Showing papers in "MedChemComm in 2014"
TL;DR: Different modifications of nucleosides/oligonucleotides are discussed in detail along with the related clinical trials, which demonstrated their potential as drug candidates for antisense and related nucleic acid based therapeutics.
Abstract: There has been an upsurge in the number of clinical trials involving chemically modified oligonucleotide-based drug candidates after the FDA approval of Vitravene, Macugen, and recently, Kynamro. Over the years, different types of backbone, nucleobase and/or sugar-modified oligonucleotides have been synthesized because natural DNA/RNA based oligonucleotides pose some limitations, such as poor binding affinity, low degree of nuclease resistance, affecting their direct use in antisense therapeutics. In this review article, we discuss in detail different modifications of nucleosides/oligonucleotides along with the related clinical trials, which demonstrated their potential as drug candidates for antisense and related nucleic acid based therapeutics.
161 citations
TL;DR: This study synthesised a novel H2S donor molecule coupled to a mitochondria-targeting moiety and compared the effectiveness of the compound against a standard non-TPP+ containing H 2S donor in the inhibition of oxidative stress-induced endothelial cell death.
Abstract: Synthesis and bioavailability of the endogenous gasomediator hydrogen sulfide (H2S) is perturbed in many disease states, including those involving mitochondrial dysfunction. There is intense interest in developing pharmacological agents to generate H2S. We have synthesised a novel H2S donor molecule coupled to a mitochondria-targeting moiety (triphenylphosphonium; TPP+) and compared the effectiveness of the compound against a standard non-TPP+ containing H2S donor (GYY4137) in the inhibition of oxidative stress-induced endothelial cell death. Our study suggests mitochondria-targeted H2S donors are useful pharmacological tools to study the mitochondrial physiology of H2S in health and disease.
102 citations
TL;DR: In this article, the authors studied the enthalpy-entropy compensation (EEC) during the association of two molecules by minimising model systems with molecular mechanics (MM) or quantum mechanics (QM), calculating translational, rotational, and vibrational contributions to the entropy with standard statistical-mechanics methods, using the rigid-rotor harmonic-oscillator approach.
Abstract: In this paper, enthalpy–entropy compensation (EEC) during the association of two molecules is studied by minimising model systems with molecular mechanics (MM) or quantum mechanics (QM), calculating translational, rotational, and vibrational contributions to the enthalpy and entropy with standard statistical-mechanics methods, using the rigid-rotor harmonic-oscillator approach. We start with simple two-atom models, for which dispersion and electrostatics can be studied separately, showing that there is no fundamental difference between dispersion, electrostatics, or even covalent interactions. All three types of interactions give rise to EEC and a saturation of TΔS as ΔH becomes strongly negative. Next, homologous series of complexes dominated either by dispersion or hydrogen bonds are studied. We see no qualitative difference between results obtained at the MM or QM level, and for all complexes except two very weak, EEC is observed, owing to the loss of translational and rotational entropy, typically counteracted by the vibrational entropy. Within homologous series, linear relations between TΔS and ΔH with slopes of 0.1–1.7 are obtained with no clear difference between dispersive or hydrogen-bonded systems (but ∼0.01 for ionic and covalent interactions). These relations often reflect the increasing size of the complexes coming from the translational and rotational entropies, but at least for the hydrogen-bonded complexes, it is significantly enhanced also by the vibrational entropy (which depends on the strength of the interaction). Thus, for homologous series of molecules with repeated interactions studied in vacuum, EEC is a rule. However, if water molecules are added, the relation is blurred and it can be predicted that for a real binding reaction in water solution, both enthalpy–entropy compensation and anti-compensation can be observed, depending on the detailed interaction of the two molecules with water before and after binding, further complicated by dynamic effects.
98 citations
TL;DR: Basic bioluminescent imaging principles are reviewed, along with applications of the technology that are relevant to the medicinal chemistry community, including noninvasive cell tracking experiments, analyses of protein function, and methods to visualize small molecule metabolites.
