Letters in Drug Design & Discovery - Volume 1, Issue 3, 2004

The human immunodeficiency virus (HIV), a retrovirus, is known to cause the acquired immunodeficiency syndrome (AIDS) as the HIV infection develops. Efforts on searching new anti-HIV agents to provide effective treatment of HIV infection / AIDS have never been slowed down since the discovery of HIV. Nowadays a promising area of research has focused on preventing HIV entry into host cells, called entry inhibitors, which work differently from the approved anti-HIV drugs. With the discovery of the x-ray crystal structure of the gp120 / CD4 / antibody complex, we have a better understanding of how HIV enters the host cell at the molecular level. These findings undoubtedly provide insights into the development of new drugs or vaccines that might prohibit host cell entry of HIV. Despite their novel mechanism of action, the potential benefits of entry inhibitors are also their potential action against drug-resistant HIV strains, minimal side effects and simplified dosing. The aim of the present article is to make a review to discuss the important compounds HIV-1 entry inhibitors in clinical development, as well as potential compounds under biological evaluation.

We present the SAR study that led us to identification of the first inhibitors of type 7 17β- hydroxysteroid dehydrogenase (17β-HSD). The conversion of E1 into E2 is reduced by nearly 90 % by 17β-(Nalkylformamido)- 4-methyl-4-aza-5α-androstan-3-one compounds bearing a side chain containing 7 to 10 carbon atoms when tested at 0.3 μM.

Several 6H-indeno[1,2-c]isoquinolin-5,11-diones and 5H-dibenzo[c,h][1,6]naphthyridin-6-ones were synthesized and evaluated for their relative topoisomerase I-targeting activity and cytotoxicity. Comparative studies were performed in P388, RPMI8402, and U937 tumor cell lines, as well as their camptothecin-resistant variants, i.e. P388 / CPT45, CPT-K5, and U937 / CR, respectively. The relative cytotoxic activity of these compounds in cell lines known to overexpress efflux transporters that are associated with multidrug resistance or are known to be resistant to topoisomerase II-targeting agents was also determined. Our results suggest that some of these compounds are highly potent TOP1-specific poisons with cytotoxic activity rivaling that of camptothecin and different drug-resistant profiles.

Peptide based vaccine design for cancer immunotherapy is currently being used in clinical trials for malignant melanoma with much success. Administration of synthetic peptides derived from proteins overexpressed in tumour cells (tumour-associated antigens) can elicit tumour-specific CD8+ T cell responses in vitro and in vivo. Currently, a number of tumour antigens from overexpressed cancer proteins such as mucin 1 (MUC1), survivin, carcinoembryonic antigen (CEA), telomerase reverse transcriptase (TERT) and HER- 2 / neu are examples of cancers whereby peptide based vaccinations are being tested for potential immunotherapy. In this review, we discuss some examples of the work being investigated with these cancer proteins, limitations to this therapy and suggestions of future directions to improve the efficacy of this treatment.

Asthma has reached epidemic proportions with approximately 200 million individuals affected worldwide. The disease is characterized by an oxidant / antioxidant imbalance in the lungs leading to activation of redox-sensitive transcription factors e.g. activator protein 1 (AP-1) and nuclear factor kappa B (NF-kappa B). We have previously described PNRI-299, a small molecule beta-strand mimetic template compound, as an inhibitor of the multifunctional AP endonuclease / redox factor 1 (Ref-1) [1]. PNRI-299 has demonstrable effects on the reduction of AP-1 driven transcription and beneficial pharmacological effects in a mouse asthma model. We now report the synthesis of this molecule and the effects of PNRI-299 on the expression of Leukotriene C4 (LTC4) synthase, a crucial enzyme for the formation of the cysteinyl leukotrienes.

Detailed SAR examination and DIStance COmparison (DISCO) computation were used for identification and superposition of common structural features of 2,3-benzodiazepines with high affinity to an allosteric AMPA binding site. Two similar 4-point models were identified; both contained 2 donor sites, a donor atom and a hydrophobic centre. At one of the donor sites a characteristic difference between the two models was observed.

Imidazopyridines and imidazopyrimidines have been prepared and tested for their antibacterial activity in vitro. Structure activity relationship studies indicate (SAR) that a modulation of both natures of arm in position 3 and atom in position 8 of these compounds has a direct impact on the antibacterial activity.

Antimicrobial peptides are essential components of the innate immunity of all animal species. These peptides have a broad range of activity against resistant microorganism strains primarily because of their distinct mechanisms of action. Several groups are currently developing synthetic and / or variant peptides as new therapeutic drugs against specific pathogens.

The proteome is described as the entirety of all proteins expressed within a cell at a given moment. In contrast to the stability of the genome, the proteome is highly dynamic and reflects the cell's current status. Since proteins carry out almost all biological functions, the proteome stands in direct relation to cellular functions. Proteomic analysis (i.e., two-dimensional electrophoresis, mass spectrometry and bioinformatics) aims at identifying changes in the composition of the proteome associated to pathophysiologic events that affect basic cellular functions. Functional proteomics expands to understanding the connection between proteomic changes and the state of a cell, taken into account that the observed modifications can be either cause or consequence of the pathological state. Proteomics will not only improve our basic understanding of the factors and molecular mechanisms underlying cardiovascular disease, but also will help identifying novel diagnostic markers and fuel the rational design and discovery of new drugs for medical intervention. This review will discuss basic proteomic approaches relevant to cardiovascular disease, as well as their applications for the identification of biomarkers and drug design.

