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A straightforward approach for the construction of the new class of conjugated pyrans based on enamination of 2-methyl-4-pyrones with DMF-DMA was developed. 2-(2-(Dimethylamino)vinyl)-4-pyrones are highly reactive substrates that undergo 1,6-conjugate addition/elimination or 1,3-dipolar cycloaddition/elimination followed by substitution of the dimethylamino group without ring opening. This strategy includes selective transformations leading to conjugated and isoxazolyl-substituted 4-pyrone structures. The photophysical properties of the prepared 4-pyrones were determined in view of further design of novel merocyanine fluorophores. A solvatochromism was found for enamino-substituted 4-pyrones accompanied by a strong increase in fluorescence intensity in alcohols. The prepared conjugated structures demonstrated valuable photophysical properties, such as a large Stokes shift (up to 204 nm) and a good quantum yield (up to 28%).

Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.

Molecules that alter the normal dynamics of microtubule assembly and disassembly include many anticancer drugs in clinical use. So far all such therapeutics target β-tubulin, and structural biology has explained the basis of their action and permitted design of new drugs. However, by shifting the profile of β-tubulin isoforms, cancer cells become resistant to treatment. Compounds that bind to α-tubulin are less well characterized and unexploited. The natural product pironetin is known to bind to α-tubulin and is a potent inhibitor of microtubule polymerization. Previous reports had identified that pironetin reacts with lysine-352 residue however analogues designed on this model had much lower potency, which was difficult to explain, hindering further development. We report crystallographic and mass spectrometric data that reveal that pironetin forms a covalent bond to cysteine-316 in α-tubulin via a Michael addition reaction. These data provide a basis for the rational design of α-tubulin targeting chemotherapeutics. Microtubule assembly and disassembly is the target of many anticancer therapies, with β-tubulin the most-frequent target. Here, the authors used biochemical and biophysical techniques to demonstrate pironetin binds to α-tubulin and thereby inhibits microtubule polymerization providing a basis for the rational design of novel anticancer drugs.

Polyketides represent an extremely diverse class of secondary metabolites often explored for their bioactive traits. These molecules are also attractive building blocks for chemical catalysis and polymerization. However, the use of polyketides in larger scale chemistry applications is stymied by limited titers and yields from both microbial and chemical production. Here, we demonstrate that an oleaginous organism (specifically, Yarrowia lipolytica) can overcome such production limitations owing to a natural propensity for high flux through acetyl–CoA. By exploring three distinct metabolic engineering strategies for acetyl–CoA precursor formation, we demonstrate that a previously uncharacterized pyruvate bypass pathway supports increased production of the polyketide triacetic acid lactone (TAL). Ultimately, we establish a strain capable of producing over 35% of the theoretical conversion yield to TAL in an unoptimized tube culture. This strain also obtained an averaged maximum titer of 35.9 ± 3.9 g/L with an achieved maximum specific productivity of 0.21 ± 0.03 g/L/h in bioreactor fermentation. Additionally, we illustrate that a β-oxidation-related overexpression (PEX10) can support high TAL production and is capable of achieving over 43% of the theoretical conversion yield under nitrogen starvation in a test tube. Next, through use of this bioproduct, we demonstrate the utility of polyketides like TAL to modify commodity materials such as poly(epichlorohydrin), resulting in an increased molecular weight and shift in glass transition temperature. Collectively, these findings establish an engineering strategy enabling unprecedented production from a type III polyketide synthase as well as establish a route through O-functionalization for converting polyketides into new materials.

Tubulin-targeted chemotherapy has proven to be a successful and wide spectrum strategy against solid and liquidmalignancies. 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. We have discovered a seventh binding site at the tubulin intradimer interface where a novel microtubule-destabilizing cyclodepsipeptide, termed gatorbulin-1 (GB1), binds. GB1 has a unique chemotype produced by a marine cyanobacterium. We have elucidated this dual, chemical and mechanistic, novelty through multidimensional characterization, starting with bioactivity-guided natural product isolation and multinuclei NMR-based structure determination, revealing the modified pentapeptide with a functionally critical hydroxamate group; and validation by total synthesis. We have investigated the pharmacology using isogenic cancer cell screening, cellular profiling, and complementary phenotypic assays, and unveiled the underlying molecular mechanism by in vitro biochemical studies and high-resolution structural determination of the α/β-tubulin–GB1 complex.

