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Enantioselective synthetic route is described for the complex anticancer antimicrobial agent kinamycin F, where the success of the route is the development of a three-step sequence for construction of the diazonapthoquinone function of the natural product. Ortho-quinone methide intermediates, formed by the reduction and loss of dinitrogen from kinamycin F, are formed in vivo and the method has provided a synthetic pathway to these compounds.

The significance of the para-OH group and the aromatic ring of [Tyr.sup.290(6.58)] of the human gonadotropin-releasing hormone (GnRH) receptor as a contact residue for both GnRH I and GnRH II is discussed. The residues present at the position 6.58 are shown to highly promote ligand binding and receptor activation.

A nonchelation strategy for construction of the [C.sub.18] stereochemistry and its application to the total syntheses of cytotoxic macrolide amphidinolide [B.sub.1] and the proposed structure of amphidinolide [B.sub.2] is reported. The results from studies provide insight into the structural differences between amphidinolide [B.sub.1] and [B.sub.2].

An investigation is carried out about [H.sub.2]S adsorption and dissociation on the gallium-rich GaAs(001)-4 x 2 surface by using hybrid density functional theory. The calculation results show that transfer of one H atom from the chemisorbed [H.sub.2]S to a second-layer As atom, with an activation barrier of 8.2 kcal/mol, is more kinetically favorable than insertion of an H atom into the Ga dimer bond or transfer of one H atom to the other Ga dangling bonds.

An optimization strategy combining global semiempirical quantum mechanical search with all-electron density functional theory was adopted to determine the lowest energy structure of (GaSb)n clusters up to n = 9. The growth pattern of the clusters differed from those of previously reported group III-V binary clusters. A cagelike configuration was found for cluster sizes n ≤ 7. The structure of (GaSb)6 deviated from that of other III-V clusters. Competition existed between core-shell and hollow cage structures of (GaSb)7. Novel noncagelike structures were energetically preferred over the cages for the (GaSb)8 and (GaSb)9 clusters. Electronic properties, such as vertical ionization potential, adiabatic electron affinities, HOMO-LUMO gaps, and average on-site charges on Ga or Sb atoms, as well as binding energies, were computed. [ABSTRACT FROM AUTHOR]

A series of cobalt(III) complexes of the potent DNA minor groove alkylator (1-(chloromethyl)-5-hydroxy-1H-pyrrolo[3,2-f]quinolin-3(2H)-yl)(5,6,7-trimethoxy-1H-indol-2-yl)methanone (3; seco-CPyI-TMI), with cyclam or cyclen auxiliary ligands (L3 and L5) containing a cross-bridging ethylene (CH2CH2) group or the N,N'-dimethyl derivatives of these (L4 and L6), was prepared. Two 8-quinolinato (2) model complexes of these, [Co(L3)(2)](ClO4)2 and [Co(L6)(2)](ClO4)2, and the aquated derivative [Co(L6)(H2O) 2](OTf)3 were characterized by X-ray crystallography. Electrochemistry of the 8-quinolinato model complexes showed that the Co(III)/(II) reduction potential was lowered relative to the unsubstituted cyclen ligand. Evaluation of the cytotoxicity of the racemic seco-CPyI cobalt complexes in vitro showed considerable attenuation of their cytotoxicity relative to the free alkylator and marked hypoxic selectivity, especially [Co(L3)(3)]2+ (9), which was 81-212-fold more potent under hypoxia than 20% oxygen in a panel of 10 human tumor cell lines. However, 9 did not elicit significant killing of hypoxic cells in HT29 tumor xenografts, suggesting possible pharmacological limitations in vivo. [ABSTRACT FROM AUTHOR]

The total syntheses of amphidinolide B1 and the proposed structure of amphidinolide B2 have been accomplished. Key aspects of this work include the development of a practical, non-transition-metal-mediated method for the construction of the C13-C15 diene, the identification of α-chelation and dipole minimization models for diastereoselective methyl ketone aldol reactions, the discovery of a spontaneous Horner-Wadsworth-Emmons macrocyclization strategy, and the development of a novel late stage method for construction of an allylic epoxide moiety. The originally proposed structure for amphidinolide B2 and diastereomers thereof display potent antitumor activities with IC50 values ranging from 3.3 to 94.5 nM against human solid and blood tumor cells. Of the different stereoisomers, the proposed structure of amphidinolide B2 is over 12-fold more potent than the C8,9-epimer and C18-epimer in human DU145 prostate cancer cells. These data suggest that the epoxide stereochemistry is a significant factor for anticancer activity. [ABSTRACT FROM AUTHOR]

