antofine and phenanthroindolizidine

Although antofine, a natural phenanthroindolizidine alkaloid, exerts potential biological activities, including anticancer effect and anti-angiogenic activity, the underlying mechanisms have not yet been investigated. In the present study, the inhibitory effect of antofine on angiogenesis was determined in cultured mouse embryonic stem (mES)/embryoid body (EB)-derived endothelial cells and vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cells (HUVECs). Antofine effectively inhibited VEGF-induced cell migration and tube formation of HUVECs. Antofine also significantly decreased ex vivo microvessel sprouting in cultured mouse aortic rings, and inhibited the vascular formation and platelet/endothelial cell adhesion molecule (PECAM) expression of mES/EB-derived cells in 3-D collagen gel. The underlying mechanism of anti-angiogenic activity of antofine was, in part, associated with the modulation of AKT/mTOR and AMP-activated protein kinase (AMPK) signaling in VEGF-stimulated HUVECs.

Topics: AMP-Activated Protein Kinases; Angiogenesis Inhibitors; Animals; Cell Proliferation; Endothelial Progenitor Cells; Humans; Indoles; Indolizines; Mice; Mouse Embryonic Stem Cells; Neovascularization, Pathologic; Phenanthrolines; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

The phenanthroindolizidine alkaloid antofine and its analogues have excellent antiviral activity against tobacco mosaic virus (TMV). To simplify the structure and the synthesis of the phenanthroindolizidine alkaloid, a series of phenanthrene-containing N-heterocyclic compounds (compounds 1 to 33) were designed and synthesised, based on the intermolecular interaction of antofine and TMV RNA, and systematically evaluated for their anti-TMV activity.. Most of these compounds exhibited good to reasonable anti-TMV activity. The optimum compounds 5, 12 and 21 displayed higher activity than the lead compound antofine and commercial ribavirin. Compound 12 was chosen for field trials of antiviral efficacy against TMV, and was found to exhibit better activity than control plant virus inhibitors. Compounds 5 and 12 were chosen for mode of action studies. The changes in fluorescence intensity of compounds 5 and 12 on separated TMV RNA showed that these small molecules can also bind to TMV RNA, but the mode is very different from that of antofine.. The compounds combining phenanthrene and an N-heterocyclic ring could maintain the anti-TMV activity of phenanthroindolizidines, but their modes of action are different from that of antofine. The present study lays a good foundation for us to find more efficient anti-plant virus reagents.

Topics: Alkaloids; Antiviral Agents; Drug Design; Heterocyclic Compounds; Indoles; Indolizines; Phenanthrenes; Phenanthrolines; Ribavirin; Structure-Activity Relationship; Tobacco Mosaic Virus

A concise and modular synthesis of phenanthroindolizidine alkaloids was achieved by combining iodoaminocylization with a free radical cyclization approach. The route described allowed the preparation of (±)-tylophorine, (±)-antofine, and (±)-deoxypergularinine in six steps. When commercially available l-prolinol was used as a chiral building block, (S)-(+)-tylophorine was also synthesized in 49% yield and >99% ee over five linear steps.

Topics: Alkaloids; Chemistry, Organic; Cyclization; Free Radicals; Indoles; Indolizines; Isoquinolines; Magnetic Resonance Spectroscopy; Phenanthrenes; Phenanthrolines; Pyrrolidines; Stereoisomerism; Structure-Activity Relationship; Temperature

Met is a receptor tyrosine kinase for hepatocyte growth factor. Met mutations have been considered as a major cause of primary resistance to Met tyrosine kinase inhibitors (TKIs). Mutated Met enhances its endosomal signaling, which includes internalization, signaling within endosomes, recycling to membrane, and sorting for degradation. These sequential events lead to a plausible mechanism for resistance. (-)-Antofine, a phenanthroindolizidine alkaloid, has exhibited potent antitumor activity but the precise underlying mechanism has been poorly understood. We found that (-)-antofine effectively inhibited the proliferation of Met-mutated Caki-1 cells, which were resistant to well-known Met TKIs. (-)-Antofine negatively regulated Met endosomal signaling and consequently inhibited the nuclear translocation of STAT3 both in vitro and in vivo. These findings emphasize the potential of Met endosomal signaling as a novel target for Met TKI-resistant cancers and (-)-antofine as a novel lead compound associated with the suppression of Met endosomal signaling.

