Microtubules (MTs) play important and diverse roles in eukaryotic cells. Their function and biophysical properties have made alpha-and beta-tubulin, the main components of MTs, the subject of intense study. Interfering with normal MT dynamics, for example, by the addition of tubulin ligands, can cause the cell great distress and affect MT stability and functions, including mitosis, cell motion and intracellular organelle transport. It has been shown in the literature that tubulin is an important target molecule for developing anticancer drugs. Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. This mode of action is also shared with other natural agents eg colchicine and podophyllotoxin. However various tubulin isotypes have shown resistance to taxanes and other MT agents. Therefore, there is a strong need to design and develop new natural analogs as antimitotic agents to interact with tubulin at sites different from those of vinca alkaloids and taxanes. This minireview provides SAR on several classes of antimitotic agents reported in the literature. The structures and data given are essential to the scientists who are involved in drug design and development in the field of anticancer drugs.

Macrophage migration inhibitory factor (MIF), a cytokine originally reported in the 1960s as the prototypic T lymphokine, has emerged in recent years as a key factor regulating inflammatory responses. Both by directly activating immune cells, and by participating in activation entrained by other stimuli, MIF is important in innate and adaptive immune responses as well as tissue-specific mechanisms of damage. As a consequence of its involvement in multiple stages of the immune-inflammatory response, MIF has the potential to be involved in the pathogenesis of a range of immune-mediated inflammatory diseases affecting multiple organ systems. Diseases in which a role for MIF has been strongly validated include rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, atherosclerosis, asthma, inflammatory liver disease, and most recently systemic lupus erythematosus. Recent data have provided mechanisms of action for MIF which further support its suitability as a therapeutic target. Finally, MIF has a unique relationship with glucocorticoids, acting to counter-regulate their anti-inflammatory effects, such that MIF antagonist therapy may be a direct route to 'steroid-sparing'. Methods of targeting MIF therapeutically have also emerged in recent years, based on the unique protein structure of MIF which affords opportunities for direct antagonism by small molecules, as well as by protein therapeutics such as monoclonal antibodies. Clinical trials of MIF antagonist therapies are likely before the end of the current decade.

Gynura procumbens is used in Thai folk medicine to treat topical inflammation, rheumatism, and viral ailments. In the present work, attempts were made to verify the folk medicinal claim that the crude ethanolic extract of G. procumbens has antiinflammatory action and to relate the activity to particular fractions using a croton oil-induced mouse ear inflammation model. The original ethanolic extract of G. procumbens was partitioned between water and ethyl acetate. The residues were subjected to antiinflammatory evaluation. While the water extract did not show any antiinflammatory activity, the administration of the original organic extract significantly inhibited the increase in ear thickness in response to croton oil (n = 5). The activity of 0.75 mg/ear original organic extract showed similar antiinflammatory activity (inhibition 65.2%) to that of 6 mg/ear hydrocortisone 21-hemisuccinate sodium salt (inhibition 64.8%). The organic extract was then fractionated with a series of solvents in order of increasing polarity. Each fraction was dried, dissolved in acetone and monitored using the same bioassay. These experiments showed that the hexane and toluene fractions showed significant inhibitions of 44.6% and 34.8%, respectively. These two fractions had similar activities to 4 mg/ear of hydrocortisone (inhibition 35.0%). The possible chemical constituents in the extracts and fractions were investigated using thin layer chromatography and specific color reagents. These tests showed that steroids might be one class of antiinflammatory compounds in this plant.

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The synthesis of a series of mono- and disubstituted N-phenylanthranilic acids is described. Substituents on the phenyl ring include Cl, CN, OH, CF3, Br, I, CH3, OCH3, and OCF2CF2H. These compounds have been tested for their inhibitory effect on triiodothyronine (T3) uptake by H4 hepatocytes. The nonsteroidal antiinflammatory drugs flufenamic acid, mefenamic acid, and meclofenamic acid and the structurally related compounds 2,3-dimethyldiphenylamine and diclofenac were also tested. The most potent compounds were found to be, in order of decreasing activity, meclofenamic acid (2,6-Cl2,3-CH3), flufenamic acid (3-CF3), mefenamic acid (2,3-(CH3)2), and the compounds with 3,5-Cl2 and 3-OCF2CF2H substituents. The least potent compounds had 3-CN and 3-OH substituents. An analysis of quantitative structure-activity relationships (QSAR) for the series of phenylanthranilic acids showed that the inhibition of T3 uptake is highly dependent on the hydrophobicity of the compound. The relationship between uptake inhibition and the calculated octanol-water partition coefficient (clogP) was found to be parabolic, with optimum inhibitory activity found when the clogP of the phenylanthranilic acid was 5.7. It was also found that the 1-carboxylic acid group of the phenylanthranilic acids was not a prerequisite for uptake inhibition to occur, but its removal or alteration resulted in reduced inhibition.

When mitoxantrone is activated by formaldehyde it can form adducts with DNA. These occur preferentially at CpG and CpA sequences and are enhanced 2-3-fold at methylated CpG sequences compared with non-methylated sites. We sought to understand the molecular factors involved in enhanced adduct formation at these methylated sites. This required, first, clarification of factors that contributed to the formation of adducts at CpG sites. For this purpose mass spectrometry of an oligonucleotide duplex (containing a single CpG adduct site) was used to confirm the presence of an additional carbon atom (derived from formaldehyde) on the drug-DNA complex. The effect of 3-flanking sequences was revealed by electrophoretic analysis of oligonucleotidedrug adducts, and the preferred adduct-forming site was identified as 5-CGG-3. Radiolabeled studies of drug-DNA adducts confirmed that the site of attachment involved the exocyclic amino of guanine. Molecular modeling analysis of the relative stability of the intercalated form of mitoxantrone was consistent with observed adduct-forming potential of CG sites with varying flanking sequences. The known preference for adduct formation at methylated CG sites was confirmed by energetics calculations and shown to be due to a shift of equilibrium of the intercalated form of the drug from the major groove (at CG sites) to the minor groove (at methylated CG sites). This increases the relative amount of drug that is located adjacent to the N-2 exocyclic amino of guanine in the minor groove, where covalent linkage is facilitated. These results account for the enhanced covalent binding of mitoxantrone to methylated CG sequences and provide a molecular model of the interactions.

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