Lomaiviticins A and B are complex antitumor antibiotics that were isolated from a strain of Micromonospora. A confluence of several unusual structural features renders the lomaiviticins exceedingly challenging targets for chemical synthesis. We report an 11-step, enantioselective synthetic route to lomaiviticin aglycon. Our route proceeds by late-stage, stereoselective dimerization of two equivalent monomeric intermediates, a transformation that may share parallels with the natural products biosyntheses. The route we describe is scalable and convergent, and it lays the foundation for determination of the mode of action of these natural products. [ABSTRACT FROM AUTHOR]

Treatment of IrCl(CS)(PPh3)2with an excess of KI gives orange IrI(CS)(PPh3)2(1). IrI(CS)(PPh3)2(1) reacts reversibly with dioxygen to form the brown dioxygen complex Ir(O2)I(CS)(PPh3)2(2). Reaction between IrI(CS)(PPh3)2(1) and 2 equiv of ethyne produces the green-brown tethered iridacyclobutadiene complex IrC3H2(CHCHS-1)I(PPh3)2(3), one ethyne combining in a cycloaddition reaction with the IrC multiple bond to the CS ligand to form the four-membered IrC3ring and the second ethyne alkylating the sulfur atom to give the vinylthio substituent at the 1-position of the metallacyclic ring, which is tethered to the iridium through an Ir−C bond. In reactions related to those with ethyne, phenylacetylene reacts with IrCl(CS)(PPh3)2to give as the major product the tethered iridacyclobutadiene IrC3H(CHCPhS-1)(Ph-3)Cl(PPh3)2(4), with the phenyl substituent adjacent to the iridium, and as the minor product the isomeric tethered iridacyclobutadiene IrC3H(CHCPhS-1)(Ph-2)Cl(PPh3)2(5). A thermal reaction of IrC3H(CHCPhS-1)(Ph-3)Cl(PPh3)2(4) with further phenylacetylene produces the tethered, substituted cyclopentadienyliridium complex Ir5-C5H2(SCPhCH-1)(Ph-3)(Ph-5)Cl(PPh3) (6), which retains the iridium−carbon bond to the vinylthio substituent. Methyl propiolate reacts with IrI(CS)(PPh3)2(1) to form exclusively the tethered iridacyclobutadiene IrC3H(CHCCO2MeS-1)(CO2Me-2)I(PPh3)2(7). Treatment of this iridacyclobutadiene, 7, with silver triflate allows introduction of a third methyl propiolate, which brings about ring expansion of the iridacyclobutadiene to form the stable tethered iridabenzene IrC5H2(CHCCO2MeS-1)(CO2Me-2)(CO2Me-4)Cl(PPh3)2(8). Complex 8retains the same vinylthio tethering group as found in 7. The structures of 2−8have been confirmed by X-ray crystal structure determinations. Both NMR spectroscopic and structural data for 8support the formulation of this compound as a tethered metallaaromatic molecule. [ABSTRACT FROM AUTHOR]

H2S adsorption and dissociation on the gallium-rich GaAs(001)-4 × 2 surface is investigated using hybrid density functional theory. Starting from chemisorbed H2S on the GaAs(001)-4 × 2 surface, two possible reaction routes have been proposed. We find that H2S adsorbs molecularly onto GaAs(001)-4 × 2 via the formation of a dative bond, and this process is exothermic with adsorption energy of 6.6 kcal/mol. For the first reaction route, one of the H atoms from the chemisorbed H2S is transferred to a second-layer As atom and the dissociated SH is inserted into the Ga−As bond with an activation barrier of 8.2 kcal/mol, which is found to be 29.3 kcal/mol more stable than the reactants. For the second case, the dissociated species may insert themselves into the Ga−Ga dimer resulting in the Ga−H−Ga and Ga−HS−Ga bridge-bonded states, which are found to be 29.8 and 22.2 kcal/mol more stable than the reactants, respectively. However, the calculations also show that the activation barrier (16.1 kcal/mol) for chemisorbed H2S dissociation through the second route is higher than the transfer of one H atom into a second-layer As atom. As a result, we conclude that sulfur insertion into the Ga−As bond is more kinetically favorable. [ABSTRACT FROM AUTHOR]