Topics: Alkaloids; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Endocytosis; Endosomes; Humans; Indoles; Indolizines; Kidney Neoplasms; Microscopy, Confocal; Phenanthrolines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-cbl; Proto-Oncogene Proteins c-met; RNA Interference; RNA, Small Interfering; Signal Transduction; STAT3 Transcription Factor; Stereoisomerism

A series of phenanthroindolizidine and phenanthroquinolizidine alkaloids and their 14-amino-derivatives (1-44) were prepared and systematically evaluated for their anti-tumor activities against A549 and HL60 cell lines. The bioassay results showed that most of these alkaloids possess good anti-tumor activities. Especially, compounds 15, 22, 28, 33-36, 40 and 42 displayed low nanomolar or subnanomolar levels of anti-tumor activity. The configuration of (13aS,14S)-14-hydroxyphenanthroindolizidines and (14aR,15R)-15-hydroxyphenanthroquinolizidines was confirmed to be optimal. 14-Amino-phenanthroindolizidines with increased polarity possess good anti-tumor activity, especially for compounds 26 and 28. Most of the phenanthroquinolizidine alkaloids exhibited higher anti-tumor activity than that of phenanthroindolizidine alkaloids. Our present study provides fundamental support for development and optimization of phenanthroindolizidine and phenanthroquinolizidine alkaloids as potential anti-tumor drugs.

Topics: Alkaloids; Antineoplastic Agents; Cell Line, Tumor; Chemistry Techniques, Synthetic; Humans; Indolizines; Phenanthrolines; Quinolizines; Structure-Activity Relationship

On the basis of our previous structure-activity relationship (SAR) and antiviral mechanism studies, a series of phenanthroindolizidines and their analogues 3-20 were designed, targeting tobacco mosaic virus (TMV) RNA, synthesized, and systematically evaluated for their antiviral activity against TMV. The bioassay results showed that most of these compounds displayed good anti-TMV activity, and some of them exhibited higher antiviral activity than that of commercial Ningnanmycin (perhaps the most successful registered antiplant viral agent). Especially, (S)-deoxytylophorinine (5) with excellent anti-TMV activity (inactivation activity, 59.8%/500 μg mL(-1) and 40.3%/100 μg mL(-1); curative activity, 65.1%/500 μg mL(-1) and 43.7%/100 μg mL(-1); and protection activity, 70.2%/500 μg mL(-1) and 51.3%/100 μg mL(-1)) emerged as a potential inhibitor of the plant virus. Compound 20 exhibited a strong in vivo protection effect against TMV at 100 μg mL(-1), which indicated that phenanthroindolizidine analogues with a seven-membered D ring have a new and interesting structural scaffold and have great potential for further development as tobacco protection agents.

Topics: Antiviral Agents; Drug Design; Indolizidines; Indolizines; Phenanthrolines; Plant Diseases; RNA, Viral; Tobacco Mosaic Virus

Due to their limited natural abundance and significant biochemical effects, we synthesized the alkaloids (+/-)-antofine (1a), (+/-)-deoxypergularinine (1b), and their dehydro congeners (2 and 3) starting from the corresponding phenanthrene-9-carboxaldehydes. We also evaluated their in vitro cytotoxic activity. Compounds 1a and 1b showed significant potency against various human tumor cell lines, including a drug-resistant variant, with EC(50) values ranging from 0.16 to 16ng/mL. Structure-activity correlations of these alkaloids and some of their synthetic intermediates were also ascertained. The non-planar structure between the two major moieties, phenanthrene and indolizidine, plays a crucial role in the cytotoxic activity of phenanthroindolizidines. Increasing the planarity and rigidity of the indolizidine moiety significantly reduced potency. A methoxy group at the 2-position (1a) was more favorable for cytotoxic activity than a hydrogen atom (1b).

Topics: Alkaloids; Bromides; Cell Line, Tumor; Chlorides; Drug Resistance, Neoplasm; Humans; Indoles; Indolizines; Isoquinolines; KB Cells; Phenanthrolines