Abstract: Bioluminescence is a ubiquitous imaging modality for visualizing biological processes in vivo. This technique employs visible light and interfaces readily with most cell and tissue types, making it a versatile technology for preclinical studies. Here we review basic bioluminescence imaging principles, along with applications of the technology that are relevant to the medicinal chemistry community. These include noninvasive cell tracking experiments, analyses of protein function, and methods to visualize small molecule metabolites. In each section, we also discuss how bioluminescent tools have revealed insights into experimental therapies and aided drug discovery. Last, we highlight the development of new bioluminescent tools that will enable more sensitive and multi-component imaging experiments and, thus, expand our broader understanding of living systems.
93 citations
TL;DR: It is essential to review the most commonly used H2S releasing compounds, some of which are currently in clinical trials along with their associated in vitro and/or in vivo biological effects.
Abstract: Hydrogen sulfide (H2S) has recently emerged as an important biological gasomediator as a result of numerous insightful studies. The use of H2S releasing compounds has attracted much attention as they can exert crucial effects on a wide range of cellular signaling processes. Some of these effects are potentially exploitable in terms of anti-inflammatory and anti-tumor effects, as well as precise ion-channel regulation, cardiovascular protection and oxidation resistance. Unfortunately, the potential therapeutic effects of H2S are controversial due to conflicting published results regarding its effects on cellular activities arising, perhaps in part, from the use of different H2S donors. Therefore it is essential to review the most commonly used H2S releasing compounds, some of which are currently in clinical trials along with their associated in vitro and/or in vivo biological effects.
84 citations
TL;DR: Compound 8k showed potent and reversible inhibition against lysine specific demethylase 1 with an IC50 value of 0.39 μM, which was 74-fold more potent than that of tranylcypromine (2-PCPA) and further investigation revealed that compound 8k was active at both recombinant and cell levels by upregulating the expression of H3K4me1, H3 k4me2 and H3k9me2.
Abstract: Two series of coumarin–1,2,3-triazole–dithiocarbamate hybrids were designed, synthesized and evaluated for their inhibitory activity towards lysine specific demethylase 1 (LSD1). Compounds 8a, 8d–8f, 8i–8l presented potent activity against lysine specific demethylase 1. Among them, compound 8k showed potent and reversible inhibition against lysine specific demethylase 1 with an IC50 value of 0.39 μM, which was 74-fold more potent than that of tranylcypromine (2-PCPA). Besides, compound 8k displayed excellent selectivity against lysine specific demethylase 1 without inhibition against monoamine oxidases (MAOs) A and B. Further investigation revealed that compound 8k was active at both recombinant and cell levels by upregulating the expression of H3K4me1, H3K4me2 and H3K9me2.
78 citations
TL;DR: This manuscript reviews important facets of lipid-based vesicles as drug carriers and their surface modifications to achieve controlled release and selective cell targeting and dedicated a section of this review to summarise some novel applications of various lipid liquid crystal phases in drug delivery.
Abstract: Vesicles formed by self-assembly of lipids and surfactants are increasingly recognised as carriers for drug delivery applications in disease targeting and many other biomedical-related areas, demonstrable by the growing number of significant publications. This manuscript reviews important facets of lipid-based vesicles as drug carriers and their surface modifications to achieve controlled release and selective cell targeting. We cover both the more commonly used ionic phospholipid vesicle carriers and the rapidly growing field of non-ionic vesicles/niosomes using self-assembly of uncharged amphiphilic molecules, which could be formed by using sugar surfactants or glycolipids, sorbitan esters, and polyoxyethylene alkyl ethers. Due to their lower cost, biodegradability, low-toxicity, low-immunogenicity and specific sugar-cell recognition, much attention would be devoted to glycolipid bio-surfactants as potential carriers for targeted delivery. Specifically, our review points to the design consideration of lipid and surfactant nano-carriers based on critical packing parameter, membrane curvature, and the effects of hydrophobic chain structures. We have also dedicated a section of this review to summarise some novel applications of various lipid liquid crystal phases in drug delivery, and how in turn these are related to chemical structures of the lipid entities. The final section of this review outlines the application of lipid vesicles as delivery agents for diagnostic imaging.