The article reports on the total synthesis of cytotoxic macrolide amphidinolide. The compound has gained interest in the synthetic community because of their potent cytotoxic activity against several cancer cell lines. Macrolides represent synthetic challenges because of their highly substituted diene functionality. The cleavage of the ester linkage could lead to the alcohols and the ketophosphonate.

Dynamic monitoring of intracellular ubiquitin (Ub) conjugates is instrumental to understanding the Ub regulatory machinery. Although many biochemical approaches have been developed to characterize protein ubiquitination, chemical tools capable of temporal resolution probing of ubiquitination events remain to be developed. Here, we report the development of the first cell-permeable and stimuli-responsive Ub probe and its application for the temporal resolution profiling of ubiquitinated substrates in live cells. The probe carrying the photolabile group N-(2-nitrobenzyl)-Gly (Nbg) on the amide bond between Ub Gly75 and Gly76 is readily prepared through chemical synthesis and can be delivered to live cells by conjugation via a disulfide bond with the cyclic cell-penetrating peptide cR10D (i.e., 4-((4-(dimethylamino)phenyl)-azo)-benzoic acid-modified cyclic deca-arginine). Both in vitro and in vivo experiments showed that Ub-modifying enzymes (E1, E2s, and E3s) could not install the Ub probe onto substrate proteins prior to removal of the nitrobenzyl group, which was easily accomplished via photoirradiation. The utility and practicality of this probe were exemplified by the time-resolved biochemical and proteomic investigation of ubiquitination events in live cells during a H 2 O 2 -mediated oxidative stress response. This work shows a conceptually new family of chemical Ub tools for the time-resolved studies on dynamic protein ubiquitination in different biological processes and highlights the utility of modern chemical protein synthesis in obtaining custom-designed tools for biological studies., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

A key objective for herbicide research is to develop new compounds with improved bioactivity. Protoporphyrinogen IX oxidase (PPO) is an essential target for herbicide discovery. Here, we report using an in silico structure-guided optimization approach of our previous lead compound 1 and designed and synthesized a new series of compounds 2 - 6 . Systematic bioassays led to the discovery of a highly potent compound 6g , 1-methyl-3-(2,2,7-trifluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-6-yl)thieno[2,3- d ]pyrimidine-2,4(1 H ,3 H )-dione, which exhibited an excellent and wide spectrum of weed control at the rates of 30-75 g ai/ha by the postemergence application and is relatively safe on maize at 75 g ai/ha. Additionally, the K i value of 6g to Nicotiana tabacum PPO (NtPPO) was found to be 2.5 nM, showing 3-, 12-, and 18-fold higher potency relative to compound 1 ( K i = 7.4 nM), trifludimoxazin ( K i = 31 nM), and flumioxazin ( K i = 46 nM), respectively. Furthermore, molecular simulations further suggested that the thieno[2,3- d ]pyrimidine-2,4-dione moiety of 6g could form a more favorable π-π stacking interaction with the Phe392 of NtPPO than the heterocyclic moiety of compound 1 . This study provides an effective strategy to obtain enzyme inhibitors with improved performance through molecular simulation and structure-guided optimization.

