Medicinal Chemistry - Volume 1, Issue 1, 2005

The field of medicinal chemistry has continued to expand rapidly, specially with the growing understanding of disease processes at the molecular level. This first issue of “Medicinal Chemistry” presents papers on recent advances in this field written by eminent experts. The articles on novel anti-malarials, anti-cancer agents, enzyme kinetics, sigma receptor binding SARS-cov genome sequences, apoptosis, lactoferrin interactions, immunotoxins and protease inhibitors should prove to be of considerable interest to researchers as well as the general community of medicinal chemists. It is hoped that “Medicinal Chemistry” would soon become an indispensable journal in this field.

Bruceantin (1), a classical quassinoid with the highest reported antimalarial activity among the quassinoids examined thus far, was selected as a natural product lead for the design of a series of A/B-ring analogs. A viable strategy for the synthesis of the series was developed. The functionalized A-ring and the C-15 ester moiety in bruceantin are incorporated in all designed compounds. The preliminary bioassay results will be discussed in detail.

The design, synthesis and DNA binding properties of a novel achiral and amino-containing secocyclopropylindoline analog (seco-amino-CI-TMI, 1) of the duocarmycins are described. Thermal induced DNA cleavage studies on pUC18 DNA revealed compound 1 to preferentially bind in the minor groove and to covalently react with ATrich sequences, particularly at the underlined adenine-N3 group of 5'-AAAAA(865)-3'. This sequence specificity is similar to adozelesin and CC-1065. Using a 4-day continuous exposure, compound 1 inhibited the growth of K562 human chronic myeloid leukemia cells in culture. Compound 1 has appreciable cytotoxicity (IC50 value of 1.30 μM) relative to compound 2 (0.15 μM), the corresponding racemic and hydroxy-seco-CI-TMI analog. These results indicate that the aminophenethyl chloride group present in compound 1 has similar sequence specific and cytotoxic properties to the hydroxy-containing seco-precursors of CC-1065 and the duocarmycins. Moreover, the results suggest that the chiral center present in the natural products is not absolutely necessary for biological activity. The novel aminophenethyl halide moiety is, therefore, a useful template from which to develop future achiral analogs of CC-1065 and the duocarmycins.

We demonstrate that a Bayesian approach (the use of prior knowledge) to the design of steady-state experiments can produce major gains quantifiable in terms of information, productivity and accuracy of each experiment. Developing the use of Bayesian utility functions, we have used a systematic method to identify the optimum experimental designs for a number of kinetic model data sets. This has enabled the identification of trends between kinetic model types, sets of design rules and the key conclusion that such designs should be based on some prior knowledge of the kinetic model. We suggest an optimal and iterative method for selecting features of the design such as the substrate range, number of measurements and choice of intermediate points. The final design collects data suitable for accurate modelling and analysis and minimises the error in the parameters estimated. It is equally applicable to enzymes, drug transport, receptor binding, microbial culture and cell transport kinetics.

Three new trishomocubane analogues based on the 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11] dodecane-3-ol skeleton have been synthesised and assessed for their affinities at both sigma-1 and sigma-2 receptors. The effect of various N-substitution on the polycyclic moiety was examined. All synthesised compounds displayed high affinity for sigma-1 receptors (9-10 nM) and good affinity for sigma-2 receptors (230-310 nM), suggesting that substitution at the nitrogen moiety of the trishomocubane is well tolerated and represents a platform for the development of improved higher affinity sigma receptor ligands. The interaction of these functionalised trishomocubanes on the binding of the known sigma receptor radioligand, 4-[123I]IBP, was evaluated in the rat brain. Although 4-[123I]IBP had been used for imaging sigma receptors in tumours, this is the first examination of sigma receptor binding in the rat brain and therefore the potential of 4-[123I]IBP for imaging the brain was also evaluated. In vivo specificity and selectivity of 4-[123I]IBP binding was examined by studying the effects of preadministration of sigma receptor binding drugs (+)-pentazocine and unlabelled 4-IBP. This resulted in a blockade of only 42% of 4-[123I]IBP uptake in the brain indicating high degree of non-specific binding suggesting that it may not be suitable for imaging sigma receptors in the brain. The inhibition of 4-[123I]IBP uptake using the two of the three trishomocubanes displayed a consistent blockade of 48-30% in all brain structures. This demonstrates for the first time the ability of functionalised trishomocubanes to interact with sigma receptors in vivo.