78 citations
TL;DR: This review presents a concise report on the endeavors to potentially use multi- and polyvalent glycoconjugates as vaccines as well as anti-infectious and anti-inflammatory drug candidates.
Abstract: Pathogens adhere to the host cells during the first steps of infection through multivalent interactions which involve protein–glycan recognition. Multivalent interactions are also involved at different stages of immune response. Insights into these multivalent interactions generate a way to use suitable carbohydrate ligands that are attached to a basic scaffold consisting of e.g., dendrimer, polymer, nanoparticle, etc., with a suitable linker. Thus a multivalent architecture can be obtained with controllable spatial and topology parameters which can interfere with pathogen adhesion. Multivalent glycoconjugates bearing natural or unnatural carbohydrate antigen epitopes have also been used as carbohydrate based vaccines to stimulate an innate and adaptive immune response. Designing and synthesizing an efficient multivalent architecture with optimal ligand density and a suitable linker is a challenging task. This review presents a concise report on the endeavors to potentially use multi- and polyvalent glycoconjugates as vaccines as well as anti-infectious and anti-inflammatory drug candidates.
77 citations
TL;DR: PRMT inhibitors can compete with cofactor, substrate, or bind at allosteric sites found in the active or inactive states.
Abstract: Protein arginine methyltransferases (PRMTs), an emerging target class in drug discovery, can methylate histones and other substrates, and can be divided into three subgroups, based on the methylation pattern of the reaction product (monomethylation, symmetrical or asymmetrical dimethylation). Here, we review the growing body of structural information characterizing this protein family, including structures in complex with substrate-competitive and allosteric inhibitors. We outline structural differences between type I, II and III enzymes and propose a model underlying class-specificity. We analyze the structural plasticity and diversity of the substrate, cofactor and allosteric binding sites, and propose that the conformational dynamics of PRMTs can be exploited towards the discovery of allosteric inhibitors that would antagonize conformationally active states.
72 citations
TL;DR: Both nitrobenzoyl sesquiterpenoids isolated from extracts of the culture of marine-derived fungus Aspergillus ochraceus showed significant cytotoxicities against 10 cancer cell lines, and the new one also showed antiviral activities against H3N2 and EV71.
Abstract: Nitrobenzoyl sesquiterpenoids are rare in natural sources, and fungi Aspergillus species are the only sources of them. A new nitrobenzoyl sesquiterpenoid, 6β,9α-dihydroxy-14-p-nitrobenzoylcinnamolide (1), and a known analogue, insulicolide A (2), were isolated from extracts of the culture of marine-derived fungus Aspergillus ochraceus Jcma1F17, which was identified by morphological and ITS phylogenetic analyses. The structures were determined by NMR, MS, CD, and optical rotation analyses. Both nitrobenzoyl sesquiterpenoids displayed significant cytotoxicities against 10 cancer cell lines, and the new one (1) also showed antiviral activities against H3N2 and EV71. This is the first time that nitrobenzoyl sesquiterpenoids from A. ochraceus have been reported.
69 citations
TL;DR: Some of the new trends observed in the use of AGs in the past decade are presented, along with the current understanding of their mechanisms of action in various bacterial and eukaryotic cellular processes.
Abstract: Despite their inherent toxicity and the acquired bacterial resistance that continuously threaten their long-term clinical use, aminoglycosides (AGs) still remain valuable components of the antibiotic armamentarium. Recent literature shows that the AGs' role has been further expanded as multi-tasking players in different areas of study. This review aims at presenting some of the new trends observed in the use of AGs in the past decade, along with the current understanding of their mechanisms of action in various bacterial and eukaryotic cellular processes.
TL;DR: Small molecules that seek to modulate multiple targets with the ultimate goal of harnessing network pharmacology for therapeutic applications in AD and NTDs are explored.
