Since the discovery of the cisplatin antitumor activity, great efforts have focused on the rational design of metal-based anticancer agents that can be potentially used in cancer chemotherapy. Over the last four decades, a large number of metal complexes have been extensively investigated and evaluated and , and some of them were at different stages of clinical studies. Amongst these complexes, platinum (Pt and Pt ), ruthenium (Ru and Ru ), gold (Au and Au ) and titanium (Ti ) complexes are the most studied metals. We describe here some most recent progresses on Pt prodrugs which can be activated once enter tumor cells, polynuclear Pt complexes which have unique DNA binding ability and mode, anti-metastatic Ru /Ru complexes, and Au /Au and Ti antitumor active complexes. The key focuses of these studies lie in finding novel metal complexes which could potentially overcome the hurdles of current clinical drugs including toxicity, resistance and other pharmacological deficiencies.
Cyclic peptides combine several favorable properties such as good binding affinity, target selectivity and low toxicity that make them an attractive modality for the development of therapeutics. Over 40 cyclic peptide drugs are currently in clinical use and around one new cyclic peptide drug enters the market every year on average. The vast majority of clinically approved cyclic peptides are derived from natural products, such as antimicrobials or human peptide hormones. New powerful techniques based on rational design and evolution have enabled the development of cyclic peptide ligands to targets for which nature does not offer solutions. A look at the cyclic peptides currently under clinical evaluation shows that several have been developed using such techniques. This new source for cyclic peptide ligands introduces a freshness to the field, and it is likely that developed cyclic peptides will be in clinical use in the near future.
This review explores the concept of using privileged scaffolds to identify biologically active compounds through building chemical libraries. We hope to accomplish three main objectives: to provide one of the most comprehensive listings of privileged scaffolds; to reveal through four selected examples the present state of the art in privileged scaffold library synthesis (in hopes of inspiring new and even more creative approaches); and also to offer some thoughts on how new privileged scaffolds might be identified and exploited.
Organisms use diverse mechanisms involving multiple complementary enzymes, particularly glycoside hydrolases (GHs), to deconstruct lignocellulose. Lytic polysaccharide monooxygenases (LPMOs) produced by bacteria and fungi facilitate deconstruction as does the Fenton chemistry of brown-rot fungi. Lignin depolymerisation is achieved by white-rot fungi and certain bacteria, using peroxidases and laccases. Meta-omics is now revealing the complexity of prokaryotic degradative activity in lignocellulose-rich environments. Protists from termite guts and some oomycetes produce multiple lignocellulolytic enzymes. Lignocellulose-consuming animals secrete some GHs, but most harbour a diverse enzyme-secreting gut microflora in a mutualism that is particularly complex in termites. Shipworms however, house GH-secreting and LPMO-secreting bacteria separate from the site of digestion and the isopod relies on endogenous enzymes alone. The omics revolution is identifying many novel enzymes and paradigms for biomass deconstruction, but more emphasis on function is required, particularly for enzyme cocktails, in which LPMOs may play an important role.
Molecular imaging often relies on the use of targeted and activatable reporters to quantitate and visualize targets, biological processes, and cells . The use of optical probes with near-infrared fluorescence allows for improved photon penetration through tissue and minimizes the effects of tissue autofluorescence. There are several parameters that define the effectiveness of imaging agents . These factors include probe targeting, activation, pharmacokinetics, biocompatibility, and photophysics. Recent advances in our understanding of these variables as they pertain to the application of optical reporters for imaging are discussed in this review.
The antibody–drug conjugate field has made significant progress recently owing to careful optimization of several parameters, including mAb specificity, drug potency, linker technology, and the stoichiometry and placement of conjugated drugs. The underlying reason for this has been obtained in pre-clinical biodistribution and pharmacokinetics studies showing that targeted delivery leads to high intratumoral free drug concentrations, while non-target tissues are largely spared from chemotherapeutic exposure. Recent developments in the field have led to an increase in the number of ADCs being tested clinically, with 3 in late stage clinical trials: brentuximab vedotin (also referred to as SGN-35) for Hodgkin lymphoma; Trastuzumab-DM1 for breast cancer; and Inotuzumab ozogamicin for non-Hodgkin lymphoma. This review highlights the recent pre-clinical and clinical advances that have been made.