It has been observed by conducting an extensive analysis of the two-dimensional cellular automata images of known SARS-CoV genome sequences that the V-shaped cross-lines only exist in some special locations, and hence can be used as a fingerprint to identify the SARS sequences. Such a discovery can be used to rapidly and reliably diagnose SARS coronavirus for both basic research in laboratories and practical application in clinics.

Evidence that apoptosis plays an important role in the pathophysiology of lung diseases has been accumulated. Apoptosis signaling is classically composed of two principle pathways. One is a direct pathway from death receptor ligation to caspase cascade activation and cell death. Death receptor ligation triggers recruitment of the precursor form of caspase-8 to a death-inducing complex, through the adaptor protein FADD, which leads to caspase-8 activation. The other pathway triggered by stimuli such as drugs, radiation, infectious agents and reactive oxygen species is initiated in mitochondria. After cytochrome c is released into the cytosol from the mitochondria, it binds to Apaf1 and ATP, which then activate caspase-9. Recently, endoplasmic reticulum has also been shown to be the organelle to execute apoptosis. Further understanding of molecular mechanisms of apoptosis and its regulation by novel drugs may lead to the development of effective strategies against lung diseases. We overview the signaling pathways of apoptosis and discuss the involvement of apoptosis in the pathophysiology of various lung diseases.

Lactoferrin is a secreted protein related to transferrin. Lactoferrin indirectly protects host cells against foreign insults by killing bacteria, scavenging free iron, and binding to receptors required for viral invasion. However, lactoferrin is also proposed to act directly on cells as a transcription factor and tumor suppressor gene. In addition to full length lactoferrin, a truncated form, called delta lactoferrin, can also be produced by alternative splicing. We show here that transformed and nontransformed cells are equally able to express both full length and delta lactoferrin. Moreover, both forms of lactoferrin failed to substantially modulate the expression of other genes. Thus, lactoferrin does not seem to directly control gene expression or inhibit tumor cell growth.

Tumour growth is characterised by the formation of a fine vessel network or neovasculature which nourishes tumour cells. Two kinds of novel anti-angiogenic therapies are based on the prevention of vessels growth and on the destruction of those vessels already formed. We report here on the design and construction of a novel immunotoxin formed with the non-toxic type II ribosome-inactivating protein ebulin l and the mouse anti-human CD105 monoclonal antibody 44G4. The 44G4-ebulin immunotoxin was formed by covalent linking of both proteins with N-succinimidyl-3- (2-pyridyldithio)propionate (SPDP) and was purified by chromatography on Superdex 200 HiLoad. The analysis of the anti-ribosomal effects in a cell-free translation system indicated that conjugation does not affect the activity of ebulin l. The immunotoxin displays cytotoxicity with nanomolar IC50 values on human CD105+ cells like the mouse fibroblasts L929 cells transfected with the short form of human CD105 and the rat myoblasts L6E9 transfected with the long form of human CD105. In contrast, cells lacking human CD105 were 2-2.5 logs less sensitive to the immunotoxin. Free ebulin displays IC50 values in the range 10-6 M. Since CD105 is being considered as a potential target for the anti-vascular therapy of tumours, the present immunotoxin could be a promising tool for the anticancer therapy, especially due to the very low in vivo toxicity of ebulin l as compared ricin and other toxins used for immunotoxins.

This review describes the clinical status (based on available information) of experimental drugs that inhibit enzymes called proteases, or more precisely a sub-class of proteases called peptidases that catalyse the hydrolysis of polypeptide main chain amide bonds. These peptidases are classified by the key catalytic residue in the active site of the enzyme that effects hydrolysis, namely aspartic, serine, cysteine, metallo or threonine proteases. In this review we show structures for 108 inhibitors of these enzymes and update the clinical disposition of over 100 inhibitors that have been considered worthy enough by pharmaceutical, biotechnology or academic researchers and their financial backers to be trialed in humans as prospective medicines. We outline some of their chemical and pharmacological characteristics and compare the current status of protease inhibitors in the clinic with what was observed about 5 years ago (Leung et al, J. Med. Chem. 2000, 43, 305-341). We assess the progress of protease inhibitors into man, predict their futures, and outline some of the hurdles that have been overcome and that still remain for this promising class of new therapeutic agents.