Biomedical subjects
Publications and source records attributed to Magdy N Iskander.
Three macrocyclic diarylheptanoids, 6'-hydroxygaruganin V (1), 9'-desmethylgarugamblin I (2) and 1,9'-didesmethylgaruganin III (3) were isolated from the petroleum ether and dichloromethane extracts of the stem bark of Garuga pinnata. The structures of these compounds were established by extensive spectroscopic studies, including high field NMR and MS measurements.
Two quinones, stereochenols A (1) and B (2) were isolated from a methanol extract of the stem bark of Stereospermum chelonoides, in addition to the known naphthoquinones, sterekunthal B (3) and sterequinone C (4). The structures of these compounds were established by extensive spectroscopic analyses and by comparison of their spectral data with those of related compounds.
Twenty two 5-HT4 agonists obtained from our laboratory and the recent literature were used to develop a CoMFA model to predict 5-HT4 agonist activity. Two models were produced and compared for predictivity, the first by alignments based on atom overlapping (model A) and the second by adding agonist binding site interacting points of the 5-HT4 receptor (model B). Comparison of the two models showed that the q2 value for model A was 0.564 vs. 0.582 for model B. Model B indicated that the predictive power model stems from far lower steric contributions, 0.270 compared to model A's 0.502. The dominant defining features were the electrostatic contributions for model B, 0.664 up from 0.477 in model A. The contributions from the LogP factor were minimal, 0.085 in both models. The synthesized compounds showed agonist activity at mumol level.
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 oligonucleotide-drug 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.
In this study, the synthesis of 15 new glibenclamide analogues is described. The conformational trends of these analogues were investigated using Monte Carlo conformational analysis. The conformational analysis results resolved the discrepancy between previous molecular modelling simulations of glibenclamide and allowed rationalizing the effect of aqueous environment on the overall conformation. The 3D-QSAR study was carried out with respect to the compounds' ability to antagonize the [(3)H]-glibenclamide binging in rat cerebral cortex. Superimposition of the antagonists was performed using the conformations derived from atom-by-atom fit to the glibenclamide crystal structure and this alignment was used to develop CoMFA models. CoMFA provided a good predictability: number of PLS components = 2, q(2) = 0.876, R(2) = 0.921, SEE = 0.455 and F = 70. Best CoMFA models showed the steric and lipophilic properties as the major interacting forces whilst the electrostatic property contribution was a minor factor.
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.
CoMFA and CoMSIA analysis were utilized in this investigation to define the important interacting regions in paclitaxel/tubulin binding site and to develop selective paclitaxel-like active compounds. The starting geometry of paclitaxel analogs was taken from the crystal structure of docetaxel. A total of 28 derivatives of paclitaxel were divided into two groups-a training set comprising of 19 compounds and a test set comprising of nine compounds. They were constructed and geometrically optimized using SYBYL v6.6. CoMFA studies provided a good predictability (q(2)=0.699, r(2)=0.991, PC=6, S.E.E.=0.343 and F=185.910). They showed the steric and electrostatic properties as the major interacting forces whilst the lipophilic property contribution was a minor factor for recognition forces of the binding site. These results were in agreement with the experimental data of the binding activities of these compounds. Five fields in CoMSIA analysis (steric, electrostatic, hydrophobic, hydrogen-bond acceptor and donor properties) were considered contributors in the ligand-receptor interactions. The results obtained from the CoMSIA studies were: q(2)=0.535, r(2)=0.983, PC=5, S.E.E.=0.452 and F=127.884. The data obtained from both CoMFA and CoMSIA studies were interpreted with respect to the paclitaxel/tubulin binding site. This intuitively suggested where the most significant anchoring points for binding affinity are located. This information could be used for the development of new compounds having paclitaxel-like activity with new chemical entities to overcome the existing pharmaceutical barriers and the economical problem associated with the synthesis of the paclitaxel analogs. These will boost the wide use of this useful class of compounds, i.e. in brain tumors as the most of the present active compounds have poor blood-brain barrier crossing ratios and also, various tubulin isotypes has shown resistance to taxanes and other antimitotic agents.