Dexniguldipine (B8509-035, (-)-(R)-niguldipine) is a new dihydropyridine derivative, that exerts selective antiproliferative activity in a variety of tumor models and, in addition, has a high potency in overcoming multidrug resistance. Dexniguldipine is ( - )-(R)-enantiomer of niguldipine, of which the ( )-(S)-enantiomer shows pronounced cardiovascular hypotensive activity due to its high affinity for the voltage-dependent Ca2 channel. As compared with the (S)-enantiomer, the (R)-enantiomer has a 40-fold lower affinity for the Ca 2 channel and, accordingly, only minimal hypotensive activity in animal pharmacology models. Dexniguldipine have shown antiproliferative activity in several tumor cell lines, but the concentrations necessary to inhibit growth have varied by several orders of magnitude between cell lines. Initial results of preclinical investigations for the evaluation of the mechanism of its antiproliferative activity demonstrate that dexniguldipine interferes with intracellular signal transduction by affecting phosphoinositol pathways, protein kinase C expression, and intracellular Ca 2 metabolism. In a series of human tumor xenografts in vitro, dexniguldipine demonstrated selective antiproliferative activity against several tumor types, e.g., melanoma and renal-cell carcinoma. Striking results were obtained in a hamster model, in which neuroendocrine lung tumors could be completely eradicated by 20 weeks of oral treatment with 32.5mg/kg dexniguldipine, whereas Clara-cell-type lung tumors were not affected. In in vitro studies, dexniguldipine has been found to bind to P-glycoprotein (P-gp) and to enhance the cytotoxicity of chemotherapeutic agents such as doxorubicin and etoposide in several cell lines The synergistic effect may well be associated with the reversal of multidrug resistance (MDR) related to the activity of P-gp. In the clinical therapy of cancer, resistance to many cytostatic drugs is a major cause of treatment failure. However, the high potency of dexniguldipine (about 10-fold as compared with that of verapamil in vitro) and its low cardiovascular activity provide the opportunity to achieve blood or tumor concentrations that might be high enough to overcome Mdr 1 resistance in patients without producing dose-limiting cardiovascular effects.

Swainsonine is an indolizidine alkaloid found in Australian Swainsona canescens, North American plants of the genera Astragalus and Oxytropis and also in the fungus Rhizoctonia leguminocola. It is competitive inhibitor of Golgi alpha-mannosidase II and lysosomal alpha-mannosidases. This compound has been reported to be a potent antiproliferative and immunomodulatory agent. However, no evidence of anti-tumor activity of swainsonine was seen in phase II clinical trial, in patients with locally advanced or metastatic renal cell carcinoma. Adverse events such as fatigue, nausea and diarrhea were common but generally mild. Swainsonine is locoweed toxin. Locoweed poisoning is seen throughout the world and annually costs the livestock industry millions of dollars. Swainsonine inhibits lysosomal alpha-mannosidase and Golgi mannosidase II. Poisoned animals are lethargic, anorexic, emaciated, and have neurologic signs that range from subtle apprehension to seizures.

Xanthohumol is a prenylated flavonoid most abundant in hops. It is found in beers and refreshment drinks. It can attenuate several factors of the metabolic syndrome. It has been reported to inhibit adipogenesis or increase cell apoptosis and therefore can be used in preventing obesity. Xanthohumol inhibited angiogenesis by suppressing NF-κB activity in pancreatic cancer. Xanthohumol may represent a novel therapeutic agent for the management of pancreatic cancer. Moreover, it is in phase I clinical trials for preventing many types of cancer. It has a range of other biological properties: antiviral, antimalarial, antibacterial and as an osteoporosis preventing agent.

Pepstatin is a pentapeptide of microbial origin. The peptide inhibits the acid proteases pepsin and cathepsin D and the pressor enzyme renin. Pepstatin was shown to provide long-lasting inhibition (3 to 6 days) of cathepsin D in vivo in non-tumor bearers particularly in spleen, liver, kidney, lung, and heart. Pepstatin may prove useful as "anticachexia" agent by decreasing proteolysis in muscle and other tissues. The in vivo pepstatin and IL-2 treatment decreased the T-cells and increased the natural killer-like LAK precursor cells, possibly also with an increase in its activity, which were further induced by in vitro IL-2 culture to generate an augmented LAK cell activity. This suggests the clinical potential of pepstatin in IL-2-related immunotherapy. In rats injected centrally with the specific cathepsin D inhibitor, pepstatin, the protease activity was inhibited up to 90% in most brain regions.

