Lipophilic Prodrugs and Formulations of Conventional (Deoxy)Nucleoside and Fluoropyrimidine Analogs in Cancer

Many drugs that are currently used for the treatment of cancer have limitations, such as induction of resistance and/or poor biological half-life, which reduce their clinical efficacy. To overcome these limitations, several strategies have been explored. Chemical modification by the attachment of lipophilic moieties to (deoxy)nucleoside analogs should enhance the plasma half-life, change the biodistribution, and improve cellular uptake of the drug. Attachment of a lipophilic moiety to a phosphorylated (deoxy)nucleoside analog will improve the activity of the drugs by circumventing the rate-limiting activation step of (deoxy)nucleoside analogs. Encapsulating drugs in nanoparticles or liposomes protects the drug against enzymatic breakdown in the plasma and makes it possible to get lipophilic compounds to the tumor site. In this review, we discuss the considerable progress that has been made in increasing the efficacy of classic (deoxy)nucleoside and fluoropyrimidine compounds by chemical modifications and alternative delivery systems.     

Decoding the mechanisms of gait generation in salamanders by combining neurobiology, modeling and robotics

Vertebrate animals exhibit impressive locomotor skills. These locomotor skills are due to the complex interactions between the environment, the musculo-skeletal system and the central nervous system, in particular the spinal locomotor circuits. We are interested in decoding these interactions in the salamander, a key animal from an evolutionary point of view. It exhibits both swimming and stepping gaits and is faced with the problem of producing efficient propulsive forces using the same musculo-skeletal system in two environments with significant physical differences in density, viscosity and gravitational load. Yet its nervous system remains comparatively simple. Our approach is based on a combination of neurophysiological experiments, numerical modeling at different levels of abstraction, and robotic validation using an amphibious salamander-like robot. This article reviews the current state of our knowledge on salamander locomotion control, and presents how our approach has allowed us to obtain a first conceptual model of the salamander spinal locomotor networks. The model suggests that the salamander locomotor circuit can be seen as a lamprey-like circuit controlling axial movements of the trunk and tail, extended by specialized oscillatory centers controlling limb movements. The interplay between the two types of circuits determines the mode of locomotion under the influence of sensory feedback and descending drive, with stepping gaits at low drive, and swimming at high drive.     

A link between the accumulation of DNA damage and loss of multi‐potency of human mesenchymal stromal cells

Human mesenchymal stromal cells (hMSCs) represent an attractive cell source for clinic applications. Besides being multi‐potent, recent clinical trials suggest that they secrete both trophic and immunomodulatory factors, allowing allogenic MSCs to be used in a wider variety of clinical situations. The yield of prospective isolation is however very low, making expansion a required step toward clinical applications. Unfortunately, this leads to a significant decrease in their stemness. To identify the mechanism behind loss of multi‐potency, hMSCs were expanded until replicative senescence and the concomitant molecular changes were characterized at regular intervals. We observed that, with time of culture, loss of multi‐potency was associated with both the accumulation of DNA damage and the respective activation of the DNA damage response pathway, suggesting a correlation between both phenomena. Indeed, exposing hMSCs to DNA damage agents led to a significant decrease in the differentiation potential. We also showed that hMSCs are susceptible to accumulate DNA damage upon in vitro expansion, and that although hMSCs maintained an effective nucleotide excision repair activity, there was a progressive accumulation of DNA damage. We propose a model in which DNA damage accumulation contributes to the loss of differentiation potential of hMSCs, which might not only compromise their potential for clinical applications but also contribute to the characteristics of tissue ageing.     

Copper(II) complexes with unsymmetrical pentadentate ed3a-type diamino-tricarboxylate ligands. Crystal structures, configurational analysis and DFT study of complexes

The O-O-N-N-O-type pentadentate ligands H₃ed3a, H₃pd3a and H₃pd3p (H₃ed3a stands ethylenediamine-N,N,N′-triacetic acid; H₃pd3a stands 1,3-propanediamine-N,N,N′-triacetic acid and H₃pd3p stands 1,3-propanediamine-N,N,N′-tri-3-propionic acid) and the corresponding novel octahedral or square-planar/trigonal-bipyramidal copper(II) complexes have been prepared and characterized. H₃ed3a, H₃pd3a and H₃pd3p ligands coordinate to copper(II) ion via five donor atoms (three deprotonated carboxylate atoms and two amine nitrogens) affording octahedral in case of ed3a³⁻ and intermediate square-pyramidal/trigonal-bipyramidal structure in case of pd3a³⁻ and pd3p³⁻. A six coordinate, octahedral geometry has been established crystallographically for the [Mg(H₂O)₆][Cu(ed3a)(H₂O)]₂ · 2H₂O complex and five coordinate square-pyramidal for the [Mg(H₂O)₅Cu(pd3a)][Cu(pd3a)] · 2H₂O. Structural data correlating similar chelate Cu(II) complexes have been used for the better understanding the pathway: octahedral → square-pyramidal ↔ trigonal- bipyramid geometry. An extensive configuration analysis is discussed in relation to information obtained for similar complexes. The infra-red and electronic absorption spectra of the complexes are discussed in comparison with related complexes of known geometries. Molecular mechanics and density functional theory (DFT) programs have been used to model the most stable geometric isomer yielding, at the same time, significant structural data. The results from density functional studies have been compared with X-ray data.     

