Wenlie Peng

β-Carboline Alkaloids: Biochemical and Pharmacological Functions

beta-Carboline alkaloids are a large group of natural and synthetic indole alkaloids with different degrees of aromaticity, some of which are widely distributed in nature, including various plants, foodstuffs, marine creatures, insects, mammalians as well as human tissues and body fluids. These compounds are of great interest due to their diverse biological activities. Particularly, these compounds have been shown to intercalate into DNA, to inhibit CDK, Topisomerase, and monoamine oxidase, and to interact with benzodiazepine receptors and 5-hydroxy serotonin receptors. Furthermore, these chemicals also demonstrated a broad spectrum of pharmacological properties including sedative, anxiolytic, hypnotic, anticonvulsant, antitumor, antiviral, antiparasitic as well as antimicrobial activities. In this review, we summerized the biochemical and pharmacological functions of beta-carboline alkaloids.

Antitumor and neurotoxic effects of novel harmine derivatives and structure-activity relationship analysis

Beta‐carboline alkaloids such as harmine are present in medicinal plants such as Peganum harmala that have been used as folk medicine in anticancer therapy. In our study, 9 harmine derivatives (including harmine) were investigated for their antitumor effects and acute toxicities in mice, and the structure‐activity relationship (SAR) was also analyzed. Administration of these compounds resulted in tumor inhibition rates of 15.3–49.5% in mice bearing Lewis Lung Cancer, sarcoma180 or HepA tumor, with the highest value of 49.5% from compound 6. Acute toxicity studies showed that all these compounds except compounds 2 and 5 caused remarkable acute neurotoxicities manifested by tremble, twitch and jumping. SAR analysis indicated that the formate substitution at R3 of the tricyclic skeleton reduced their neurotoxicity, while the short alkyl or aryl substitution at R9 increased the antitumor activity. The harmine and its derivatives resulted in in vitro cytotoxicity (IC50) values of 0.011–0.021 μmol/ml in HepG2 cells, with compound 8 being the most potent among all agents tested. Compounds 1, 6, 7 and 8 induced apoptosis in HepG2 cells, with the highest apoptotic rate (55.34%) from compound 6. Western blotting analysis demonstrated that compound 6 completely inhibited the expression of Bcl‐2 gene, and compounds 1 and 8 produced a significant inhibition by 40 and 60%, respectively, compared to the control, while compound 7 did not alter the level of Bcl‐2. Compounds 1, 6, 7 and 8 upregulated the expression of death receptor Fas by approximately 50–120%. All these findings indicate that compounds with both substitutions at R3 and R9 (such as compound 5) have high antitumor activity and low toxicity, which might be chosen as lead molecules for further development. Further studies on the effects of harmine derivatives on key regulators for tumor cell apoptosis are needed.

Synthesis and biological evaluation of novel 4-hydroxybenzaldehyde derivatives as tyrosinase inhibitors.

A series of novel 4-hydroxybenzaldehyde derivatives were synthesized and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were investigated. Most of target compounds had more potent inhibitory activities than the parent compound 4-hydroxybenzaldehyde (IC(50)=1.22 mM). Interestingly, compound 3c bearing a dimethoxyl phosphate was found to be the most potent inhibitor with IC(50) value of 0.059 mM. The inhibition kinetics analyzed by Lineweaver-Burk plots revealed that compound 3c was a non-competitive inhibitor (K(I)=0.0368 mM). In particular, compound 3c showed no side effects at dose of 1600 mg/kg in mice. These results suggested that such compounds might be served as lead compounds for further designing new potential tyrosinase inhibitors.

Design, synthesis and 3D-QSAR of β-carboline derivatives as potent antitumor agents

In a continuing effort to develop novel beta-carbolines endowed with better pharmacological profiles, a series of beta-carboline derivatives were designed and synthesized based on the previously developed SARs. Cytotoxicities in vitro of these compounds against a panel of human tumor cell lines were also investigated. The results demonstrated that the N2-benzylated beta-carbolinium bromides 56-60 represented the most potent compounds with IC50 values lower than 10 microM. The application of 3D-QSAR to these compounds explored the structural basis for their biological activities. CoMFA (q2=0.513, r2=0.862) and CoMSIA (q2=0.503, r2=0.831) models were developed for a set of 47 beta-carbolines. The results indicated that the antitumor pharmacophore of these molecules were marked at position-1, -2, -3, -7 and -9 of beta-carboline ring.

NaoXinQing, an anti-stroke herbal medicine, reduces hydrogen peroxide-induced injury in NG108-15 cells

NaoXinQing (NXQ) is a patented and approved drug of Traditional Chinese Medicine that has been used for years for the treatment of syndrome of apoplexy, but the underlying mechanism remains unclear. The present study is designed to investigate the effects of NXQ on hydrogen peroxide (H(2)O(2))-induced cell damage in NG108-15 cells. Exposure to H(2)O(2) induces apoptosis-like cell injury. Preincubation of cells with NXQ alleviated H(2)O(2)-induced cell injury and apoptosis. This herb medicine also improves redox imbalance in cells under the exposure of H(2)O(2) as indicated by the attenuation in the reduction of activities of intracellular endogenous antioxidants, glutathione and glutathione peroxidase as well as catalase, and by the decrease in the leak of lactate dehydrogenase and the accumulation of malondialdehyde. These results indicate that NXQ significantly protects NG108-15 cells against H(2)O(2) challenge by improving redox imbalance and inhibiting apoptosis, which might represent mechanisms underlying its potential usage in the prevention and treatment of syndrome of apoplexy.