Development of a water-soluble prodrug of doxorubicin-formaldehyde conjugate, a labile, active metabolite of doxorubicin, is described. The lead compound is the doxorubicin-salicylamide N-Mannich base, N-(2-hydroxybenzamidomethyl)-doxorubicin (doxsaliform), prepared in 72% yield from reaction of salicylamide with doxorubicin in the presence of formaldehyde. Doxsaliform releases doxorubicin-formaldehyde conjugate under physiological conditions with a half-life of 57 min. The stability of the prodrug is augmented both by salt formation in acidic media and by covalent modification of the 2-hydroxyl of the salicylamide moiety. Doxsaliform is 4 fold more active than doxorubicin against MCF-7 breast and PC-3 prostate cancer cell lines and 10 fold more active against the doxorubicin resistant MCF-7 / ADR cell line.

A novel gene modulation system was identified within mammalian introns, regulating intracellular gene transcripts homologous to certain 5'-proximal non-snRNP-binding regions of spliced introns. This gene modulation system can be manipulated for the analysis of gene function and development of gene-specific therapeutics, using artificial introns with 5'-proximal hairpin inserts.

Apoptosis plays a major role in homeostasis as well as proliferation and differentiation. The important role of epithelial and endothelial cell apoptosis in lung injury and repair has been demonstrated. Modulating signaling molecules of apoptosis may be effective treatment against lung injury.

Atorvastatin therapy (20 mg / day given for 2 months) to hypercholesterolemic patients resulted in a reduction, by 59%, in their human monocyte-derived macrophages (HMDM) cholesterol content. The macrophage lipid peroxides content, and cell-mediated oxidation of LDL were reduced by 25% and 48% after atorvastatin therapy, as compared to the patients' macrophages before therapy. This therapy increased paraoxonases 2 (PON2) mRNA expression and activity by 76% and 200%, respectively. Similar results were obtained upon adding atorvastatin to macrophages in vitro. By adding acetylated-LDL or atorvastatin in the presence of mevalonate to macrophages from control healthy subject we were able to demonstrate that macrophage cholesterol content determines the extent of PON2 expression. The increased macrophage PON2 expression after atorvastatin therapy can be related to atorvastatin induced reduction in cellular cholesterol content. These beneficial effects of atorvastatin contribute to the attenuation of atherosclerosis development in hypercholesterolemic patients.

The stereospecific synthesis of nine trans-combretastatin analogs (5 - 13) is described. The trans geometry of these products was ascertained by the vinylenic proton NMR coupling constants of 15 - 16 Hz, and also by a single crystal x-ray structure of the tetramethoxy compound 6. Continuous 3-day exposure of murine B16 melanoma cells to the trans-combretastatin analogs 5 - 13 showed that two of the analogs (2 and 4) had good cytotoxicity. According to a MTT assay, the IC50 values for compounds 2 and 4 were 4.5 μM and 13.5 μM, respectively. Compounds that exhibited cytotoxic properties contain a 4,4'-dimethoxy-transstilbene skeleton.

Ischaemic diseases, a major public health problem worldwide, are associated with a decrease in oxygen supply to mitochondria that impairs respiration, energy production and constitute stimuli for cell death. This paper summarises the pharmacological strategies targeting the mitochondrial respiratory chain, which represents an interesting therapeutic perspective.

The thioxylation of the potent Neurokinin A antagonist MEN 10627 by Lawesson's reagent showed to be potentially useful for the post-synthetic manipulation of the related family of structurally peculiar bicyclic hexapeptides, whose synthesis in combinatorial manner has been recently described.

Rabies, a viral zoonosis is usually transmitted to humans through the bite of an infected animal. In many parts of the world, predominantly developing countries human rabies is still a disease of significant public health concern. Rabies also less frequently afflicts humans in the developed world, most cases occurring as the result of exposure to infected wild animals, especially rabid bats. Therapy administered following the onset of rabies symptoms is unsuccessful and the disease has a mortality rate of nearly 100% in humans. Post-exposure vaccination initiated shortly after exposure or prophylactic vaccination of humans considered to be at high risk to rabies virus exposure effectively controls or prevents infections. Current vaccines for human use are either based on brain derived or tissue culture grown inactivated rabies virus. Unfortunately, the former is inexpensive but associated with significant and often fatal side effects while the latter is safe but costly. The development of new, safe and affordable rabies vaccines is thus warranted. In recent years, researchers have developed second-generation recombinant viral and DNA vaccines for rabies. Overall, the DNA based rabies vaccines were found to be immunogenic in mice. However, the efficacy of these vaccines in larger species such as non-human primates was disappointing. Recombinant viral vaccines based on vaccinia or adenoviral vectors have demonstrated good efficacy in pre-exposure vaccination of rodents and of larger mammals, not withstanding they remain to be tested in post-exposure models.