Nanoparticle-based therapeutics have received increasing attention, as these systems can alleviate many drawbacks of conventional therapy. Metal–organic frameworks (MOFs), a new class of hybrid materials composed of metal ions and organic bridging ligands, have emerged as a promising platform for drug delivery, owing to their high drug loadings, biodegradability, and versatile functionality. The bulk MOF materials can absorb and release large amounts of therapeutics including ibuprofen, procainamide, and nitric oxide. Scale-down of MOFs to the nanoregime yields nanoscale metal–organic frameworks (NMOFs) that are more applicable as delivery vehicles, such as selective delivery of cisplatin prodrugs. Although progress has been made in utilizing NMOFs for drug delivery, many improvements must occur before they can become viable nanotherapeutics.
Available biomass, preferentially residues, can be divided in two groups: biomass with a high or natural water content (‘wet’ or ‘green’ biomass) and biomass with low water content such as wood and straw. In ‘dry’ biomass gasification processes, originating in most coal processing technologies, biomass of low water content is necessary to avoid the energy loss by water evaporation. In contrast, hydrothermal processes need water as reaction medium; therefore, these processes are preferentially used for wet or ‘green’ biomass. In this review paper we will describe the main research directions in the hydrothermal conversion of biomass into fuels and carbon throughout gasification to produce H or CH , liquefaction to produce crude oils and phenols from lignin as well as carbonization to produce carbonaceous materials which can be either used as fuels (carbon negative chars) or interesting energetic materials (hydrothermal carbons).
Fluorescent dyes based on small organic molecules that function in the near infrared (NIR) region are of great current interest in chemical biology. They allow for imaging with minimal autofluorescence from biological samples, reduced light scattering, and high tissue penetration. Herein, examples of ongoing NIR fluorophore design strategies as well as their properties and anticipated applications relevant to the bioimaging are presented.
► Organometallic complexes have a huge potential in medicinal chemistry. ► Organometallic compounds have specific advantages over purely organic compounds. ► The use of organometallics compounds is not limited to anti-cancer research. ► An organometallic compound could be the next anti-malarial drug on the market. Organometallic complexes have unique physico-chemical properties, which have been widely used in homogenous catalysis, for example, for the synthesis of lead compounds and drug candidates. Over the past two decades, a few scientists from all over the world have extended the use of the specific characteristics of these compounds (e.g. structural diversity, possibility of ligand exchange, redox and catalytic properties) for medicinal purposes. The results are stunning. A few organometallic compounds have already entered clinical trials and it can be anticipated that several more will follow in coming years. In this short review, we present the specific advantages that organometallic metal complexes have over purely organic and also coordination compounds. Furthermore, using specific examples, we illustrate how these particular properties can be put to good use in medicinal chemistry. The examples we present have an emphasis on, but are not restricted to, anti-cancer activity.
Medicinal inorganic chemistry can exploit the unique properties of metal ions for the design of new drugs. This has, for instance, led to the clinical application of chemotherapeutic agents for cancer treatment, such as cisplatin. The use of cisplatin is, however, severely limited by its toxic side-effects. This has spurred chemists to employ different strategies in the development of new metal-based anticancer agents with different mechanisms of action. Recent trends in the field are discussed in this review. These include the more selective delivery and/or activation of cisplatin-related prodrugs and the discovery of new non-covalent interactions with the classical target, DNA. The use of the metal as scaffold rather than reactive centre and the departure from the cisplatin paradigm of activity towards a more targeted, cancer cell-specific approach, a major trend, are discussed as well. All this, together with the observation that some of the new drugs are organometallic complexes, illustrates that exciting times lie ahead for those interested in ‘metals in medicine’.
Over the last two decades, directed evolution has become a staple in protein engineering and ushered in a new era of industrial biocatalysis. Directed evolution has provided the tools to not only improve the activity of known biocatalysts, but also to endow biocatalysts with chemical reactivities not previously encountered in nature. Here we will discuss the recent successes in the quest to enhance thermostability, stereoselectivity and activity of biocatalysts, as well as to create novel enzymes, over the last two years.
Upconverting luminescent nanoparticles (UCNPs) display the unique property of emitting visible light following photoexcitation with near-infrared laser light. This results in features such as virtually zero autofluorescence of (biological) matter and easy separation of the emission peaks from stray light. Other features include rather narrow emission bands, very high chemical stability, the lack of bleaching, and the absence of blinking effects. This article reviews the work performed in the past few years with UCNPs in terms of surface modifications, bioconjugation, and optical (cellular) imaging.
Plant biomass represents a renewable carbon feedstock that could potentially be used to replace a significant level of petroleum-derived chemicals. One major challenge in its utilization is that the majority of this carbon is trapped in the recalcitrant structural polymers of the plant cell wall. Deconstruction of lignin is a key step in the processing of biomass to useful monomers but remains challenging. Microbial systems can provide molecular information on lignin depolymerization as they have evolved to break lignin down using metalloenzyme-dependent radical pathways. Both fungi and bacteria have been observed to metabolize lignin; however, their differential reactivity with this substrate indicates that they may utilize different chemical strategies for its breakdown. This review will discuss recent advances in studying bacterial lignin degradation as an approach to exploring greater diversity in the environment.
