Synthesis, solution structure, and bioactivity of six new simplified analogues of the natural cyclodepsipeptide jaspamide

Recently, we described the synthesis and the biological evaluation of three modified analogues of jaspamide (1), a natural cyclodepsipeptide possessing a potent antitumor activity as a consequence of its ability to interfere with actin cytoskeleton. To obtain additional information on the potential pharmacophoric core of the target molecule, which is of fundamental importance to discover new and more effective anticancer products, we decided to explore the biological effects of further structural modifications carried out on the parent molecule. The synthesis and the chemical characterization of six jaspamide analogues (2-7) are reported and their conformational and biological properties are described.     

At the crossroads of chemistry and biology

The life sciences are molecular and the harnessing of information gleaned from genomics and proteomics will require interdisciplinary research integrating chemistry and biology. This approach is illustrated by the synthesis and biological evaluation of lipidated peptides and proteins and the delineation of a concept arguing for natural product guided combinatorial chemistry.     

Synthesis of chiral phosphorus mustards derived from serine

The synthesis and biological evaluation of chiral, diastereomeric phosphorus mustards derived from natural and unnatural serine are reported herein.     

4-Aminothiazolyl analogs of GE2270 A: design, synthesis and evaluation of imidazole analogs

Imidazole analogs of the antibiotic natural product GE2270 A (1) were designed, synthesized, and evaluated for Gram positive bacteria growth inhibition. A recently reported, copper-mediated synthesis was exploited to prepare 4-thiazolyl imidazole analogs of 1. The synthesis described represents a structurally complex, natural product-based application of this recently reported synthetic methodology. In addition, the biological evaluation of the imidazole-based analogs further define the SAR of the 4-aminothiazolyl-based antibacterial template.     

Design, synthesis, and biological evaluation of novel human 5'-deoxy-5'-methylthioadenosine phosphorylase (MTAP) substrates

The structure-based design, chemical synthesis, and biological evaluation of novel MTAP substrates are described. These compounds incorporate various C5'-moieties and are shown to have different k(cat)/K(m) values compared with the natural MTAP substrate (MTA).     

The enone motif of (+)-grandifloracin is not essential for ‘anti-austerity’ antiproliferative activity

We report the synthesis and biological evaluation of three analogues of the natural product (+)-grandifloracin (+)-1. All three analogues exhibit enhanced antiproliferative activity against PANC-1 and HT-29 cells compared to the natural product. The retention of activity in an analogue lacking the enone functional group, 9, implies this structural element is not an essential part of the (+)-grandifloracin pharmacophore.     

γ-Pyrone natural products—A privileged compound class provided by nature

In “Biology Oriented Synthesis” (BIOS), the inherent biological relevance of natural products is employed for the design and synthesis of compound libraries. Towards this end, library generation in BIOS is focused on compound classes from biologically relevant space such as the natural product space or also the drug space and only scaffolds of these areas of proven relevance are employed for synthesis of small focused libraries with limited diversity. We here present a short overview of γ-pyrone natural products, highlighting their biological properties and their potential applicability in a BIOS of a compound library.     

Synthesis and biological evaluation of thielocin B1 analogues as protein-protein interaction inhibitors of PAC3 homodimer

The synthesis and biological evaluation of thielocin B1 analogues have been demonstrated. Fourteen analogues modified in the central core and terminal carboxylic acid moiety were concisely synthesized by simple esterification or etherification reaction. The evaluation of synthetic analogues as inhibitors of proteasome assembling chaperone (PAC) complexes (the PAC3 homodimer and PAC1/PAC2) revealed that the natural product-like bending structure and terminal carboxylic acid groups were crucial for its biological activity. Moreover, SAR and in silico docking studies indicated that all methyl groups on the diphenyl ether moiety of thielocin B1 contribute to the potent and selective inhibition of the PAC3 homodimer via hydrophobic interactions.     

