In vitro assessment of the toxicity of metal compounds

A review of in vitro mutagenesis assessment of metal compounds in mammalian and nonmammalian test systems has been compiled. Prokaryotic assays are ineffective or inconsistent in their detection of most metals as mutagens, with the notable exception of hexavalent chromium. Mammalian assay systems appear to be similarly inappropriate for the screening of metal compounds based upon the limited number of studies that have employed those compounds having known carcinogenic activity. Although of limited value as screening tests for the detection of potentially carcinogenic metal compounds, the well-characterized in vitro mutagenesis systems may prove to be of significant value as a means to elucidate mechanisms of metal genotoxicity.     

Ferulic acid–carbazole hybrid compounds: Combination of cholinesterase inhibition,antioxidant and neuroprotection as multifunctional anti-Alzheimer agents

In order to search for novel multifunctional anti-Alzheimer agents, a series of ferulic acid–carbazole hybrid compounds were designed and synthesized. Ellman’s assay revealed that the hybrid compounds showed moderate to potent inhibitory activity against the cholinesterases. Particularly, the AChE inhibition potency of compound 5k (IC₅₀ 1.9 μM) was even 5-fold higher than that of galantamine. In addition, the target compounds showed pronounced antioxidant ability and neuroprotective property, especially against the ROS-induced toxicity. Notably, the neuroprotective effect of 5k was obviously superior to that of the mixture of ferulic acid and carbazole, indicating the therapeutic effect of the hybrid compound is better than the combination administration of the corresponding mixture.     

α-Glucosidase inhibition activity and in silico study of 2-(benzo[d][1,3]dioxol-5-yl)-4H-chromen-4-one,a synthetic derivative of flavone

A synthetic flavone derivative 2-(benzo[d][1,3]dioxol-5-yl)-4H-chromen-4-one (BDC) was synthesized by the one pot reaction method and assessed for α-glucosidase inhibitory activity. The BDC demonstrated dose dependent inhibition of α-glucosidase activity. A maximum inhibition (99.3 ± 0.26%) of α-glucosidase was observed at 27.6 µM. The maximum α-glucosidase inhibitory activity depicted by BDC 27.6 µM concentration was 22.4 fold over the maximum inhibition observed with acarbose (97.72 ± 0.59% at 669.57 µM), a standard commercial anti-diabetic drug. In contrast to acarbose that depicted competitive type inhibition, kinetic studies of α-glucosidase inhibition by BDC demonstrated non-competitive inhibition with Km of 0.71 mM⁻¹ and a Vmax of 0.028 mmol/min. In silico studies suggest allosteric interaction of BDC with α-glucosidase at a minimum binding energy (ΔG) of −8.64 kcal/mol and Ki of 465.3 nM, whereas, acarbose interacted at the active site of α-glucosidase with ΔG of −9.23 kcal/mol and Ki of 172 nM. Thus BDC significantly inhibited α-glucosidase in comparison to acarbose. Moreover, BDC has been endorsed for drug likeness by evaluating it as per Lipinski rule of five. Thus, BDC can be a lead compound for the management of type-2 diabetes mellitus.     

The oxo/peroxo debate: a nonheme iron perspective

The oxygen activation mechanisms proposed for nonheme iron systems generally follow the heme paradigm in invoking the involvement of iron-peroxo and iron-oxo species in their catalytic cycles. However, the nonheme ligand environments allow for end-on and side-on dioxygen coordination and impart greater flexibility in the modes of dioxygen activation. The currently available evidence for nonheme iron-peroxo and iron-oxo intermediates is summarized and discussed in light of the ongoing discussion on the nature of the oxidant(s) in heme enzymes.     

Optional tool use: The case of wild bearded capuchins (Sapajus libidinosus) cracking cashew nuts by biting or by using percussors

Tool use in humans can be optional, that is, the same person can use different tools or no tool to achieve a given goal. Strategies to reach the same goal may differ across individuals and cultures and at the intra‐individual level. This is the first experimental study at the intra‐individual level on the optional use of a tool in wild nonhuman primates. We investigated optional tool use by wild bearded capuchins (Sapajus libidinosus) of Fazenda Boa Vista (FBV; Piauí, Brazil). These monkeys habitually succeed in cracking open the mesocarp of dry cashew nuts (Anacardium spp.) by pounding them with stones and/or by biting. We assessed whether availability of a stone and resistance of the nut affected capuchins' choice to pound or to bite the nuts and their rates of success. Sixteen capuchins (1–16 years) received small and large dry cashew nuts by an anvil together with a stone (Stone condition) or without a stone (No‐Stone condition). In the Stone conditions, subjects used it to crack the nut in 89.1% (large nuts) and 90.1% (small nut) of the trials. Nut size significantly affected the number of strikes used to open it. Availability of the stone significantly increased the average percent of success. In the No‐Stone conditions, monkeys searched for and used other percussors to crack the nuts in 54% of trials. In all conditions, age affects percentage of success and number of strikes to reach success. We argue that exclusive use of stones in other sites may be due to the higher abundance of stones at these sites compared with FBV. Since capuchins opened cashews with a tool 1–2 years earlier than they succeed at cracking more resistant palm nuts, we suggest that success at opening cashew nuts with percussors may support the monkeys' persistent efforts to crack palm nuts.     

