Separation of anti-angiogenic and cytotoxic activities of borrelidin by modification at the C17 side chain
Barrie WilkinsonMatthew A. GregorySteven J. MossIsabelle CarlettiRose SheridanAndrew L. KajaMichael J. WardCarlos OlanoCármen MéndezJosé A. SalasPeter F. LeadlayRob vanGinckelMing‐Qiang Zhang
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Normal murine peritoneal macrophages were rendered cytotoxic against 51Cr-labelled allogeneic and syngeneic target cells by incubation with supernatant of selected cell cultures.'Active' culture supernatant was produced both by specifically sensitized cytotoxic T lymphocytes as well as by mitogen-stimulated T cells, but not by mitogen-stimulated B cells. The in vitro induced macrophage-mediated cytotoxicity was found to be non-specific in the sense that 51Cr-labelled target cells of different H-2 haplotype were lysed equally well.
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Macrophage-mediated cytotoxicity in vitro was studied by a tritiated thymidine incorporation inhibition assay as well as by microscopic examination and optical transmitance determination. It was found that macrophages from patients with malignant diseases showed cytotoxic effects on two malignant human cell lines. The cytotoxic activity was more marked in patients who were clinically tumor-free. Some patients with benign diseases and normal subjects also exhibited cytotoxic macrophages. Macrophage-mediated cytotoxicity (MMC) was thus nonspecific in nature. Cell-free exudate from cancer patients did not influence MMC appreciably. The experimental methods and the possible significance of MMC are discussed.
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Four metabolites of mogrol were separated, identified and characterized. Their antitumor activity was evaluated, and the results showed side chain modification would probably enhance the cytotoxicity. Therefore, three types of amines, alcohols and rigid planar derivatives were synthesized. Compounds 20 and 21 containing a tetrahydro-β-carboline structure at the end of the side chain exhibited IC50 values around 2-9 μM against A549 and CNE1 cell comparing with 80-90 μM of mogrol. Structure analysis suggested that the perhydrocyclopentanophenanthrene moiety and the tetrahydro-β-carboline moiety could probably enhance the activity through an intramolecular synergistic effect.[Formula: see text].
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Hybrid donor extractants are a promising class of compounds for the separation of trivalent actinides and lanthanides. Here, we investigated a series of sterically loaded diphosphonate ligands based on bipyridine (BiPy-PO-iPr and BiPy-PO-cHex) and phenanthroline (Phen-PO-iPr and Phen-PO-cHex). We studied their complex formation with nitrates of trivalent f-elements in solvent extraction systems (Am and Eu) and homogeneous acetonitrile solutions (Nd, Eu, and Lu). Phenanthroline extractants demonstrated the highest efficiency and selectivity [SF(Am/Eu) up to 14] toward Am(III) extraction from nitric acid solutions among all of the studied diphosphonates of N-heterocycles. The binding constants established by UV–vis titration also indicated stronger binding of sterically impaired diphosphonates compared to the primary substituted diphosphonates. NMR titration and slope analysis during solvent extraction showed the formation of 2:1 complexes at high concentrations (>10–3 mol/L) for phenanthroline-based ligands. According to UV–vis titrations at low concentrations (10–5–10–6 mol/L), the phenanthroline-based ligands formed 1:1 complexes. Bipyridine-based ligands formed 1:1 complexes regardless of the ligand concentration. Luminescence titrations revealed that the quantum yields of the complexes with Eu(III) were 81 ± 8% (BiPy-PO-iPr) and 93 ± 9% (Phen-PO-iPr). Single crystals of the structures [Lu(μ2,κ4-(iPrO)2P(O)Phen(O)2(OiPr))(NO3)2]2 and Eu(Phen-PO-iPr)(NO3)3 were obtained by chemical synthesis with the Phen-PO-iPr ligand. X-ray diffraction studies revealed a closer contact of the f-element with the aromatic N atoms in the case of sterically loaded P═O ligands compared with sterically deficient ligands. Density functional theory calculations allowed us to rationalize the observed selectivity trends in terms of the bond length, Mayer bond order, and preorganization energy.