Abstract: In the past decade, scientific advances in network pharmacology have laid the foundations for a polypharmacological approach to discover new drugs for complex diseases. There is now a comprehensive understanding that many incurable diseases are multifactorial in nature and, consequently, conventional drugs directed to a single molecular target are inadequate. To achieve a desired clinical outcome, a polypharmacological approach seeks to intervene in the diseased network using either combinations of multiple drugs or single small molecules modulating multiple targets. Both these approaches are equally feasible from a clinical standpoint. However, for various reasons which will be discussed in this review, the latter approach may be favoured for Alzheimer's disease (AD) and neglected tropical diseases (NTDs). With each passing year, an increasing number of multitarget drugs and drug candidates are being identified, and several proof-of-concepts for treating these two diseases have emerged. Herein, with an awareness of the obstacles and challenges faced, we explore small molecules that seek to modulate multiple targets with the ultimate goal of harnessing network pharmacology for therapeutic applications in AD and NTDs.
TL;DR: In this Review, recent years' progress in the development of cationic amphiphiles that target the bacterial membrane bilayer as a strategy for theDevelopment of antibiotics is presented.
Abstract: Infections caused by drug resistant and/or slow-growing bacteria are increasingly becoming some of the greatest challenges of health organizations worldwide. The decrease in the efficacy of a large percentage of the current repertoire of clinically used antibiotics against these types of infections emphasizes the need for the development of novel antimicrobial agents that will effectively eradicate a broad spectrum of bacteria regardless of the bacterial cell cycle stage. In this Review, we present recent years' progress in the development of cationic amphiphiles that target the bacterial membrane bilayer as a strategy for the development of antibiotics. Synthesis, antimicrobial activity, membrane selectivity and modes of action aspects are discussed.
TL;DR: A series of potent LSD1 inhibitors based on a novel 1,2,4-triazole scaffold are described, which show a high degree of specificity for LSD1 in vitro, and cause increases in cellular histone 3 dimethyllysine 4 (H3K4me2), a gene transcription activating mark.
Abstract: The chromatin remodeling amine oxidase lysine-specific demethylase 1 (LSD1) has become an attractive target for the design of specific inhibitors with therapeutic potential. We, and others, have described LSD1 inhibitors that have potential as antitumor agents. Many of the currently known LSD1 inhibitors are poor drug candidates, or are structurally based on the tranylcypromine backbone, thus increasing the potential for off-target effects mediated by other amine oxidases. We now describe a series of potent LSD1 inhibitors based on a novel 1,2,4-triazole scaffold; these inhibitors show a high degree of specificity for LSD1 in vitro, and cause increases in cellular histone 3 dimethyllysine 4 (H3K4me2), a gene transcription activating mark. Importantly, these inhibitors exhibit low toxicity towards mammalian cells in vitro, and thus they may show utility in the treatment of epigenetically-based diseases where cell death is not a desired endpoint.
TL;DR: The design and synthesis of a dual active histone deacetylase (HDAC)/bromodomain and extra terminal (BET) small molecule tool inhibitor, DUAL946 is described, which was confirmed by in vitro biochemical and biophysical testing and through chemoproteomic competition experiments in cell lysates.
Abstract: Herein we describe the design and synthesis of a dual active histone deacetylase (HDAC)/bromodomain and extra terminal (BET) small molecule tool inhibitor, DUAL946 (1). Exploiting our extensive epigenetic toolbox, we achieved the functionalisation of a BET active tetrahydroquinoline (THQ) core, with a hydroxamic acid HDAC inhibitor (HDACi) motif. Dual inhibition of BET and HDAC proteins was confirmed by in vitro biochemical and biophysical testing and through chemoproteomic competition experiments in cell lysates. This activity was translated into potent cellular activity in both immune and cancer cells.
TL;DR: Recent progress in affinity-based approaches for small-molecule target identification with a focus on affinity purification are reviewed, including a nonselective universal coupling method based on a photo-affinity reaction.
