Letters in Drug Design & Discovery - Volume 3, Issue 8, 2006

Chemotherapy and immunotherapy are two distinct approaches for the treatment for high-grade gliomas. Used independently, neither is curative. However, if the appropriate chemotherapeutic agent is selected and its administration is timed in conjunction with immunotherapy, a potent synergistic effect may occur, resulting in a more favorable outcome.

Brostallicin, a specific adenine-thymine minor groove binder belonging to a new class of distamycin A-derivatives, proved to be active in vitro against a panel of human tumor cell lines. We demonstrated here the cytotoxic and apoptotic potential of this compound on gastric and colon cancer cell lines with either wt or mutated p53.

Palladium(II) acetate complexes with diethyl 8-quinolylmethylphosphonate (8-dqmp) and monoethyl 2- quinolylmethylphosphonate (2-Hmqmp) were synthesized and evaluated for their cytotoxic and antiviral activity in vitro in different cell lines. Structure-activity relationship studies comprise acetate and chloro complexes of the phosphonate ligands. Cell growth inhibitory effects in micro molar range were observed for the dichloro adduct and acetate bridged dimer of 8-dqmp.

Overcoming chemotherapy and radiation resistance presents one of the greatest obstacles to improving clinical outcome for the majority of solid cancers. Chemotherapy and radiotherapy owe their clinical efficacy to their ability to kill cancer cells. A significant body of evidence has established programmed cell death, or apoptosis, as a final common pathway by which these modalities mediate cancer cell kill. The multi-domain BCL-2 family proapoptotic proteins BAX and BAK are critical regulators of mitochondrial outer membrane permeability (MOMP), a switch that irreversibly pushes cells into apoptosis. Several cancers commonly express at least one or more antiapoptotic BCL-2 family members, capable of arresting BAX and BAK activation. These proteins are now targets for a new generation of small molecule inhibitors that have the potential to mediate apoptosis sensitisation and therefore reverse clinical drug resistance. Development of several small molecule mimics of the BH3 domain has been based on a variety of methods including molecular modelling, ligand mimicry, natural library screening and perhaps most successfully, synthetic library screening. Novel BH3 mimetics with BAX BAK derepressing activity are now entering the clinic and may provide real opportunities for improving the efficacy of current therapy. This review focuses on small molecule inhibitors of the BCL-2 family proteins and their potential application in cancer therapies.

The epidermal growth factor receptor (EGFR) provides survival signals and is overexpressed in the majority of colorectal cancer. Cetuximab is a recombinant human/mouse monoclonal antibody(MoAb) against EGFR, clinically active in the treatment of human colorectal cancer. Unlike the predictable correlation of response to trastuzumab, another MoAb clinically active in a subgroup of breast cancer patients expressing HER-2/neu, responses to cetuximab in EGFR-expressing colorectal cancer is not predictable. The search for a reliable marker that would allow clinicians to select patients for cetuximab therapy remains a major challenge.

Combretastatin A-4 (CA-4) is a potent anti-tumor agent, which strongly inhibits tubulin polymerization. A common problem is the inactivation of derivatives with cis-configurated ethylene bridges during storage. β-Lactam analogs of CA-4 were synthesized in order to avoid isomerization to E-forms. Moreover, B-ring modifications (3,4,5-trimethoxyphenyl ring, furan ring) were studied with regard to biological activity. Their cytotoxic effects were evaluated in vitro against L1210 leukemia cell. The derivatives might provide some rational basis for further optimal structural modification.

We investigated the synthesis of the disaccharide units of Manβ(1→ 6)Manα1→ OPh, Manα(1→ 6)Manα1→ OPh and Glcα(1→ 6)Manβ1→ OPh as the analogues of the α(1→6) arm of the mannotrisaccharide core in N-linked glycopeptides using the dimethylphosphinothioate method. Studies using a surface plasmon resonance optical biosensor indicated that the Manβ(1→6)Manα1→ OPh had an association constant of 1.15 104 M-1 for immobilized Concanavalin A, which almost corresponded to that of the Manα(1→ 6)Manα1→ OPh.