Trigonelline is a pyridine derivative known to contribute indirectly to the formation of desirable flavor products, including furans, pyrazine, alkyl-pyridines, and pyrroles, during coffee roasting. The amount of trigonelline in arabica is higher than that in robusta green coffee beans, and thus it can be used as a marker compound to distinguish the coffee bean species. During the roasting process of coffee beans, trigonelline changes into N-methylpyridinium and nicotinic acid as its major products, which makes it a useful index of the degree of roasting. The importance of trigonelline in coffee is connected to nutritional aspects. It has been revealed in recent studies that the administration of trigonelline allows diabetic rats to avoid diabetes-related organ damage and live longer, which can make it a potentially strong candidate for industrial application as a pharmacological agent for the treatment of hyperglycemia, hyperlipidemia, and liver/kidney dysfunctions. In addition, the urinary concentrations of trigonelline and its thermal product N-methylpyridinium of coffee drinkers are higher than those of noncoffee drinkers, which indicates that trigonelline and N-methylpyridinium may have potential as dietary biomarkers that could be used as analytical probes to control compliance in human intervention studies on coffee. Trigonelline has been isolated from many plants: fenugreek seeds (Trigonella foenum-graecum, hence the name), garden peas, hemp seed, oats, potatoes, Stachys species, dahlia, Strophanthus species, and Dichapetalum cymosum. In a randomized cross-over trial, the critical effect of Trigonelline on glucose tolerance has been studied during a 2-hour oral glucose tolerance test (OGTT) in 15 overweight men. Results showed that glucose and insulin concentrations significantly reduced 15minutes after Trigonelline consumption compared with placebo.

Finrozole is a nonsteroidal competitive aromatase inhibitor that is being evaluated in Phase II trials for the treatment of lower urinary tract symptoms associated with reduced androgen/estrogen ratio in aging males associated with benign prostatic hyperplasia. But this research was discontinued in 2005. In dimethylbenzanthracene-induced rat mammary carcinoma model, Finrozole causes regression of more than 80% of the established tumors. The hormone-dependent mammary tumors are inhibited to a level seen in ovariectomised animals.

Fostriecin, an antitumor antibiotic produced by Streptomyces pulveraceus, is a strong inhibitor of serine/threonine protein phosphatases type 2A and type 4, and inhibits the catalytic activity of partially purified Topo II (type II topoisomerase) in a non-competitive manner.

Dofequidar (MS-209), a quinolone-derived sphingomyelin synthase inhibitor that blocks P-glycoprotein and multidrug resistance-associated protein-1, is under development by Schering for the potential treatment of multidrug resistant tumors. MS-209 had been in phase III clinical trials for the treatment of breast cancer and non-small lung cancer. But this research was discontinued in 2004. Detected adverse events are: nausea, vomiting, leukopenia, neutropenia, anorexia, constipation.

Acridine Orange is a cell-permeant nucleic acid binding dye that emits green fluorescence when bound to double-stranded DNA and red fluorescence when bound to single-stranded DNA or RNA. This unique characteristic makes acridine orange useful for cell-cycle studies. Acridine orange has been widely accepted and used in many different areas, such as epifluorescence microscopy, the assessment of sperm chromatin quality. Acridine orange stain is particularly useful in the rapid screening of normally sterile specimens, and its recommended for the use of fluorescent microscopic detection of microorganisms in direct smears prepared from clinical and nonclinical materials. The staining has to be performed at an acid pH in order to obtain this differential staining effect with bacteria showing orange stain and tissue components yellow to green. Acridine orange can be used in conjunction with ethidium bromide to differentiate between viable, apoptotic and necrotic cells. Additionally, acridine orange may be used on blood samples to cause bacterial DNA to fluoresce, aiding in the clinical diagnosis of bacterial infection once serum and debris have been filtered. Acridine orange can be used in photodynamic Cancer Therapy.

JNJ-26854165 (Serdemetan), a novel tryptamine derivative, was developed as an activator of p53, and its initially proposed mechanism of action involved preventing the association of HDM2 with the proteasome and thereby stabilizing HDM2 substrates such as p53. Consistent with this proposed mechanism, Serdemetan induced apoptosis in acute myeloid and lymphoid leukemia cell lines and in primary acute leukemia isolates. Serdemetan is currently being evaluated in Phase I clinical trials in patients with non-small cell lung cancer; prostate cancer; solid tumours.