phenanthroquinolizidine and phenanthroindolizidine

Phenanthroindolizidine and phenanthroquinolizidine derivatives constitute a series of compounds that are being intensively studied as potential anticancer agents. Related natural products such as antofine and tylophorine alkaloids are well known for their high cytotoxic activity; however, their clinical application has been limited because of their side effects. In this review we report, in detail, on the main structural modifications applied to the phenanthroindolizidine and phenanthroquinolizidine skeletons, and we also describe their associated anticancer activities. New derivatives with promising antitumoral activities have emerged. Simplified analogues were prepared using rapid synthetic routes, and a certain number of these analogues displayed increased anticancer activity and selectivity towards tumor cell lines. It is hoped that a better understanding of the mechanisms of action associated with structure-activity relationships (SAR) will enable us to rationalize the development of new anticancer drugs.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Indolizines; Phenanthrolines; Quinolizines

Phenanthroindolizidines and phenanthroquinolizidines were concisely synthesized by the reductive decyanization of cyano-promoted intramolecular aza-Diels-Alder cycloadducts followed by aryl-aryl coupling. Cyano groups were removed from α-aminoacrylonitriles via treatment with sodium borohydride in 2-propanol in almost quantitative yields; a possible mechanism was proposed and examined using D-labeling experiments. A systematic study of the effects of the phenanthrene substitution pattern on the anticancer activity against three human cancer cell lines was discussed.

Topics: 2-Propanol; Antineoplastic Agents; Borohydrides; Catalysis; Drug Screening Assays, Antitumor; Humans; Indolizines; Molecular Structure; Phenanthrolines; Quinolizines; Structure-Activity Relationship

To investigate the influence of the variation of the original skeletons of natural phenanthroindo/quinolizidine alkaloids on antiviral activities, two types of structurally totally novel analogues 7a, 7b, 16a, and 16b were designed, synthesized, and evaluated against tobacco mosaic virus (TMV) for the first time. Bioassay results indicated that all four of the newly designed analogues showed good to excellent antiviral activities, among which analogue 16a dispalyed comparable activity with that of ningnanmycin, perhaps one of the most successful commercial antiviral agents, thus emerging as a potential inhibitor of plant virus and serving as a new lead for further optimization. Further structure-activity relationships are also discussed, demonstrating for the first time that the same changes of the original skeletons of phenanthroindolizidine and phenanthroquinolizidine exihibted totally different antiviral activities results, providing some original and useful information about the preferential conformation for maintaining high activities.

Topics: Antiviral Agents; Drug Design; Indolizidines; Indolizines; Phenanthrenes; Phenanthrolines; Plant Diseases; Quinolizines; Structure-Activity Relationship; Tobacco Mosaic Virus

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

The discovery and development of new, highly potent anti-coronavirus agents and effective approaches for controlling the potential emergence of epidemic coronaviruses still remains an important mission. Here, we identified tylophorine compounds, including naturally occurring and synthetic phenanthroindolizidines and phenanthroquinolizidines, as potent in vitro inhibitors of enteropathogenic coronavirus transmissible gastroenteritis virus (TGEV). The potent compounds showed 50% maximal effective concentration (EC₅₀) values ranging from 8 to 1468 nM as determined by immunofluorescent assay of the expression of TGEV N and S proteins and by real time-quantitative PCR analysis of viral yields. Furthermore, the potent tylophorine compounds exerted profound anti-TGEV replication activity and thereby blocked the TGEV-induced apoptosis and subsequent cytopathic effect in ST cells. Analysis of the structure-activity relations indicated that the most active tylophorine analogues were compounds with a hydroxyl group at the C14 position of the indolizidine moiety or at the C3 position of the phenanthrene moiety and that the quinolizidine counterparts were more potent than indolizidines. In addition, tylophorine compounds strongly reduced cytopathic effect in Vero 76 cells induced by human severe acute respiratory syndrome coronavirus (SARS CoV), with EC₅₀ values ranging from less than 5 to 340 nM. Moreover, a pharmacokinetic study demonstrated high and comparable oral bioavailabilities of 7-methoxycryptopleurine (52.7%) and the naturally occurring tylophorine (65.7%) in rats. Thus, our results suggest that tylophorine compounds are novel and potent anti-coronavirus agents that may be developed into therapeutic agents for treating TGEV or SARS CoV infection.

Topics: Alkaloids; Animals; Antiviral Agents; Apocynaceae; Chlorocebus aethiops; Coronavirus Infections; Cytopathogenic Effect, Viral; Dose-Response Relationship, Drug; Gastroenteritis, Transmissible, of Swine; Indolizines; Phenanthrenes; Phenanthrolines; Quinolizines; Rats; Rats, Sprague-Dawley; Severe Acute Respiratory Syndrome; Severe acute respiratory syndrome-related coronavirus; Structure-Activity Relationship; Swine; Transmissible gastroenteritis virus; Tylophora; Vero Cells

The total synthesis of alkaloids phenanthroindolizidine 1a, tylophorine 1b, and phenanthroquinolizidine 1c, has been achieved in 46%, 49%, and 42% overall yield, respectively, starting from the corresponding phenanthrene-9-carboxaldehyde. Compound exhibited potent inhibition activity in three human cancer cell lines, with IC(50) values ranging from 104 to 130 nM. The structure-activity relations of these alkaloids and some of their synthetic intermediates against the three cell lines were also described.

Topics: Alkaloids; Antineoplastic Agents; Biochemistry; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Indolizines; Phenanthrenes; Phenanthrolines; Quinolizines; Structure-Activity Relationship