Catalysis using iron–sulfur clusters and transition metals can be traced back to the last universal common ancestor. The damage to metalloproteins caused by reactive oxygen species (ROS) can prevent cell growth and survival when unmanaged, thus eliciting an essential stress response that is universal and fundamental in biology. Here we develop a computable multiscale description of the ROS stress response inEscherichia coli, called OxidizeME. We use OxidizeME to explain four key responses to oxidative stress: 1) ROS-induced auxotrophy for branched-chain, aromatic, and sulfurous amino acids; 2) nutrient-dependent sensitivity of growth rate to ROS; 3) ROS-specific differential gene expression separate from global growth-associated differential expression; and 4) coordinated expression of iron–sulfur cluster (ISC) and sulfur assimilation (SUF) systems for iron–sulfur cluster biosynthesis. These results show that we can now develop fundamental and quantitative genotype–phenotype relationships for stress responses on a genome-wide basis.
As part of our continuing search for potential anticancer drug candidates in the 2-aryl-1,8-naphthyridin-4(1H)-one series, we have synthesized two series of 3'-substituted 2-phenyl-1,8-naphthyridin-4(1H)-ones and 2-naphthyl-1,8-naphthyridin-4(1H)-ones. All compounds showed significant cytotoxic effects (log GI50 < -4.0; log molar drug concentration required to cause 50% growth inhibition) against a variety of human tumor cell lines of the National Cancer Institute's in vitro screen, including cells derived from solid tumors such as non-small cell lung, colon, central nervous system, melanoma, ovarian, prostate, and breast cancers. All 3'-substituted compounds demonstrated strong cytotoxic effects in almost all tumor cell lines. Introduction of an aromatic ring at the 2'- and 3'-positions also generated compounds with potent antitumor activity. Incorporation of an aromatic ring at the 3'- and 4'-positions produced compounds with reduced activity. Interestingly, introduction of a halogen at the 3'-position yielded compounds with different selectivity for the tumor cell lines tested. All 3'-halogenated compounds (29-36) and compounds 38 and 42-44 were potent inhibitors of tubulin polymerization with activities nearly comparable to those of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4. Active agents also inhibited the binding of [3H]colchicine to tubulin.
Herein, the cytocompatibility of selected MAX phases, Ti3AlC2, Ti3SiC2, and Ti2AlN, were systematically evaluated using in vitro tests for the first time. These phases were anoxic to preosteoblasts and fibroblasts. Compared with the strong viable fibroblasts, the different cellular responses of these materials were clearly distinguishable for the preosteoblasts. Under an osteoblastic environment, Ti2AlN exhibited better cell proliferation and differentiation performance than Ti3AlC2 and Ti3SiC2. Moreover, the performance was superior to that of a commercial Ti–6Al–4V alloy and comparable to that of pure Ti. A possible mechanism was suggested based on the different surface oxidation products, which were determined from the binding energy of adsorbed Ca2+ ions using first-principles calculations. Compared with the partially oxidized TiC x O y layer on Ti3AlC2 and Ti3SiC2, the partially oxidized TiN x O y layer on the Ti2AlN had a stronger affinity to the Ca2+ ions, which indicated the good cytocompatibility of Ti2AlN.
7-O-Substituted analogues of allothiocochicine were synthesized and evaluated for their inhibitory effects on tubulin polymerization in vitro. Ketone 6, a key compound in this study, was derived from thiocolchicone 5 by ring contraction. The structure of 6 was determined from spectral data. Optically active alcohols 7a and 7b were obtained by reduction of ketone 6 followed by chemical resolution including a separation of the camphanate diastereomers 8a and 8b and basic hydrolysis. The aR,7R configuration of 8b was verified by X-ray crystallographic analysis. Almost all compounds had strong inhibitory effects on the tubulin polymerization reaction, with IC50 values from 1.7 to 9.0 μM. The camphanates, cyclohexanates, and, most notably, the 7S-benzoate ester (10a), were inactive with IC50 values >40 μM. Compounds 6 and 7a also showed potent antitumor activity with GI50 values at nM concentration range for most cell lines in NCI's in vitro screening. Generally, the 7S enantiomers of colchicinoids with a troplone C-ring showed greater activity than the 7R enantiomers. In the current allothiocolchicinoid (with a benzenoid C-ring) study, only small differences occurred between the two active enantiomers of each pair. The acyl esters with a 7S configuration were slightly more active than the 7R isomers. However, the aroyl ester with a 7S configuration was less active than the 7R isomer. NMR, optical rotation, and molecular modeling studies revealed two conformers in a solvent-dependent equilibrium for both 7S and 7R isomers. In polar solvents, the molecular chirality in esters with a 7-O-aroyl substituent was reversed from aS to aR or from aR to aS at an intensified rate.
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