Letters in Drug Design & Discovery - Volume 2, Issue 6, 2005

Chemotherapy can result in partial or temporary remission, but often does not completely eradicate cancer. The treatment failures are, at least in part, due to tumor cell resistance to chemotherapeutics. One contributing factor for impaired responses to chemotherapy is that only proliferating cells are affected by the action of chemotherapeutic drugs (kinetic resistance of tumors). Another contributing factor is the genetic resistance mediated by genes encoding proteins such as ABC transporters. A basic understanding of changes associated with tumorigenesis is needed to design and deploy novel and effective strategies for treating cancers. This paper focuses on aspects of energy flow and entropy in tumorigenesis and changes in the interaction between cancer cells and the host. We propose that correlating those changes with the progression of tumors will assist in the design and deployment of novel and more efficacious strategies for chemotherapy and combined therapies.

Triple therapy with octreotide, galanin and serotonin reduces the volume and weight of both rat and human colon carcinoma in xenografts. The reduction in tumour volume and weight seems to be caused by tumour necrosis, reduced proliferation and decreased expression of epidermal growth factor EGF of cancer cells, as well as induction apoptosis in cancer cells. Tumour necrosis has been suggested to be caused by induction of tumour ischemia due to a reduction in the tumour blood flow, which is caused by decreased incidence of tumour-feeding blood vessels and by constrictions of tumour feeding arterioles. The effects of single, double and triple therapy with octreotide, galanin and serotonin on rat colon cancer have shown that galanin alone reduced significantly the tumour-feeding blood vessels. The single and double treatment had a certain effect, but far from the triple treatment. Triple therapy had no apparent side effects. Triple therapy has equivalent antitumour and therapeutic efficacy as standard treatment with 5-fluorouracil/leucovorin. Triple therapy prolongs the survival rate of the mice bearing human pancreatic carcinoma and decreased both the volume and weight of tumours. However, the proliferation index and the labelling index for EGF were increased. It did not affect the apoptotic index, necrosis, or density of tumour blood vessels. In vitro investigations with single and double combinations of octreotide, galanin and serotonin have shown that single treatment with octreotide or serotonin reduces the number of viable cells and the proliferation index. Galanin increases the number of viable cells and the proliferation index. It has been concluded that treatment with a combination of octreotide, serotonin and galanin antagonist may be useful in clinical settings. The effect of triple therapy on gastric cancer is doubtful.

We reported that the extract of Mulgedium tatarica DC. exhibits anticancer activity. With the help of a tumor cell killing bioassay, the sesquiterpene lactones lactucopicrin (1), 11,13β-dihydrolactucopicrin (2), lactucin (3) and 11,13β-dihydrolactucin (4) were isolated and identified from this medicinal herb. SAR studies indicate that the ester group at position 8 and the exocyclic methylene group at position 11 play a major role in anticancer activities of lactucin-like guaianolides, a kind of sesquiterpene lactone.

2-Phenyl-5,6-dihydroxypyrimidine-4-carboxylic acids were discovered as specific inhibitors of the NS5B polymerase of the Hepatitis C Virus. In-depth structure-activity investigations at the ortho and meta positions of the phenyl ring were undertaken, and compounds with greatly improved activity over the original lead have been discovered.

5,6-Dihydroxypyrimidine-4-carboxylic acids are a promising series of hepatitis C virus (HCV) NS5B polymerase inhibitors that bind at the active site of the enzyme. Here we report the evolution and SAR of a series of 2-{2-[(arylsulfonyl)amino]phenyl analogues that show greater than 2 orders of magnitude improved activity over the original lead.

Methionine aminopeptidase type 2 catalyzes the removal of the amino-terminal methionine from newly translated polypeptides and has been shown to be a promising target for anti-angiogenesis and anticancer drugs. We describe a novel μARCS HTS method to identify inhibitors of this target utilizing porous matrices to introduce reagents throughout the assay. A library of 250,000 compounds was screened and compounds with IC50 values of less than 10μM were identified. These compounds may serve as initial lead molecules for further medicinal chemistry optimization.

The current antiretroviral regimens in the long run, can lead to poor adherence to treatment, to emergence of resistant viral strains and different adverse effects limiting benefits of HAART. A variety of novel treatment strategies have been proposed to help the long-term management of HAART. The principal innovative therapeutic strategies under investigation will be discussed: treatment simplification, once daily regimens, structured or response guided treatment interruptions and proactive antiretroviral switching.

We have developed a general strategy for the selection of genes that encode active enzymes. In our strategy, the product of a catalytic reaction in vivo is displayed on secreted phage via the g8p protein. The subsequent affinity-capture of the product in vitro results in enrichment of the gene that encodes an active enzyme. In a model study, we succeeded in the selection of a gene for biotin protein ligase.

Although iron is essential in maintaining the function of the central nervous system, it is a source of reactive oxygen species, which is potentially neurotoxic. Excess iron accumulation has been reported to be associated with many neurodegenerative diseases including Alzheimer disease. Because oxidative damage to neurons is suggested to be an early event of Alzheimer disease, iron deposition in the central nervous system may play a pivotal role in its pathogenesis. In fact, in Alzheimer disease, iron has been demonstrated histochemically to be present in senile plaques and neurofibrillary tangles, the main constituents being amyloid-β and tau, respectively. Since these molecules are key in the pathogenesis of Alzheimer disease, many studies have focused on the relationship of iron with them. However, it has been shown that the oxidative change in neurons is observed before the formation of these pathological hallmarks. This review discusses the suggested role of iron in the progression of Alzheimer disease.

We describe a method for locating and characterizing the optimal binding site for ligands on the surface of a protein of known structure. The method identifies the contiguous constant-volume region with the most favorable binding affinity using a grid-based representation of interaction energies between the ligand and protein. By scanning through a range of ligand volumes and following the value of the average binding affinity per unit volume, optimal binding sites may be identified and ranked, and the ideal size for a ligand may be identified for each binding site. For use in drug design, the ideal volumes identify regions of primary binding affinity and regions of suboptimal binding strength. We demonstrate the utility of the method in design of inhibitors for HIV-1 protease.

Thirteen imidazolone derivatives were synthesized and characterized by 1H NMR, EI, IR and UV spectroscopic and CHN analysis. Among the compounds tested, two compounds, 3-hydroxy-2-phenyl-5-[Ephenylmethylidene]- 3,5-dihydro-4H-imidazol-4-one (12) and 4-[E-(5-methyl-2-furyl) methylidene]-1,2- diphenyl-1H-imidazol-5-one (13) shown to have suppressing activities on the oxidative burst of neutrophils. These two compounds were then further investigated for their effects on different cellular immune responses including neutrophils, phagocytosis and chemotaxis activities of T-cell proliferation, and cytokine production from mononuclear cells. The results demonstrate that compounds 12 and 13 inhibit reactive oxygen species (ROS) generation and phytohemagglutinin (PHA)-induced T-cell proliferation in a dose dependent manner.