The Streptomyces sp. is considered the vast reservoir of bioactive natural products belonging to different classes like polyketides, terpenoids, lanthipeptides, and non-ribosomal peptides to name a few. The ubiquitous distribution of the genus makes them capable of producing distinct compounds. Many of those compounds contain a unique γ-pyrone with various chemical structures and exhibit different bioactivities. One such class, nitrophenyl-γ-pyrone, constitutes different bioactive compounds isolated from Streptomyces sp. from different sources ranging from soil to marine environments. In addition, such compounds have antinematodal, cytotoxicity activities, and inhibition of adipogenesis. These compounds include aureothin (3) , spectinabilin (7) , and their derivatives. Moreover, there are other compounds like actinopyrones (11–16) , benwamycins (22–23) , and peucemycin and its derivatives (24–26) that also have antibacterial and anticancer activities. The other group classified as anthra-γ-pyrone has various bioactive natural products. For instance, tetrahydroanthra-γ-pyrone, shellmycin A-D (27–30) possess antibacterial as well as anticancer activities. In addition, the pluramycin family compounds belonging to anthra-γ-pyrone group also possess cytotoxic activity, for instance, kidamycin (31), rubiflavin, and their derivatives (33–37) . Xanthones are another important group of natural products that also contain γ-pyrone ring producing different bioactivities. Albofungin (42) and its derivatives (43–46) belong to subgroup polycyclic tetrahydro xanthones that possess antibacterial, anticancer, and antibiofilm, antimacrofouling activities. Similarly, other compounds, belonging to this subgroup, exhibit different bioactivities like antifungal, antimalarial, and antibacterial activities and block transient receptor potential vanilloid 1 (TRPV1). These compounds include cervinomycins (48–55) , citreamycins (56–57) , sattahipmycin (59) , and chrexanthomycins (60–63) . This review gives succinct information on the γ-pyrone containing natural products isolated from Streptomyces sp. focusing on their structure and bioactivities. Key points • The Streptomyces sp. is the producer of various bioactive natural products including the one with γ-pyrone ring. • These γ-pyrone compounds are structurally different and possess different bioactivities. • The Streptomyces has the potential to produce such compounds and the reservoir of these compounds is expected to increase in the future.

Significance Microtubules are dynamic protein filaments assembled from tubulin subunits, which play a key role for cell division. Ligands that target microtubules and affect their dynamics belong to the most successful classes of chemotherapeutic drugs against cancer by inhibiting cell proliferation. Here we have analyzed three structurally unrelated drugs that destabilize microtubules, using X-ray crystallography. The data reveal a new tubulin-binding site for these drugs, which renders their mechanism of action distinct from that of other types of microtubule assembly inhibitors. Similar key interactions with tubulin are observed for all three ligands, thus defining a common pharmacophore. Our results offer an opportunity for the rational design of potent tubulin modulators for the development of more efficient cancer therapies. The recent success of antibody–drug conjugates (ADCs) in the treatment of cancer has led to a revived interest in microtubule-destabilizing agents. Here, we determined the high-resolution crystal structure of the complex between tubulin and maytansine, which is part of an ADC that is approved by the US Food and Drug Administration (FDA) for the treatment of advanced breast cancer. We found that the drug binds to a site on β-tubulin that is distinct from the vinca domain and that blocks the formation of longitudinal tubulin interactions in microtubules. We also solved crystal structures of tubulin in complex with both a variant of rhizoxin and the phase 1 drug PM060184. Consistent with biochemical and mutagenesis data, we found that the two compounds bound to the same site as maytansine and that the structures revealed a common pharmacophore for the three ligands. Our results delineate a distinct molecular mechanism of action for the inhibition of microtubule assembly by clinically relevant agents. They further provide a structural basis for the rational design of potent microtubule-destabilizing agents, thus opening opportunities for the development of next-generation ADCs for the treatment of cancer.