Abstract: Identification of the cellular targets of bioactive small molecules is a crucial step in drug discovery and chemical genetics. Classical affinity purification with small-molecule affinity probes remains the most common approach, but it remains a considerable challenge. To overcome various drawbacks in probe preparation, nonspecific interactions, and the sensitivity of target detection, new methods and techniques are being developed, such as a nonselective universal coupling method based on a photo-affinity reaction, which enables introduction of a variety of small molecules to a solid support without chemical modification to generate small-molecule affinity probes. Here, we review recent progress in affinity-based approaches for small-molecule target identification with a focus on affinity purification.
TL;DR: H hierarchical structure-based virtual screening utilizing the receptor–ligand binding model of Nrf2–Keap1 is first reported, which can serve as a promising starting point for the discovery of potent inhibitors of NRF2– Keap1 interaction.
Abstract: Herein we first reported hierarchical structure-based virtual screening utilizing the receptor–ligand binding model of Nrf2–Keap1. The most promising compound, 15, which is one of the most potent direct PPI inhibitors of Nrf2–Keap1 reported so far, can effectively disrupt the Nrf2–Keap1 interaction with the in vitro EC50 of 9.80 μM in the fluorescence polarization (FP) assay. 15 can also activate the Nrf2 transcription activity in the cell-based ARE–luciferase reporter assays in a dose-dependent manner. The compound can serve as a promising starting point for the discovery of potent inhibitors of Nrf2–Keap1 interaction.
TL;DR: It is shown that 2d is a promising candidate for the development of safer and more potent fruit and food browning preventatives and skin-lightening medicines and the “β-phenyl-α,β-unsaturated carbonyl” group is essential for potent anti-tyrosinase activity.
Abstract: Based on the structural characteristics of the heterocyclic scaffolds of substituted benzylidene-hydantoin, -pyrrolidinedione, and -thiazolidinedione derivatives with potent tyrosinase inhibitory activity, substituted benzylidene derivatives with a 2-thiohydantoin heterocyclic scaffold were synthesized by modified Knoevenagel condensation between benzaldehydes and 2-thiohydantoin with a view toward producing more potent, safer tyrosinase inhibitors capable of being utilized in the agricultural, food, cosmetics, and pharmaceutical industries. Of the twelve compounds synthesized, three compounds, 2c, 2d and 2i, exhibited even more potent inhibitory activities against mushroom tyrosinase than kojic acid or resveratrol, which are well-known potent tyrosinase inhibitors. The inhibitory pattern of compounds with a thiohydantoin template differed from that of compounds with a hydantoin, pyrrolidinedione, or thiazolidine scaffold, probably because of the loss of the hydrogen bonding ability of the thiocarbonyl group of thiohydantoin. Considering the high tyrosinase inhibitory activities of 5-(substituted benzylidene)thiohydantoin derivatives, the thiohydantoin template is considered a near perfect surrogate for hydantoin, pyrrolidinedione, and thiazolidinedione scaffolds. (Z)-5-(2,4-Dihydroxybenzylidene)-2-thiohydantoin (2d, IC50 = 1.07 ± 2.30 μM) had 24 times the inhibitory effect of resveratrol (IC50 = 26.63 ± 0.55 μM) and 18 times that of kojic acid (IC50 = 19.69 ± 4.90 μM) against mushroom tyrosinase and showed anti-melanogenesis through the inhibition of tyrosinase activity in B16 cells with no appreciable cytotoxicity, which suggests that 2d is a promising candidate for the development of safer and more potent fruit and food browning preventatives and skin-lightening medicines. This result and our previous data indicate that it is the “β-phenyl-α,β-unsaturated carbonyl” group that is essential for potent anti-tyrosinase activity.
TL;DR: A series of twenty six structurally diverse α-aminophosphonates have been synthesized and evaluated for in vitro anti-leishmanial activity and cytotoxicity using the MTT assay and seven compounds exhibited anti-Leishmanian potency against the L. donovani promastigote.
