3-nitropyridine analogues as novel microtubule-targeting agents.

Microtubule-targeting agents are an important class of anti-cancer drugs; their full potential is however not realized because of significant myelotoxicity and neurotoxicity. We here report 3-nitropyridine analogues as a novel group of microtubule-targeting agents with potent anti-cancer effects against a broad range of cancer types. We show that these 3-nitropyridines induce cell cycle arrest in the G2-M phase and inhibit tubulin polymerization by interacting with tubulin.

Highly Cytotoxic Cryptophycin Derivatives with Modification in Unit D for Conjugation.

Cytotoxic payloads for drug conjugates suitable for directed tumor therapy need to be highly potent and require a functional group for conjugation with the homing device (antibody, peptide, or small molecule). Cryptophycins are cyclodepsipeptides that stand out from the realm of natural products due to their extraordinarily high cytotoxicity. However, the installation of a suitable conjugation handle without compromising the toxicity is highly challenging.

Structure-based discovery and rational design of microtubule-targeting agents.

Microtubule-targeting agents (MTAs) have demonstrated remarkable efficacy as antitumor, antifungal, antiparasitic, and herbicidal agents, finding applications in the clinical, veterinary, and agrochemical industry. Recent advances in tubulin and microtubule structural biology have provided powerful tools that pave the way for the rational design of innovative small-molecule MTAs for future basic and applied life science applications. In this mini-review, we present the current status of the tubulin and microtubule structural biology field, the recent impact it had on the discovery and rational design of MTAs, and exciting avenues for future MTA research.

Bridging the maytansine and vinca sites: Cryptophycins target β-tubulin's T5-loop.

Cryptophycins are microtubule-targeting agents (MTAs) that belong to the most potent antimitotic compounds known to date; however, their exact molecular mechanism of action remains unclear. Here, we present the 2.2 Å resolution X-ray crystal structure of a potent cryptophycin derivative bound to the αβ-tubulin heterodimer.

Modular synthesis of functional libraries by accelerated SuFEx click chemistry.

Accelerated SuFEx Click Chemistry (ASCC) is a powerful method for coupling aryl and alkyl alcohols with SuFEx-compatible functional groups. With its hallmark favorable kinetics and exceptional product yields, ASCC streamlines the synthetic workflow, simplifies the purification process, and is ideally suited for discovering functional molecules. We showcase the versatility and practicality of the ASCC reaction as a tool for the late-stage derivatization of bioactive molecules and in the array synthesis of sulfonate-linked, high-potency, microtubule targeting agents (MTAs) that exhibit nanomolar anticancer activity against multidrug-resistant cancer cell lines.

Effects of Defects on Masonry Confinement with Inorganic Matrix Composites.

Fabric-reinforced cementitious matrix (FRCM) composites are currently considered a suitable solution for strengthening existing structures. Confinement applications are still being investigated, since experimental programs showed significant scatter in the results and theoretical models are struggling to become established as a consequence. The main aim of this study is the identification of potential sources of scatter in the confinement efficiency of FRCM wrappings, in defects such as fiber slip within the matrix or imperfect straightening of fibers, or premature failure of fibers once exposed after complete matrix cracking.

Effect of buoyancy loads on the tsunami fragility of existing reinforced concrete frames including consideration of blow-out slabs.

Currently available performance-based methodologies for assessing the fragility of structures subjected to tsunami neglect the effects of tsunami-induced vertical loads due to internal buoyancy. This paper adopts a generalized methodology for the performance assessment of structures that integrates the effects of buoyancy loads on interior slabs during a tsunami inundation. The methodology is applied in the fragility assessment of three case-study frames (low, mid and high-rise), representative of existing masonry-infilled reinforced concrete (RC) buildings typical of Mediterranean region.

Reinforcement Corrosion in RC Hollow Piers: Destructive and Non-Destructive Tests.

In this work, cyclic-load tests on reduced-scale corroded reinforced-concrete hollow cross-section bridge piers have been experimentally performed and compared to the results of similar non-corroded piers. Piers were aged by using an imposed electric current and sodium chloride water solution before performing a mechanical cyclic-load test. The corrosion process has been detected with Non-Destructive Evaluation techniques by means of SonReb method (to check concrete degradation) and by measuring corrosion potential (to check steel degradation).

Structural insight into the stabilization of microtubules by taxanes.

Paclitaxel (Taxol) is a taxane and a chemotherapeutic drug that stabilizes microtubules. While the interaction of paclitaxel with microtubules is well described, the lack of high-resolution structural information on a tubulin-taxane complex precludes a comprehensive description of the binding determinants that affect its mechanism of action. Here, we solved the crystal structure of baccatin III the core moiety of paclitaxel-tubulin complex at 1.

Maytansinol Functionalization: Towards Useful Probes for Studying Microtubule Dynamics.

Invited for the cover of this issue are the groups of Professors Passarella and Pieraccini at the University of Milan, in collaboration with some of the members of TubInTrain consortium. The image depicts work with the elements of nature, in particular the destabilising effect of maytansinol (the constellation) on microtubules (the trees). Read the full text of the article at 10.

Maytansinol Functionalization: Towards Useful Probes for Studying Microtubule Dynamics.

Maytansinoids are a successful class of natural and semisynthetic tubulin binders, known for their potent cytotoxic activity. Their wider application as cytotoxins and chemical probes to study tubulin dynamics has been held back by the complexity of natural product chemistry. Here we report the synthesis of long-chain derivatives and maytansinoid conjugates.

Chemical modulation of microtubule structure through the laulimalide/peloruside site.