Strigolactones (SLs) are plant hormones that play various roles in plant physiology, including provoking the germination of parasitic weeds Orobanche and Striga . A family of α/β-hydrolases have been proposed to be the SL receptor proteins. Effective assays for measuring the activity of SL receptors could promote the development of SL-related biology and chemistry. In this study, we developed a new approach called pharmacophore-linked probe virtual screening (PPVS). Its application yielded an effective "off-on" probe named Xilatone Red ( XLR ). This probe showed a broad spectrum and excellent sensitivity toward SL receptors, including ShD14 ( Striga D14), for which the detection limit was determined to be in the micromolar range, outperforming that of the commercial fluorogenic agonist Yoshimulactone Green (YLG). Upon hydrolysis by SL receptors, XLR provided fluorogenic and colorimetric signaling responses. Furthermore, XLR could induce germination of Phelipanche aegyptiaca seeds and prevent Arabidopsis max 4-1 branching defects at micromolar concentrations. Our molecular simulations revealed the essential factors in the molecular perception of XLR . We anticipate that this study can prompt the discovery of high-performance SL agonists/antagonists to combat parasitic weeds.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is an effective target for green herbicide discovery. In this work, we reported the unexpected discovery of a novel series of N -phenylaminomethylthioacetylpyrimidine-2,4-diones ( 2 - 6 ) as promising PPO inhibitors based on investigating the reaction intermediates of our initially designed N -phenyluracil thiazolidinone ( 1 ). An efficient one-pot procedure that gave 41 target compounds in good to high yields was developed. Systematic Nicotiana tabacum PPO (NtPPO) inhibitory and herbicidal activity evaluations led to identifying some compounds with improved NtPPO inhibition potency than saflufenacil and good post-emergence herbicidal activity at 37.5-150 g of ai/ha. Among these analogues, ethyl 2-((((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2 H )-yl)phenyl)amino)methyl)thio)acetate ( 2c ) ( K i = 11 nM), exhibited excellent weed control at 37.5-150 g of ai/ha and was safe for rice at 150 g of ai/ha, indicating that compound 2c has the potential to be developed as a new herbicide for weed management in paddy fields. Additionally, our molecular simulation and metabolism studies showed that the side chains of compound 2c could form a hydrogen-bond-mediated seven-membered ring system; substituting a methyl group at R 1 could reinforce the hydrogen bond of the ring system and reduce the metabolic rate of target compounds in planta .

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is an important target for green agrochemical discovery. Herein, a novel N -phenylisoxazoline-thiadiazolo[3,4- a ]pyridazine herbicidal active scaffold was designed by the scaffold hybridization strategy. Systematic structural optimization enabled the discovery of a series of derivatives with excellent weed control at 9.375-150 g ai/ha by the post-emergent application. Some derivatives exhibited improved Nicotiana tabacum PPO (NtPPO)-inhibitory activity than fluthiacet-methyl. Of these, 2b , with K i = 21.8 nM, displayed higher weed control than fluthiacet-methyl at the rate of 12-75 g ai/ha, and selective to maize at 75 g ai/ha. In planta , 2b was converted into a bioactive metabolite 5 ( K i = 4.6 nM), which exhibited 4.6-fold more potency than 2b in inhibiting the activity of NtPPO. Molecular dynamics simulation explained that 5 formed stronger π-π interaction with Phe392 than that of 2b . This work not only provides a promising lead compound for weed control in maize fields but is also helpful to understand the molecular mechanism and basis of the designed hybrids.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is a promising target for herbicide discovery. Search for new compounds with novel chemotypes is a key objective for agrochemists. Here, we describe the discovery and systematic SAR-based structure optimization of novel N -isoxazolinylphenyltriazinones 5 - 9 as PPO inhibitors. The in vivo herbicidal activity and in vitro Nicotiana tabacum PPO ( Nt PPO) inhibitory activity were explored in detail. A number of the new synthetic compounds displayed strong PPO inhibitory activity with K i values in the nanomolar range. Some compounds exhibited excellent and broad-spectrum weed control at the rate of 9.375-37.5 g ai/ha by postemergence application and showed improved monocotyledonous weed control compared to saflufenacil. Most promisingly, ethyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazinan-1-yl)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate, 5a , with a K i value of 4.9 nM, displayed over 2- and 6-fold higher potency than saflufenacil ( K i = 10 nM) and trifludimoxazin ( K i = 31 nM), respectively. Moreover, 5a showed excellent and broad-spectrum weed control against 32 kinds of weeds at 37.5-75 g ai/ha. Rice exhibited relative tolerance to 5a at 150 g ai/ha by postemergence application, indicating that 5a could be a potential herbicide candidate for weed control in paddy fields.