Abstract: A series of twenty six structurally diverse α-aminophosphonates have been synthesized and evaluated for in vitro anti-leishmanial activity and cytotoxicity using the MTT assay. Among them, seven compounds (1–7) exhibited anti-leishmanial potency against the L. donovani promastigote with IC50 values in the low micromolar range. The structure–activity relationships were quantitatively evaluated by a statistically reliable CoMFA model with high predictive abilities (r2pred = 0.87, r2ncv = 0.985).
TL;DR: The following review highlights key developments in the biological studies conducted on α-hydroxytropolones to date, including the few synthetic chemistry-driven optimization studies.
Abstract: α-Hydroxytropolones are a subclass of the troponoid family of natural products that are of high interest due to their broad biological activity and potential as treatment options for several diseases. Despite this promise, there have been scarce synthetic chemistry-driven optimization studies on the molecules. The following review highlights key developments in the biological studies conducted on α-hydroxytropolones to date, including the few synthetic chemistry-driven optimization studies. In addition, we provide an overview of the methods currently available to access these molecules. This review is intended to serve as a resource for those interested in biological activity of α-hydroxytropolones, and inspire the development of new synthetic methods and strategies that could aid in this pursuit.
TL;DR: This work introduces synthetically accessible MMPs that are automatically generated by applying reaction rules following the retrosynthetic combinatorial analysis procedure (RECAP), and a library of more than 92 000 RECAP-MMPs was generated from public domain compounds active against 435 different targets exclusively utilizing high-confidence activity data.
Abstract: Matched molecular pairs (MMPs) are defined as pairs of compounds that only differ by a chemical change at a single site. MMPs have become popular in medicinal chemistry to support lead optimization, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis, and other applications. Thus far, MMPs have been algorithmically defined and not on the basis of reaction information. This often limits the chemical interpretability and practical utility of MMPs. Therefore, we introduce synthetically accessible MMPs that are automatically generated by applying reaction rules following the retrosynthetic combinatorial analysis procedure (RECAP). A library of more than 92 000 RECAP-MMPs was generated from public domain compounds active against 435 different targets exclusively utilizing high-confidence activity data. This library is made freely available for use in medicinal chemistry.
TL;DR: Nine crystal structures of fragments including thymidine, a novel acetyl-lysine mimetic ligand are described and the evaluation of the binding properties of the identified fragments using NMR chemical shift perturbation experiments offer chemical starting points for the development of more potent ATAD2 inhibitors.
Abstract: The transcriptional co-regulator ATAD2 is a prognostic marker for patient survival in many cancers. ATAD2 harbours a bromodomain which may offer an opportunity for pharmacological intervention, but its shallow, polar binding surface makes the development of inhibitors challenging. Here we optimized crystal transfer/soaking conditions enabling crystallographic fragment screening. We describe nine crystal structures of fragments including thymidine, a novel acetyl-lysine mimetic ligand and the evaluation of the binding properties of the identified fragments using NMR chemical shift perturbation experiments. The presented binding modes offer chemical starting points for the development of more potent ATAD2 inhibitors.
TL;DR: In this study, multiple non-toxic compounds with high potency against T. brucei and P. falciparum are identified with good selectivity and may represent an opportunity for continued optimization.
Abstract: Hesperadin, an established human Aurora B inhibitor, was tested against cultures of Trypanosoma brucei, Leishmania major, and Plasmodium falciparum, and was identified to be a potent proliferation inhibitor. A series of analogs was designed and tested to establish the initial structure–activity relationships for each parasite. In this study, we identified multiple non-toxic compounds with high potency against T. brucei and P. falciparum with good selectivity. These compounds may represent an opportunity for continued optimization.
TL;DR: The discovery of amphiphilic kanamycins that are antifungal, but not antibacterial, and that inhibit the growth of fungi by perturbation of plasma membrane functions are summarized.