Taxanes are microtubule-stabilizing agents used in the treatment of many solid tumors, but they often involve side effects affecting the peripheral nervous system. It has been proposed that this could be related to structural modifications on the filament upon drug binding. Alternatively, laulimalide and peloruside bind to a different site also inducing stabilization, but they have not been exploited in clinics.

Cu ions modulate the interaction between α-synuclein and lipid membranes.

α-synuclein protein aggregates are the major constituent of Lewy bodies, which is a main pathogenic hallmark of Parkinson's disease. Both lipid membranes and Cu ions can bind to α-synuclein and modulate its aggregation propensity and toxicity. However, the synergistic effect of copper ions and lipid membranes on α-synuclein remains to be explored.

Novel fragment-derived colchicine-site binders as microtubule-destabilizing agents.

Microtubules (MTs) are dynamic filaments of the cytoskeleton, which are formed by the polymerization of their building block tubulin. Perturbation of MT dynamics by MT-targeting agents (MTAs) leads to cell cycle arrest or cell death, a strategy that is pursued in chemotherapy. We recently performed a combined computational and crystallographic fragment screening approach and identified several tubulin-binding fragments.

Crystallization Systems for the High-Resolution Structural Analysis of Tubulin-Ligand Complexes.

Since the first moderate resolution, structural description of Taxol bound to tubulin by electron crystallography in 1998, several tubulin crystal systems have been developed and optimized for the high-resolution analysis of tubulin-ligand complexes by X-ray crystallography. Here we describe three tubulin crystal systems that have allowed investigating the molecular mechanisms of action of a large number of diverse anti-tubulin agents.

Rational Design of a Novel Tubulin Inhibitor with a Unique Mechanism of Action.

In this study, we capitalized on our previously performed crystallographic fragment screen and developed the antitubulin small molecule Todalam with only two rounds of straightforward chemical synthesis. Todalam binds to a novel tubulin site, disrupts microtubule networks in cells, arrests cells in G2/M, induces cell death, and synergizes with vinblastine. The compound destabilizes microtubules by acting as a molecular plug that sterically inhibits the curved-to-straight conformational switch in the α-tubulin subunit, and by sequestering tubulin dimers into assembly incompetent oligomers.

Maytansinol Derivatives: Side Reactions as a Chance for New Tubulin Binders.

Maytansinol is a valuable precursor for the preparation of maytansine derivatives (known as maytansinoids). Inspired by the intriguing structure of the macrocycle and the success in targeted cancer therapy of the derivatives, we explored the maytansinol acylation reaction. As a result, we were able to obtain a series of derivatives with novel modifications of the maytansine scaffold.

Cost and Effectiveness of Fiber-Reinforced Polymer Solutions for the Large-Scale Mitigation of Seismic Risk in Reinforced Concrete Buildings.

Recent seismic events have demonstrated that the high vulnerability of existing reinforced concrete (RC) buildings is mainly due to a lack of proper seismic detailing and the employment of poor-quality concrete. The reconstruction process following the 2009 L'Aquila earthquake highlighted that strengthening these buildings using solutions based on fiber-reinforced polymers (FRPs) can be both efficient and cost-effective. Indeed, their light weight, ease of installation, and the availability of specific guidelines and standards strongly supported their use in design practices, where they were the strengthening technique employed the most.

Preclinical and Early Clinical Development of PTC596, a Novel Small-Molecule Tubulin-Binding Agent.

PTC596 is an investigational small-molecule tubulin-binding agent. Unlike other tubulin-binding agents, PTC596 is orally bioavailable and is not a P-glycoprotein substrate. So as to characterize PTC596 to position the molecule for optimal clinical development, the interactions of PTC596 with tubulin using crystallography, its spectrum of preclinical anticancer activity, and its pharmacokinetic-pharmacodynamic relationship were investigated for efficacy in multiple preclinical mouse models of leiomyosarcomas and glioblastoma.

1,3-Benzodioxole-Modified Noscapine Analogues: Synthesis, Antiproliferative Activity, and Tubulin-Bound Structure.

Since the revelation of noscapine's weak anti-mitotic activity, extensive research has been conducted over the past two decades, with the goal of discovering noscapine derivatives with improved potency. To date, noscapine has been explored at the 1, 7, 6', and 9'-positions, though the 1,3-benzodioxole motif in the noscapine scaffold that remains unexplored. The present investigation describes the design, synthesis and pharmacological evaluation of noscapine analogues consisting of modifications to the 1,3-benzodioxole moiety.

Comprehensive Analysis of Binding Sites in Tubulin.

Tubulin plays essential roles in vital cellular activities and is the target of a wide range of proteins and ligands. Here, using a combined computational and crystallographic fragment screening approach, we addressed the question of how many binding sites exist in tubulin. We identified 27 distinct sites, of which 11 have not been described previously, and analyzed their relationship to known tubulin-protein and tubulin-ligand interactions.

Ectopic positioning of the cell division plane is associated with single amino acid substitutions in the FtsZ-recruiting SsgB in .

In most bacteria, cell division begins with the polymerization of the GTPase FtsZ at mid-cell, which recruits the division machinery to initiate cell constriction. In the filamentous bacterium , cell division is positively controlled by SsgB, which recruits FtsZ to the future septum sites and promotes Z-ring formation. Here, we show that various amino acid (aa) substitutions in the highly conserved SsgB protein result in ectopically placed septa that sever spores diagonally or along the long axis, perpendicular to the division plane.

Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site.

Tubulin-targeted chemotherapy has proven to be a successful and wide spectrum strategy against solid and liquid malignancies. Therefore, new ways to modulate this essential protein could lead to new antitumoral pharmacological approaches. Currently known tubulin agents bind to six distinct sites at α/β-tubulin either promoting microtubule stabilization or depolymerization.