Synthesis and structure-activity studies of schweinfurthin B analogs: Evidence for the importance of a D-ring hydrogen bond donor in expression of differential cytotoxicity

The synthesis and biological evaluation of several enantioenriched schweinfurthin B analogs were undertaken to develop structure-activity relationships and guide design of probes for their putative molecular target. The desired stilbenes contain a common left-half hexahydroxanthene ring system and an aromatic right-half with varied substituents. The synthesis involves penultimate Horner-Wadsworth-Emmons coupling of one of several right-half phosphonates with the aldehyde comprising the left-half of 3-deoxyschweinfurthin B. Preparation of the requisite phosphonates, and the respective stilbenes, as well as the cytotoxicity profiles of these new compounds in the National Cancer Institute's 60 cell-line anticancer screen is described. Several of these analogs displayed cytotoxicity patterns well-correlated with the natural product and differences in activity of approximately 10(3) across the various cell lines. Together, these assay results indicate the importance of at least one free phenol group on the aromatic D-ring of this system for differential cytotoxicity.     

Synthesis of biotinylated photoaffinity probes based on arylsulfonamide gamma-secretase inhibitors

Synthesis and biological evaluation of an arylsulfonamide class of gamma-secretase inhibitors are described. Design, synthesis, and biological evaluation of multifunctional molecular probes harboring a benzophenone photophore as a cross-linking group and a biotin tag are also reported.     

Ecological considerations for biological control of aphids in protected culture

Several braconid and aphelinid parasitoids, midges, lacewings, and ladybird beetles are used to control aphids in greenhouses. Here, I review three topics as ecological bases for the biological control of aphids in a protected culture: the preliminary evaluation of biological control agents, natural enemy release strategies, and the effects of intraguild predation (IGP) on biological control. A comparison of several parasitoid species was conducted to select agents for the biological control of aphids; the intrinsic rate of natural increase was a useful criterion in the preliminary evaluation. To compare predators as biological control agents, the aphid-killing rate must be considered as a critical criterion, rather than reproductive criteria. The banker plant system (open rearing system) is used as a release method for Aphidius colemani and other natural enemies of aphids. Continuous release of parasitoid adults, which is the important characteristic of this method, has a stabilizing effect on population fluctuation in the aphid–parasitoid system. Two species of natural enemies can be used to control aphids in greenhouses. When one parasitoid and one predator are used simultaneously in a greenhouse, IGP of the parasitoid by the predator can occur, but the effect of IGP is less important in greenhouses than in the field.     

Synthesis, biological evaluation and supramolecular assembly of novel analogues of peptidyl nucleosides

This work concerns the synthesis, the supramolecular assembly and the evaluation of some biological properties, such as DNA and RNA-binding ability and human serum stability, of novel nucleopeptides. These compounds are of potential interest for the well-known properties that similar compounds, such as natural peptidyl nucleosides, possess in biology and medicine and also for the possibility to realize nucleopeptide-based supramolecular systems useful for drug and gene delivery applications. More particularly, all four nucleobase-containing peptides were synthesized by solid phase synthesis, purified by HPLC and characterized by NMR and ESI-MS. Subsequently, nucleopeptide self-assembly as well as DNA and RNA-binding ability were investigated by CD spectroscopy and further information on the formation of molecular networks, based on the peptidyl nucleoside analogues and nucleic acids, was obtained by Laser Light Scattering. Finally, nucleopeptide enzymatic stability was studied and a half life of about 2 hours was found in the presence of 50% fresh human serum.     

Sulfur-containing peptides: Synthesis and application in the discovery of potential drug candidates

Peptides act as biological mediators and play a key role of various physiological activities. Sulfur-containing peptides are widely used in natural products and drug molecules due to their unique biological activity and chemical reactivity of sulfur. Disulfides, thioethers, and thioamides are the most common motifs of sulfur-containing peptides, and they have been extensively studied and developed for synthetic methodology as well as pharmaceutical applications. This review focuses on the illustration of these three motifs in natural products and drugs, as well as the recent advancements in the synthesis of the corresponding core scaffolds.     