Abstract: The attachment of alkyl and other hydrophobic groups to traditional antibacterial kanamycins and neomycins creates amphiphilic aminoglycosides with altered antimicrobial properties. In this review, we summarize the discovery of amphiphilic kanamycins that are antifungal, but not antibacterial, and that inhibit the growth of fungi by perturbation of plasma membrane functions. With low toxicities against plant and mammalian cells, they appear to specifically target the fungal plasma membrane. These new antifungal agents offer new options for fighting fungal pathogens and are examples of reviving old drugs to confront new therapeutic challenges.
TL;DR: The synthesis of heterocyclic betulin derivatives and their activity against Leishmania donovani is reported and compound 8 showed the best activity and selectivity, and its activity was tested on infected macrophages using a concentration, 5 μM, where no macrophage toxicity was exhibited.
Abstract: The synthesis of heterocyclic betulin derivatives and their activity against Leishmania donovani is reported. Betulonic acid was used as a versatile intermediate. Several different fused heterocycles were introduced at the 2,3-position of the lupane skeleton including isoxazole, pyrazine, pyridine, indole and pyrazole rings. Also the 28-position was modified. Three compounds, 5, 8 and 25, showed low micromolar activity with IC50 values of 13.2, 4.3 and 7.2 μM, respectively. Compound 8 showed the best activity and selectivity, and its activity was tested on infected macrophages using a concentration, 5 μM, where no macrophage toxicity was exhibited. Interestingly, the activity of compound 8 on axenic amastigotes and Leishmania-infected macrophages was similar.
TL;DR: Some of the most advanced preclinical and clinical activities in the field of armed antibodies are reviewed and a personal perspective on the opportunities and challenges associated with the use of this type of anti-cancer therapeutics is presented.
Abstract: Monoclonal antibodies represent the largest and fastest growing type of biopharmaceuticals. Their commercial and clinical success has fueled research activities aiming to improve safety and efficacy. In oncology, there is a trend towards the development of ‘armed’ antibody products, in which the immunoglobulin moiety serves for the selective in vivo pharmacodelivery of bioactive payloads such as cytotoxic drugs, bispecific antibodies, radionuclides or cytokines to sites of disease, thereby sparing healthy tissues. In this article, we review some of the most advanced preclinical and clinical activities in the field of armed antibodies and present a personal perspective on the opportunities and challenges associated with the use of this type of anti-cancer therapeutics.
TL;DR: The molecular docking studies of 5bf predict it to be a ligand for the M. tuberculosis HisG, the putative drug target for tuberculosis and could serve as a guiding principle for lead optimization.
Abstract: Benzothiazole-2-carboxyarylalkylamides are reported as a new class of potent anti-mycobacterial agents. Forty-one target compounds have been synthesized following a green synthetic strategy using water as the reaction medium to construct the benzothiazole scaffold followed by (i) microwave-assisted catalyst-free and (ii) ammonium chloride-catalyzed solvent-free amide coupling. The anti-mycobacterial potency of the compounds was determined against H37Rv strain. Twelve compounds exhibited promising anti-TB activity in the range of 0.78–6.25 μg mL−1 and were found to be non-toxic ( 64). The molecular docking studies of 5bf predict it to be a ligand for the M. tuberculosis HisG, the putative drug target for tuberculosis and could serve as a guiding principle for lead optimization.
TL;DR: The in-house IIIM natural product repository of 302 small molecules was screened for their ability to inhibit P-glycoprotein in Pgp-overexpressing human adenocarcinoma LS-180 cells and curcumin and osthol showed significant inhibition of the S. aureus NorA efflux pump.
