et al, 2000Staerk et al, , 2002Komatsu et al, 2001;Lee et al, 2003;Gao et al, 2004). As far as we are aware, this is the first report describing a planar compound of phenanthroindolizidine alkaloids that could exert significant cytotoxicity to carcinoma cells.…”

Total Syntheses of the Tylophora Alkaloids Cryptopleurine, (−)‐Antofine, (−)‐Tylophorine, and (−)‐Ficuseptine C

“…Thus, 9-MeO-9-BBN mediated cross-coupling [27] of 32 with iodide 20 already used in the cryptopleurine series followed by platinum-catalyzed rearrangement [11] of the resulting alkynylated biphenyl derivative 33 furnished the desired phenanthrene 34. Cleavage of the Boc group followed by Pictet-Spengler cyclization [13] could again be performed as a one-pot operation which furnished antofine (2) in high yield. Not only did the analytical and spectroscopic data of our samples match those of the natural product reported in the literature, [29] but the synthetic material was also found to be optically pure within the limits of detection (> 98 %, HPLC).…”

“…Since the first isolation of tylophorine in 1935 from the perennial climbing plant Tylophora indica (previously T. asthmatica) native to the plains, hills and forests of southern and eastern India, [1] the class of "tylophora alkaloids" produced by various plants of the Asclepiadaceae family has grown considerably, [2] presently encompassing close to 100 structurally related phenanthroindolizidines and phenanthroquinolizidines together with their seco-derivatives and N-oxides. [3] As can be seen from the representative examples depicted in Scheme 1, the defining feature of these pentacyclic natural products is the presence of a highly oxygenated phenanthrene ring fused to a saturated N-heterocycle.…”

“…[2,5,6] Prototype members such as antofine (2) are not only distinguished by IC 50 values in the low nanomolar range, but were also found to be equally effective against drug-sensitive as well as multidrug-resistant (MDR) human cancer cell lines.…”

Novel Mode of Action of Tylophorine Analogs as Antitumor Compounds

“…These compounds, commonly referred to as tylophora alkaloids, because of their reported antitumor activity (1)(2)(3)(4)(5)(6)(7)(8), have been the targets of synthesis, modification, and antitumor evaluation in our laboratories. Evaluation of (ϩ)-(S)-tylophorine [DCB-3500 (NSC-717335)] and its analog DCB-3503 (NSC-716802) in the antitumor screen at the National Cancer Institute showed a fairly uniform and potent growth-inhibitory activity (GI 50 , ϳ10 Ϫ8 M) in all 60 cell lines, with notable selectivity toward several refractory cell lines, including melanoma and lung tumor cell lines based on LC 50 values (concentration of drug resulting in a 50% reduction in the measured protein at the end of the drug treatment as compared with that at the beginning).…”