2-pyrones possessing antimicrobial and cytotoxic activities

The 2-pyrone sub-unit is found in a number of natural products possessing broad spectrum biological activity. Such compounds are validated as being capable of binding to specific protein domains and able to exert a remarkable range of biological effects. In an effort to identify synthetic 2-pyrones with interesting biological effects, herein we report the synthesis and biological evaluation of 4-substituted-6-methyl-2-pyrones. Synthetic routes to 4-alkyl/alkenyl/aryl/alkynyl-6-methyl-2-pyrones have been developed utilising Sonogashira, Suzuki and Negishi cross-coupling starting from readily available 4-bromo-6-methyl-2-pyrone. Specific conditions for each organometallic protocol were required for successful cross-coupling. In particular, a triethylamine/acetonitrile--base/solvent mixture was crucial to Sonogashira alkynylation of 4-bromo-6-methyl-2-pyrone, whereas thallium carbonate was a mandatory base for the Suzuki cross-coupling of trialkylboranes. The 2-pyrones demonstrate potent inhibitory activity against Bacillus subtilis, Escherichia coli, Staphylococcus aureus, Schizosaccharomyces pombe and Botrytis cinerea. The growth inhibitory activities of selected 2-pyrones were determined in A2780 human ovarian carcinoma and K562 human chronic myelogenous leukaemia cell lines using an in vitro cell culture system (MTT assay). These studies demonstrate that 4-phenylethynyl-, 4-tetrahydropyranylpropargyl ether- and 4-ethynyl-6-methyl-2-pyrones have excellent potential as a new class of anticancer agents.     

Synthesis of a novel family of diterpenes and their evaluation as anti-inflammatory agents

The synthesis and biological evaluation of a new family of diterpenes, represented by structures 2 and 3, is presented. These compounds constitute isomeric analogues of acanthoic acid (1) and were examined as potent anti-inflammatory agents. Among them, methyl ester 12 exhibited a low non-specific cytotoxicity, inhibited TNF-alpha synthesis and displayed good specificity in suppressing cytokine expression.     

Natural mimetic 4-benzyloxychalcones as potent pancreatic lipase inhibitors: Virtual screening,synthesis and biological evaluation

Pancreatic lipase is a well-known target for obesity drug development. The inhibition of this enzyme mitigates the digestion and absorption of dietary fat. Despite some inconvenient side effects, orlistat is currently the only medication with FDA approval that works by inhibition of pancreatic lipase. Several natural flavonoids, including chalcones, have been reported to possess promising lipase inhibitory activity. In this paper, we describe the evaluation of the lipase inhibitory activity of our in-house natural mimetic chalcone library via virtual screening, followed by the synthesis and biological evaluation of the hits. Compound C82 showed low-micromolar activity against pancreatic lipase in vitro (IC₅₀ = 1.01 ± 0.86 µM). The interaction of C82 and lipase was additionally confirmed by a fluorescence quenching study.     

Racemic and optically active alpha-tocopherol analogues with a modified side chain: synthesis and biological activity

Information on the synthesis and biological activity of natural and synthetic analogues of alpha-tocopherol with a modified side chain is systematized. These compounds are of interest as vitamin E metabolites, hydrophilic antioxidants, and precursors of drugs with combined pharmacological properties useful in therapy of pathological disorders caused by oxidative stress.     

Replacement of pyrazol-3-yl amine hinge binder with thiazol-2-yl amine: Discovery of potent and selective JAK2 inhibitors

Thiazol-2-yl amine was identified as an isosteric replacement for pyrazol-3-yl amine during our efforts to identify potent and selective JAK2 inhibitors. The rationale, synthesis and biological evaluation of several analogs is reported, along with the in vivo evaluation of the lead compounds.     

Scaffold oriented synthesis. Part 4: design, synthesis and biological evaluation of novel 5-substituted indazoles as potent and selective kinase inhibitors employing heterocycle forming and multicomponent reactions

We report the synthesis and biological evaluation of 5-substituted indazoles as kinase inhibitors. The compounds were synthesized in a parallel synthesis fashion from readily available starting materials employing heterocycle forming and multicomponent reactions and were evaluated against a panel of kinase assays. Potent inhibitors were identified for Gsk3β, Rock2, and Egfr.     

Natural product–drug conjugates for modulation of TRPV1-expressing tumors

We report the design, synthesis and biological evaluation of natural product–drug conjugates for treatment of prostate cancers over-expressing the transient receptor potential vanilloid 1 (TRPV1) channel. We validate the relevance of TRPV1 as a target in prostate cancer patients by using a bioinformatics approach and provide proof-of-concept for the drug delivery strategy through bioorthogonal chemistry and stability assays under simulated physiological conditions. In cell-based assays, the constructs displayed modest activity. Moreover, we serendipitously discover that a stoichiometric combination of a TRPV1 agonist with a small, positively charged cytotoxic may provide new research avenues in personalized medicines for prostate cancer.