Abstract: The in-house IIIM natural product repository of 302 small molecules was screened for their ability to inhibit P-glycoprotein (Pgp) in Pgp-overexpressing human adenocarcinoma LS-180 cells. The screening has identified 13 natural products displaying significant Pgp-inhibition activity, which include praeruptorin B, curcumin, imperatorin, osthol, 5,7-diacetoxy-8-(3-methyl-2-butenyl)-coumarin, 5,7-dihydroxy-8-(3-methyl-2-butenyl) coumarin, pongamol, phellopterin, tangeretin, 3-(2-methyl but-3-en-2-yl) xanthyletin, 7-demethyl osthol, allorottlerin and tetrahydroangeolide. These natural products were then screened for their effects on bacterial efflux pump inhibition activity against NorA (Staphylococcus aureus), MdeA (S. aureus Mupr-1), TetK (S. aureus SA-K2192), and MsrA (S. aureus SA-K2191) efflux pumps. Curcumin and osthol showed significant inhibition of the S. aureus NorA efflux pump with 8- and 4-fold reductions in the MIC of ciprofloxacin at 25 μM. The molecular docking studies of curcumin and osthol with the human Pgp and S. aureus NorA efflux pump identified plausible binding modes and binding sites for these natural products.
TL;DR: The pharmaceutical industry has much that it can share in terms of drug discovery capacity, know-how, and expertise, and in some cases has been moving towards new paradigms of collaborative pre-competitive research with the PDPs and partners.
Abstract: Neglected and tropical diseases affect a large proportion of the world's population and impose a huge economic and health burden on developing countries. Despite this, there is a dearth of safe, effective, suitable medications for treatment of these diseases, largely as a result of an underinvestment in developing new drugs against these diseases by the majority of research-based pharmaceutical companies. In the past 12 years, the situation has begun to improve with the emergence of public-private product development partnerships (PDPs), which foster a collaborative approach to drug discovery and have established strong drug development pipelines for neglected and tropical diseases. Some large pharmaceutical companies have also now established dedicated research sites for developing world diseases and are working closely with PDPs on drug development activities. However, drug discovery in this field is still hampered by a lack of sufficient funding and technological investment, and there is a shortage of the tools, assays, and well-validated targets needed to ensure strong drug development pipelines in the future. The availability of high-quality chemically diverse compound libraries to enable lead discovery remains one of the critical bottlenecks. The pharmaceutical industry has much that it can share in terms of drug discovery capacity, know-how, and expertise, and in some cases has been moving towards new paradigms of collaborative pre-competitive research with the PDPs and partners. The future of drug discovery for neglected and tropical diseases will depend on the ability of those working in the area to collaborate together and will require sustained resourcing and focus.
TL;DR: A series of novel 2-aryl-3-arylamino-imidazo-pyridines/pyrazines as potential antitubulin anticancer agents showed potent anticancer activities in kidney, breast and cervical cancer cell lines, and relatively low toxicity to normal cells, compared to CA-4.
Abstract: Based on the pharmacophoric features of the natural product combretastatin A-4 (CA-4) and its synthetic analogues that inhibit tubulin polymerization, a series of novel 2-aryl-3-arylamino-imidazo-pyridines/pyrazines as potential antitubulin anticancer agents were designed. They were synthesized by a one-pot method involving preparation of isocyanides from the anilines via formylation and subsequent dehydration followed by their reactions with heterocyclic-2-amidines and aldehydes. Compounds 1, 2, 14, and 15 were found to exhibit significant tubulin polymerization inhibition and disruption of tubulin–microtubule dynamics similar to that of CA-4. They showed potent anticancer activities in kidney, breast and cervical cancer cell lines, and relatively low toxicity to normal cells, compared to CA-4. The compounds induced DNA and chromosomal damage, and apoptosis via cell cycle arrest in the G2/M phase. The molecular docking and molecular dynamics (MD) simulation studies revealed that disruption of microtubule dynamics might occur by interaction of the compounds at the colchicine binding site of the α,β-tubulin heterodimer interface, similar to that of CA-4. Molecular modelling analysis showed that two of the three methoxy groups at ring A of all four potent compounds (1, 2, 14, and 15) were involved in bifurcated hydrogen bonding with Cysβ241, an important molecular recognition interaction to show tubulin inhibitory activity. In comparison to CA-4, the bridging NH and the imidazo-pyridine/pyrazine moieties in the title compounds provide flexibility for attaining the required dihedral relationship of two aryls and additional pharmacophoric features required for the interaction with the key residues of the colchicine binding site.