Computational Oral Absorption Simulation for Low‐Solubility Compounds

Bile micelles play an important role in oral absorption of low‐solubility compounds. Bile micelles can affect solubility, dissolution rate, and permeability. For the pH–solubility profile in bile micelles, the Henderson–Hasselbalch equation should be modified to take bile‐micelle partition into account. For the dissolution rate, in the Nernst–Brunner equation, the effective diffusion coefficient in bile‐micelle media should be used instead of the monomer diffusion coefficient. The diffusion coefficient of bile micelles is 8‐ to 18‐fold smaller than that of monomer molecules. For permeability, the effective diffusion coefficient in the unstirred water layer adjacent to the epithelial membrane, and the free fraction at the epithelial membrane surface should be taken into account. The importance of these aspects is demonstrated here using several in vivo and clinical oral‐absorption data of low‐solubility model compounds. Using the theoretical equations, the food effect on oral absorption is further discussed.     

Pretubulysin: a new option for the treatment of metastatic cancer

Tubulin-binding agents such as taxol, vincristine or vinblastine are well-established drugs in clinical treatment of metastatic cancer. However, because of their highly complex chemical structures, the synthesis and hence the supply issues are still quite challenging. Here we set on stage pretubulysin, a chemically accessible precursor of tubulysin that was identified as a potent microtubule-binding agent produced by myxobacteria. Although much simpler in chemical structure, pretubulysin abrogates proliferation and long-term survival as well as anchorage-independent growth, and also induces anoikis and apoptosis in invasive tumor cells equally potent to tubulysin. Moreover, pretubulysin posseses in vivo efficacy shown in a chicken chorioallantoic membrane (CAM) model with T24 bladder tumor cells, in a mouse xenograft model using MDA-MB-231 mammary cancer cells and finally in a model of lung metastasis induced by 4T1 mouse breast cancer cells. Pretubulysin induces cell death via the intrinsic apoptosis pathway by abrogating the expression of pivotal antiapoptotic proteins, namely Mcl-1 and Bcl-x_L, and shows distinct chemosensitizing properties in combination with TRAIL in two- and three-dimensional cell culture models. Unraveling the underlying signaling pathways provides novel information: pretubulysin induces proteasomal degradation of Mcl-1 by activation of mitogen-activated protein kinase (especially JNK (c-Jun N-terminal kinase)) and phosphorylation of Mcl-1, which is then targeted by the SCF^Fbw7 E3 ubiquitin ligase complex for ubiquitination and degradation. In sum, we designate the microtubule-destabilizing compound pretubulysin as a highly promising novel agent for mono treatment and combinatory treatment of invasive cancer.     

Efficient synthesis of novel glutamate homologues and investigation of their affinity and selectivity profile at ionotropic glutamate receptors

A convenient synthesis of four new enantiomerically pure acidic amino acids is reported and their affinity at ionotropic glutamate receptors was determined. The new compounds are higher homologues of glutamic acid in which the molecular complexity has been increased by introducing an aromatic/heteroaromatic ring, that is a phenyl or a thiophene ring, that could give additional electronic interactions with the receptors. The results of the present investigation indicate that the insertion of an aromatic/heteroaromatic ring into the amino acid skeleton of glutamate higher homologues is well tolerated and this modification could be exploited to generate a new class of NMDA antagonists.     

Synthesis,Molecular Modeling,and Biological Evaluation of Novel Chiral Thiosemicarbazone Derivatives as Potent Anticancer Agents

A series of new chiral thiosemicarbazones derived from homochiral amines in both enantiomeric forms were synthesized and evaluated for their in vitro antiproliferative activity against A549 (human alveolar adenocarcinoma), MCF‐7 (human breast adenocarcinoma), HeLa (human cervical adenocarcinoma), and HGC‐27 (human stomach carcinoma) cell lines. Some of compounds showed inhibitory activities on the growth of cancer cell lines. Especially, compound 17b exhibited the most potent activity (IC₅₀ 4.6 μM) against HGC‐27 as compared with the reference compound, sindaxel (IC₅₀ 10.3 μM), and could be used as a lead compound to search new chiral thiosemicarbazone derivatives as antiproliferative agents. Chirality 27:177–188, 2015. © 2014 Wiley Periodicals, Inc.     

Separation of enantiomeric amines and acids using chiral ion-pair chromatography on porous graphitic carbon

The application of porous graphitic carbon as adsorbing phase for direct separation of enantiomeric acids and amines using chiral ion-pair chromatography is described. The enantiomeric amines were separated as diastereomeric ion pairs with N-benzyloxycarbonylglycyl-L -proline, N-benzyloxycarbonylglycylglycyl-L -proline, or captopril as the chiral counterion. High enantioselectivities were obtained for amines having a hydrogen bonding function in the vicinity of the asymmetrical carbon atom. Quinine was the chiral counterion used to separate the enantiomeric acids. The strongly UV-absorbing quinine improved detection of solutes having low UV-absorbing properties, e.g., (R,S)-2-chloropropionic acid, by “indirect detection.” Retention and stereoselectivity of enanticmeric acids were regulated by the quinine concentration and by the addition of carboxylic acids as well as polar modifiers, e.g., methanol and 2-propanol, to the mobile phase. © 1992 Wiley-Liss, Inc.