In continuation of our search for potent protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) inhibitors, we designed and synthesized a series of novel herbicidal cycloalka[ d ]quinazoline-2,4-dione-benzoxazinones. The bioassay results of these synthesized compounds indicated that most of the compounds exhibited very strong Nicotiana tabacum PPO (NtPPO) inhibition activity. More than half of the 37 synthesized compounds displayed over 80% control of all three tested broadleaf weeds at 37.5-150 g ai/ha by postemergent application, and a majority of them showed no phytotoxicity toward at least one kind of crop at 150 g ai/ha. Promisingly, 17i ( K i = 6.7 nM) was 6 and 4 times more potent than flumioxazin ( K i = 46 nM) and trifludimoxazin ( K i = 31 nM), respectively. Moreover, 17i displayed excellent, broad-spectrum herbicidal activity, even at levels as low as 37.5 g ai/ha, and it was determined to be safe for wheat at 150 g ai/ha in postemergent application, indicating the great potential for 17i development as a herbicide for weed control in wheat fields.

The purpose of this research is to establish an injectable hydrogel encapsulating copper sulfide (CuS) nanodots for photothermal therapy against cancer. The CuS nanodots were prepared by one-pot synthesis, and the thermosensitive Pluronic F127 was used as the hydrogel matrix. The CuS nanodots and the hydrogel were characterized by morphous, particle size, serum stability, photothermal performance upon repeated 808 nm laser irradiation, and rheology features. The effects of the CuS nanodots and the hydrogel were evaluated qualitatively and quantitatively in 4T1 mouse breast cancer cells. The retention, photothermal efficacy, therapeutic effects, and systemic toxicity of the hydrogel were assessed in tumor bearing mouse model. The CuS nanodots with a diameter of about 8 nm exhibited satisfying serum stability, photoheat conversion ability, and repeated laser exposure stability. The hydrogel encapsulation did not negatively influence the above features of the photothermal agent. The nanodot-loaded hydrogel shows a phase transition at body temperature and, as a result, a long retention in vivo. The photothermal-agent-embedded hydrogel played a promising photothermal therapeutic effect in the tumor bearing mouse model with low systemic toxicity after peritumoral administration.

Dihydroquercetin (DHQ) is a well-known antioxidant agent. In the present investigation, we reported for the first time that DHQ stimulates the expression of phase II detoxifying enzymes through the Nrf2-dependent signaling pathway. The IC50 values of DHQ for reduction of 2,2-diphenyl-1-picrylhydrazol (DPPH), reducing power assay, lipid peroxidation assay, and xanthine oxidase inhibition were 5.96, 4.31, 2.03, and 13.24 μM, respectively. DHQ possessed considerable protective activity from oxidative DNA damage. A luciferase reporter assay also demonstrated that DHQ-activated signaling resulted in the increased transcriptional activity of Nrf2 through binding to the ARE (antioxidant response element) enhancer sequence. Furthermore, Western blotting and luciferase assay revealed DHQ activated ERK1/2, Akt, and JNK signaling pathways, subsequently leading to Nrf2 nuclear translocation. DHQ upregulated the Nrf2-related antioxidant genes heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO1), and glutamate-cysteine ligase modifier subunits. Inhibition of Nrf2 by siRNA reduced DHQ-induced upregulation of these antioxidant genes.

Incorporation of organic fertilizers/amendments in soils has been, and will continue to be, a popular strategy for improving the quality of arable soils. However, the mechanism by which the dissolved organic matters (DOMs) affect soil properties or interact with other substances in soils is largely unknown. In this study, a batch equilibrium experiment was performed to evaluate the effect of two types of DOMs on the behavior of prometryne (a herbicide) in soils. Two sorts of DOMs were derived from lakebed sludge (SL) and rice straw (ST), respectively. The results show that sorption capacity in one soil for prometryne was significantly reduced by application of DOMs, whereas desorption of prometryne was promoted by DOM treatments. To understand the mobility behavior of prometryne in soils with DOMs, a column leaching experiment was carried out. It is shown that both DOMs enhanced the solubility and migration of prometryne in soils. To confirm the role of DOMs in regulating the mobility of prometryne in soils, a soil thin-layer chromatography was performed. The migration of prometryne was promoted by DOMs, which were used as a developing solvent or directly incorporated in the soil thin layer. The data indicate that DOM extracts can modify the mobility of prometryne in soil.