► Hydrogen sulfide (H S) can mediate physiology and disease pathology in mammalian systems. ► The development of molecular probes for H S detection allows H S to be studied in intact cells, tissues, or whole organisms. ► Current probes employ a variety of reaction-based strategies to achieve selectivity for H S over other biological thiols. Hydrogen sulfide (H S) has long been recognized as a toxic molecule in biological systems. However, emerging studies now link controlled fluxes of this reactive sulfur species to cellular regulation and signaling events akin to other small molecule messengers, such as nitric oxide, hydrogen peroxide, and carbon monoxide. Progress in the development of fluorescent small-molecule indicators with high selectivity for hydrogen sulfide offers a promising approach for studying its production, trafficking, and downstream physiological and/or pathological effects.
In 2000, the first chemical screen using living zebrafish in a multi-well plate was reported. Since then, more than 60 additional screens have been published describing whole-organism drug and pathway discovery projects in zebrafish. To investigate the scope of the work reported in the last 14 years and to identify trends in the field, we analyzed the discovery strategies of 64 primary research articles from the literature. We found that zebrafish screens have expanded beyond the use of developmental phenotypes to include behavioral, cardiac, metabolic, proliferative and regenerative endpoints. Additionally, many creative strategies have been used to uncover the mechanisms of action of new small molecules including chemical phenocopy, genetic phenocopy, mutant rescue, and spatial localization strategies.
Interest in multicomponent reactions (MCRs) has surged during the past two decades as interest in the efficient synthesis of small molecule libraries has gained prominence. MCRs fill an important niche in library synthesis by providing direct access to library compounds and by serving as starting points for Diversity-Oriented Synthesis (DOS). Recent advances in the area of MCR chemistry have included the discovery of new reactions, development of the first asymmetric catalysts, and the application of MCRs to natural products and other targets of biological interest. This review will highlight recent developments in MCRs as a rich source of molecular diversity.
Novel enzyme activities and chemoenzymatic reaction concepts have considerably expanded the biocatalytic toolbox for chiral amine synthesis. Creating new activities or extending the scope of existing enzymes by protein engineering is a common trend in biocatalysis and in chiral amine synthesis specifically. For instance, an amine dehydrogenase that allows for the direct asymmetric amination of ketones with ammonia was created by mutagenesis of an amino acid dehydrogenase. Another trend in chiral amine chemistry is the development of strategies allowing for the synthesis of secondary amines. For example the smart choice of substrates for amine transaminases provided access to secondary amines by chemoenzymatic reactions. Furthermore novel biocatalysts for the synthesis of secondary amines such as imine reductases and Pictet-Spenglerases have been identified and applied. Recent examples showed that the biocatalytic amine synthesis is emerging from simple model reactions towards industrial scale preparation of pharmaceutical relevant substances, for instance, as shown in the synthesis of a Janus kinase 2 inhibitor using an amine transaminase. A comparison of important process parameters such as turnover number and space–time yield demonstrates that biocatalytic strategies for asymmetric reductive amination are maturing and can already compete with established chemical methods.
The aromatic heteropolymer lignin is a major component of plant cell walls, and is produced industrially from paper/pulp manufacture and cellulosic bioethanol production. Conversion of lignin into renewable chemicals is a major unsolved problem in the development of a biomass-based biorefinery. The review describes recent developments in the understanding of bacterial enzymes for lignin breakdown, such as DyP peroxidases, bacterial laccases, and beta-etherase enzymes. The use of pathway engineering methods to construct genetically modified microbes to convert lignin to renewable chemicals (e.g. vanillin, adipic acid) via fermentation is discussed, and the search for novel applications for lignin (e.g. carbon fibre).
This review deals with the design and application strategies of new antibiotics based on naturally occurring antimicrobial peptides (AMPs). The initial candidate can be designed based on three-dimensional structure or selected from a library of peptides from natural or laboratory sources followed by optimization via structure-activity relationship studies. There are also advanced application strategies such as induction of AMP expression from host cells by various factors ( ., metals, amino acids, vitamin D and sunlight), the use of engineered probiotic bacteria to deliver peptides, the design of prodrug and peptide conjugates to improve specific targeting. In addition, combined uses of newly developed AMPs with existing antimicrobial agents may provide a practical avenue for effective management of antibiotic-resistant bacteria (superbugs), including biofilms. Finally, we highlight AMPs already in use or under clinical trials.