Intron selection during the formation of prespliceosomes is a critical event in pre-mRNA splicing. Chemical modulation of intron selection has emerged as a route for cancer therapy. Splicing modulators alter the splicing patterns in cells by binding to the U2 snRNP (small nuclear ribonucleoprotein)—a complex chaperoning the selection of branch and 3′ splice sites. Here we report crystal structures of the SF3B module of the U2 snRNP in complex with spliceostatin and sudemycin FR901464 analogs, and the cryo-electron microscopy structure of a cross-exon prespliceosome-like complex arrested with spliceostatin A. The structures reveal how modulators inactivate the branch site in a sequence-dependent manner and stall an E-to-A prespliceosome intermediate by covalent coupling to a nucleophilic zinc finger belonging to the SF3B subunit PHF5A. These findings support a mechanism of intron recognition by the U2 snRNP as a toehold-mediated strand invasion and advance an unanticipated drug targeting concept. Chemical modulation of intron selection has emerged as a route for cancer therapy. Here, structures of the U2 snRNP’s SF3B module and of prespliceosome- both in complexes with splicing modulators- provide insight into the mechanisms of intron recognition and branch site inactivation.

In this study, two series of kojic acid triazole hybrids, namely 6a–6p and 13a–13t , were designed and synthesized. Subsequently, their biological activities including anti-tyrosinase, antioxidant, and as anti-browning effects were investigated. The results showed that most of compounds demonstrated excellent inhibitory effect against mushroom tyrosinase compared with standard reference drug (kojic acid, IC 50  = 26.090 µM). Of particular note, 13t proved to be the most potent tyrosinase inhibitor with an IC 50 value as low as 1.363 µM. Further kinetic inhibition studies suggested that 13t presented such powerful anti-tyrosinase efficacy by functioning as a mixed-type inhibitor ( K i = 0.3647 µM, K is = 0.8492 µM). Moreover, the results from molecular docking and fluorescence quenching studies revealed that 13t ’s inhibitory effect on tyrosinase stemmed from its ability to directly bind to the active site of mushroom tyrosinase. Besides, the antioxidant activity, anti-browning effect, and cytotoxicity of 13t were accordingly investigated, all yielding highly satisfactory results. Collectively, these findings position 13t as a highly promising candidate, providing a valuable molecular framework for the development of novel, efficient, and safe tyrosinase inhibitors endowed with potent antioxidant and anti-browning capabilities.

Plants interact with root microbes via chemical signaling, which modulates competence or symbiosis. Although several volatile organic compounds (VOCs) from fungi may affect plant growth and development, the signal transduction pathways mediating VOC sensing are not fully understood. 6‐pentyl‐2H‐pyran‐2‐one (6‐PP) is a major VOC biosynthesized by Trichoderma spp. which is probably involved in plant–fungus cross‐kingdom signaling. Using microscopy and confocal imaging, the effects of 6‐PP on root morphogenesis were found to be correlated with DR5:GFP, DR5:VENUS, H2B::GFP, PIN1::PIN1::GFP, PIN2::PIN2::GFP, PIN3::PIN3::GFP and PIN7::PIN7::GFP gene expression. A genetic screen for primary root growth resistance to 6‐PP in wild‐type seedlings and auxin‐ and ethylene‐related mutants allowed identification of genes controlling root architectural responses to this metabolite. Trichoderma atroviride produced 6‐PP, which promoted plant growth and regulated root architecture, inhibiting primary root growth and inducing lateral root formation. 6‐PP modulated expression of PIN auxin‐transport proteins in a specific and dose‐dependent manner in primary roots. TIR1, AFB2 and AFB3 auxin receptors and ARF7 and ARF19 transcription factors influenced the lateral root response to 6‐PP, whereas EIN2 modulated 6‐PP sensing in primary roots. These results indicate that root responses to 6‐PP involve components of auxin transport and signaling and the ethylene‐response modulator EIN2.