Protein tyrosine kinase (p56lck) is known for its role in T cells, in which deficiency of Lck is shown to impair cell activation via T-cell antigen receptor. Benzothiazoles have been reported to be the molecules of interest, with potent anticancer activity and they act by binding to ATP binding site of protein kinases. ATP binding site of protein kinases provided an extensive opportunity to design newer analogs. With this background, we report an attempt to discern the structural and physicochemical requirements for inhibition of p56lck. QSAR studies were performed on a set of 45 analogs of benzothiazoles using Molecular Operating Environment (MOE) software. The models developed gave good predictive correlation coefficient (r2pred) of 0.765. A training set of 35 compounds was developed with correlation coefficient (r2) of 0.983 and a significant cross validated correlation coefficient (q2) of 0.723. Various sets of descriptors to meet the orthogonality of model to ensure that each descriptor is encoding different properties from others were used. Subdivided surface area, water accessible surface area, partial charge and adjacency and distance matrix were the major contributing descriptors. Leave one out and $ Z-score values were used to optimize the model. The model developed to predict the structural features of benzothiazole, revealed useful information about the structural features required for the molecules to inhibit p56lck. Major contributing descriptors were subdivided surface area, partial charges and water accessible surface area.

During peptidoglycan recycling in Escherichia coli, L, D-carboxypeptidase A cleaves the tetrapeptide L-Ala-γ-D-Glu-meso-diaminopimelic acid-D-Ala, producing tripeptide and D-Ala. Previous studies utilized substrate purified from bacteria, with HPLC detection of tripeptide. Herein, synthetic peptide substrate containing L-Lys in place of diaminopimelic acid, and a fluorescent assay for D-Ala, were used to identify a benzoxazine as a non-β-lactam inhibitor of the enzyme.

Receptors that undergo nucleo-cytoplasmic shuttling require microtubules for proper physiologic function. Is it the collapse of microtubules network or simply the arrest of cell cycle in G2/M phase that changes receptors function? The terms of disengagement and the integrity versus dynamics of the microtubules shall guide the ideal drug design.

Most drugs initiate their effects by binding to a drug target. The kinetics of binding have the potential to influence the utility of a drug. Physiology uses the magnitude of kinetic barriers to differentiate between reversible and irreversible states, leading to differentiated phenotypes. Under the appropriate circumstances the therapeutic index of some drugs is influenced by the kinetics and reversibility of a system. The ability for differentiated binding kinetics to define irreversible or reversible states and the impact of these differentiated states on a clinical outcome is proposed here to contribute to the magnitude of gastrointestinal toxicity observed with nonsteroidal anti-inflammatory agents (NSAIDs). This example and others highlight the potential for differentiated binding kinetics to provide clinical differentiation.

The “cure” for the ever rising cost of in vitro ADME screening performed to support drug discovery may be readily at hand. Rationally putting into practice and real use existing in silico technology based on available ADME data can reduce costs in terms of volume of ADME screening and in some cases compound generation (potential compounds predicted to have poor attributes would not be synthesized). It is clear that in order for an in silico model to be successful; its development must require not only reliable and relevant data input, but also clarity and realistic expectations of its output. This work focuses on the development and application of an in silico passive apparent permeability (Papp) model, created with a specific purpose and end user in mind (i.e., medicinal chemist & pharmacokineticist working in early drug discovery). In addition, this work describes how this in silico model can be used in combination with experimental permeability screens such as PAMPA (Parallel Artificial Membrane Permeability Assay) & MDCK (Madin Darby Canine Kidney) cells to further guide drug discovery while enabling a resource sparing approach.

Circulating oxidized low-density lipoprotein (LDL) is a biochemical risk marker for cardiovascular disease in humans. Several groups have developed specific enzyme-linked immunosorbent assay systems to measure plasma levels of oxidized LDL. However, most of the studies did not address the issue whether circulating oxidized LDL that they measured could exert actually atherogenic properties on endothelial cells (ECs). In this study, we purified oxidized LDL from human plasma with a modified high performance liquid chromatographic (HPLC) method using a diethylaminoethyl-type anion-exchange gel column and then examined the effects of oxidized LDL on ECs. Our HPLC method separated LDL into three fractions, which were designated LDL-1, -2, and -3 by their elution order. LDL-3, the most strongly retained fraction identified as oxidized LDL not only induced apoptotic cell death, but also stimulated monocyte chemoattractant protein-1 production in cultured human umbilical vein endothelial cells, both of which were blocked by the treatment with an anti-oxidant N-acetylcysteine. The present results demonstrate that oxidized LDL present in human plasma is pro-apoptotic and pro-inflmmatory to ECs, thus suggesting the active participation of plasma oxidized LDL in the process of atherosclerosis. Our HPLC method for measuring plasma levels of oxidized LDL may be useful to evaluate the efficacy of novel therapeutics on atherosclerosis.

In this paper we review and discuss three of the most exciting and promising cytokines for therapeutic intervention and immunomodulation of immune responses including those on mucosal surfaces. The main properties of IL-12, IL-15 and IL-7 are described and the studies utilizing these cytokines as immunomodulators and vaccine adjuvants discussed.