Synthesis of novel β-carbolines with efficient DNA-binding capacity and potent cytotoxicity

A series of water-soluble beta-carbolines, bearing a flexible amino side chain, was prepared and evaluated in vitro against a panel of human tumor cell lines. The N(9)-arylated alkyl substituted beta-carbolines represented the most interesting cytotoxic activities, and compound 7b was found to be the most potent antitumor agent with IC(50) values lower than 10microM against eight human tumor cell lines. The results confirmed that the N(9)-arylated alkyl substituents of beta-carboline nucleus played an important role in the modulation of the cytotoxic potencies. In addition, these compounds were found to exhibit significant DNA-binding affinity.

Synthesis of 4-[(diethylamino)methyl]-phenol derivatives as novel cholinesterase inhibitors with selectivity towards butyrylcholinesterase.

A series of novel cholinesterase inhibitors, being composed of 4-[(diethylamino)methyl]-phenoxy and secondary amine which were linked with a different length alkyl chain, were designed and synthesized from the starting material p-hydroxybenzaldehyde. These compounds were evaluated as acetylcholinesterase and butyrylcholinesterase (AChE/BChE) inhibitors. Compounds 25-31 having a secondary amine moiety connected to the phenyl ring via eight CH(2) units spacer were found to be the most potent inhibitors with IC(50) value lower than 220nM and 48nM against AChE and BChE, respectively. Interestingly, these inhibitors showed a surprising selectively toward BChE, and compounds 26, 27, and 30 displayed 12.5, 18.6, and 18.8-fold higher affinity to BChE. The inhibition kinetics analyzed by Linewear-Burk plots revealed that such compounds were mix-type inhibitors.

Apoptosis of a human non-small cell lung cancer (NSCLC) cell line, PLA-801, induced by acutiaporberine, a novel bisalkaloid derived from Thalictrum acutifolium (Hand.-Mazz.) Boivin

Acutiaporberine is a novel ether-linked bisalkaloid isolated from the traditional Chinese medicinal herb Thalictrum acutifolium (Hand.-Mazz.) Boivin (TAB). The present study demonstrates for the first time, by means of nuclear staining, DNA agarose gel electrophoresis, and flow cytometry, that acutiaporberine induces apoptosis in PLA-801 cells, a cultured human non-small cell lung cancer (NSCLC) cell line. An immunohistochemical assay and western immunoblot analysis showed down-regulation of the bcl-2 gene and up-regulation of the bax and c-myc genes in the acutiaporberine-treated cells. The observations also indicate that acutiaporberine induces apoptosis of PLA-801 cells in a concentration- and time-dependent manner. These results suggest that acutiaporberine may be a potential, natural apoptosis-inducing agent for NSCLC.

Synthesis and cytotoxic evaluation of N2-benzylated quaternary β-carboline amino acid ester conjugates

The beta-carboline alkaloids have been characterized as a class of potential antitumor agents. To further enhance the cytotoxic potency and improve water solubility of beta-carboline, a series of new beta-carboline amino acid ester, beta-carboline amino acid and N(2)-benzylated quaternary beta-carboline amino acid ester conjugates were designed and synthesized, and the cytotoxic activities of these compounds were evaluated using a panel of human tumor cell lines. The N(2)-benzylated quaternary beta-carboline amino acid ester conjugates represented the most interesting cytotoxic activities. Particularly, compounds 8b and 8g were found to be the most potent compounds with IC(50) values lower than 20 microM against all human tumor cell lines investigated. These results confirmed that the N(2)-benzyl substituent on the beta-carboline ring played an important role in the modulation of the cytotoxic potencies.

Synthesis and antibacterial evaluation of novel 4-alkyl substituted phenyl β-aldehyde ketone derivatives

A series of novel 4-alkylphenyl beta-aldehyde ketones and their derivatives were designed and synthesized on the basis of the chemical structures of Houttuynin and beta-lactam antibiotics. Antibacterial activities of these compounds were investigated. The results demonstrated that most of the compounds tested had moderate antibacterial activities against gram-positive pathogen Staphylococcus aureus (ATTC-25923) than Houttuynin, and gram-positive bacteria were more susceptible to the compounds than gram-negative bacteria. Compound 23 was found to be the most potent compound with MIC of 1.0 microg/mL against S. aureus. Particularly, compounds 16, 22 and 23 showed more active antibacterial activities against the clinically important pathogenic bacteria, methicillin-resistant S. aureus (MRSA) than Houttuynin and levofloxacin. The preliminary structure-activity relationship (SAR) analysis suggested that (1) the introduction of appropriate alkyl substituents into position 4 of phenyl ring enhanced antibacterial activities of these compounds, and isopropyl substituent might be more favorable; (2) the presence of ketone carbonyl moiety might play a vital role in determining significant antibacterial activities of these compounds.