Discovery and development of anticancer agents from plants

Abstract

A novel in vitro assay for the discovery of anticancer agents was used to examine aqueous and organic extracts from 1847 plants collected mainly in the U.S. Southwest and West. The assay results were separated into 5 categories: inactive (62%), equally active (36%), equally active and potent (0.5%), solid tumor selective (1.4%), and human selective (0.8%). Extracts from the latter three categories were fractionated using the in vitro assay to biodirect each step. Psorothamnus emoryi extracts were solid tumor selective and yielded two active compounds upon fractionation: dalrubone and 5-methoxydalrubone. Calocedrus decurrens was equally active and potent and yielded deoxypodophyllotoxin as the active compound. Linanthus floribundus was human selective and yielded strophanthidin as the active compound. The potential of this assay to discover novel anticancer agents from the active extracts is discussed.

Highly N-Methylated Linear Peptides Produced by an Atypical Sponge-Derived Acremonium sp.

“…02172; collection locale: Milne Bay, Papua New Guinea) displayed potent cytotoxicity in a primary screen using leukemia and solid tumor murine and human cancer cell lines (Table 1). 18 This prompted the growth of a larger-scale culture (20 L) to facilitate the purification of metabolites from dichloromethane-soluble broth (EFD) and mycelial extracts (TFD) (Table 1, Figure S1). Bioassay against a murine lymphocytic cell line (L1210) and Staphylococcus epidermidis and NMR data were used to guide the fractionation, resulting in two new related linear octapeptides, RHM1 (1) and RHM2 (2), and the known peptaibiotic efrapeptin G (3).…”

“…Efrapeptin G (3) was slightly less active against S. epidermidis (MIC 80 μg/mL, Table 1), while RHM2 (2) did not exhibit antimicrobial activity (MIC > 400 μg/mL, Table 1). Both 1 and 2 exhibited mild cytotoxicity against murine L1210 cells in a disk diffusion soft agar colony-forming assay 18 (Table 1). Alternatively, 3 exhibited potent cytotoxicity against murine L1210 cells and against HCT-116 with an IC 50 of 3.5 × 10 -3 μg/ mL.…”

A Distinctive Structural Twist in the Aminoimidazole Alkaloids from a Calcareous Marine Sponge: Isolation and Characterization of Leucosolenamines A and B

“…The methanol-soluble fraction, coded XFM, had selective bioactivity (for murine adenocarcinoma C-38 cell line) in the disk diffusion solid tumor whole cell assay with an inhibitory zone differential of 9 mm between murine C-38 and CFU-GM cells at 180 µg per disk. 14 Because of this selective bioactivity, the MeOH fraction was subjected to HPLC purification to afford five fractions ( Figure S2). Fraction 3 was pure leucosolenamine A (5) (5.6 mg) with an m/z of 384.2 [M + H] + (ESI-TOF) and exhibited inhibition zones of 10.5 mm (at 180 µg per disk) against murine colon 38 (vs 0 mm against CFU-GM).…”

“…These were confirmed by gHMBC correlations as illustrated in Figure 1, substructure B, and in Figure 5 Our investigation of the biological properties was restricted to an evaluation of 5 due to sample limitation and stability. The data set summarized in Table 3 employed our standard disk diffusion assay 14 and revealed that 5, at 180 μg/disk, inhibited murine C-38 cells with a 10.5 mm zone as compared to 0 mm against CFU-GM cells. This is the profile for a mildly potent selective cytotoxin when compared to the in vivo active agent bengamide E, 20 displaying at 7.8 μg/disk inhibition zones of 21 mm against C-38 and 16.5 mm against CFU-GM cells.…”

“…During recent expeditions to Papua New Guinea (PNG), specimens of the genus Leucosolenia (order Leucosolenida, family Lecucosoleniidae) were obtained and became high priority for further investigation because the crude MeOH extract showed positive activity in our primary screen for in vitro solid tumor selectivity. 14 Disclosed below are the results of this study culminating in the characterization two new compounds, leucosolenamines A (5) and B (6), possessing a 2-amino imidazole core substituted at C-4 and C-5, and the isolation of thymidine (7).…”