Lipophilic prodrugs and formulations of conventional (deoxy)nucleoside and fluoropyrimidine analogs in cancer

Many drugs that are currently used for the treatment of cancer have limitations, such as induction of resistance and/or poor biological half-life, which reduce their clinical efficacy. To overcome these limitations, several strategies have been explored. Chemical modification by the attachment of lipophilic moieties to (deoxy)nucleoside analogs should enhance the plasma half-life, change the biodistribution, and improve cellular uptake of the drug. Attachment of a lipophilic moiety to a phosphorylated (deoxy)nucleoside analog will improve the activity of the drugs by circumventing the rate-limiting activation step of (deoxy)nucleoside analogs. Encapsulating drugs in nanoparticles or liposomes protects the drug against enzymatic breakdown in the plasma and makes it possible to get lipophilic compounds to the tumor site. In this review, we discuss the considerable progress that has been made in increasing the efficacy of classic (deoxy)nucleoside and fluoropyrimidine compounds by chemical modifications and alternative delivery systems.     

Crystal and molecular structure of polymeric [MnCl2(bpy)]n

A crystal and molecular structure determination of MnCl₂(bpy) showed that it exists as polymeric octahedral [MnCl₂(bpy)]_n. [MnCl₂(bpy)_n crystallizes in the monoclinic space group I2/a with A = 7.007(1), B = 9.200(1), C = 16.495(1) Å, β = 91.313(5)° and Z = 4. On the basis of 979 unique observed reflections with I 2.5σ(I) the structure was refined to R = 0.032.     

MODEM: a multi-agent hierarchical structure to model the human motor control system

In this study, based on behavioral and neurophysiological facts, a new hierarchical multi-agent architecture is proposed to model the human motor control system. Performance of the proposed structure is investigated by simulating the control of sit to stand movement. To develop the model, concepts of mixture of experts, modular structure, and some aspects of equilibrium point hypothesis were brought together. We have called this architecture MODularized Experts Model (MODEM). Human motor system is modeled at the joint torque level and the role of the muscles has been embedded in the function of the joint compliance characteristics. The input to the motor system, i.e., the central command, is the reciprocal command. At the lower level, there are several experts to generate the central command to control the task according to the details of the movement. The number of experts depends on the task to be performed. At the higher level, a “gate selector” block selects the suitable subordinate expert considering the context of the task. Each expert consists of a main controller and a predictor as well as several auxiliary modules. The main controller of an expert learns to control the performance of a given task by generating appropriate central commands under given conditions and/or constraints. The auxiliary modules of this expert learn to scrutinize the generated central command by the main controller. Auxiliary modules increase their intervention to correct the central command if the movement error is increased due to an external disturbance. Each auxiliary module acts autonomously and can be interpreted as an agent. Each agent is responsible for one joint and, therefore, the number of the agents of each expert is equal to the number of joints. Our results indicate that this architecture is robust against external disturbances, signal-dependent noise in sensory information, and changes in the environment. We also discuss the neurophysiological and behavioral basis of the proposed model (MODEM).     

Organotin(IV) 4-methoxyphenylethanoates: Synthesis, spectroscopic characterization, X-ray structures and in vitro anticancer activity against human prostate cell lines (PC-3)

A series of organotin(IV) carboxylates, [Bu₂SnL₂] (1), [Et₂SnL₂] (2), [Me₂SnL₂] (3), [Bu₃SnL]_n(4), [Me₆Sn₂L₂]_n(5), [Ph₃SnL]_n(6) and [Oct₂SnL₂] (7), where L = O₂CCH₂C₆H₄OCH₃-4, have been synthesized. These complexes have been characterized by elemental analysis, FT-IR and multinuclear NMR (¹H, ¹³C and ¹¹⁹Sn). Based on spectroscopic results, the ligand appeared to coordinate to the Sn atom through COO moiety. Single crystal analysis has shown a bridging behavior of ligand in tributyl- and trimethyltin(IV) derivatives, and a chelating bidentate mode in diethyltin(IV) complex. Bioassay results have shown that these compounds have good antibacterial, antifungal and antitumor activity. The activity against prostate cancer cell lines (PC-3) decreased in the order 1 > 5 > 2 > 3 > 7.