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In previous studies, we have grouped regions in space occupied by the vitamin D side chain into four: A, G, EA, and EG. We showed that the receptor (VDR) affinity of 1alpha,25-dihydroxyvitamin D3 derivatives increases, in terms of side-chain region, in the order EG, G, A, and EA. We called this the active space group concept. In the present study, we used this active space group concept to analyze the conformation-activity relationship of about 40 representative potent 1alpha,25-dihydroxyvitamin D3 analogues. We initially listed structural modifications in the side chain of potent vitamin D analogues and estimated their potency factor. Possible side-chain conformations of representative analogues were calculated by the molecular mechanics method and plotted on a dot map compared with the regions A, G, EA, and EG. The cell-differentiating potency of the analogues was correlated with our active space group concept with few exceptions. Among potent analogues with a natural configuration at C(20), the side chains of those with a 22-oxa, 22-ene, 16-ene, or a 18-nor modification were located in front of region EA (termed F). The side chains of the most potent 20-epi-22-oxa-24-homovitamin D analogues were concentrated at the left side of the EA region (L-EA). Thus, the side chains of almost all potent analogues were distributed around the EA region, and potency increased in the order A, F, EA, and L-EA.
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A series of 48 bicyclohydantoin−phenylpiperazines (1−4) with affinity for 5-HT1A and α1 receptors was subjected to three-dimensional quantitative structure−affinity relationship analysis using comparative molecular field analysis (CoMFA), in order to get insight into the structural requirements that are responsible for 5-HT1A/α1 selectivity. Good models (high cross-validation correlations and predictive power) were obtained for 5-HT1A and α1 receptors. The resulting 3D-QSAR models rationalize steric and electrostatic factors which modulate binding to 5-HT1A and α1 receptors. A comparison of these models gives an additional understanding for 5-HT1A/α1 selectivity: (a) Substitution at the ortho position by a group with negative potential is favorable to affinity for both receptors. (b) The meta position seems to be implicated in 5-HT1A/α1 selectivity. While the 5-HT1A receptor is able to accommodate bulky substituents in the region of its active site, the steric requirements of the α1 receptor are more restricted (optimum volume of substituent 11−25 Å3). (c) For both receptors the para position represents a region where the volume accessible by the ligands is limited. (d) The hydantoin moiety and the side chain length seem to modulate not only the affinity but also 5-HT1A/α1 selectivity. The 3D-QSAR models reveal an useful predictive information for the design of new selective ligands.
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A novel quantitative structure−activity relationship (QSAR) for the side-chain region of Δ8-tetrahydrocannabinol (Δ8-THC) analogues is reported. A series of 36 side-chain-substituted Δ8-THCs with a wide range of pharmacological potency and CB1 receptor affinity was investigated using computational molecular modeling and QSAR analyses. The conformational mobility of each compound's side chain was characterized using a quenched molecular dynamics approach. The QSAR techniques included a modified active analogue approach (MAA), multiple linear regression analyses (MLR), and comparative molecular field analysis (CoMFA) studies. All three approaches yielded consistent results. The MAA approach applied to a set of alkene/alkyne pairs identified the most active conformers as those with conformational mobility constrained within an approximately 8 Å radius. MLR analyses (restricted to 15 hydrocarbon side-chain analogues) identified two variables describing side-chain length and terminus position that were able to fit the pharmacological data for receptor affinity with a correlation coefficient for pKD of 0.82. While chain length was found to be directly related to receptor affinity, the angle made by the side chain from its attachment point to its terminus (angle defined by C3−C1'−side-chain terminus carbon, see Figure 1) was found to be inversely related to affinity. These results suggest that increased side-chain length and increased side-chain ability to wrap around the ring system are predicted to increase affinity. Therefore, the side chain's conformational mobility must not restrict the chain straight away from the ring system but must allow the chain to wrap back around toward the ring system. Finally, the CoMFA analyses involved all 36 analogues; they also provided data to support the hypothesis that for optimum affinity and potency the side chain must have conformational freedom that allows its terminus to fold back and come into proximity with the phenolic ring.
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